14.3: Bacterial Virulence Factors - Biology

Skills to Develop

  • Explain how virulence factors contribute to signs and symptoms of infectious disease
  • Differentiate between endotoxins and exotoxins
  • Describe and differentiate between various types of exotoxins
  • Describe the mechanisms viruses use for adhesion and antigenic variation

In the previous section, we explained that some pathogens are more virulent than others. This is due to the unique virulence factors produced by individual pathogens, which determine the extent and severity of disease they may cause. A pathogen’s virulence factors are encoded by genes that can be identified using molecular Koch’s postulates. When genes encoding virulence factors are inactivated, virulence in the pathogen is diminished. In this section, we examine various types and specific examples of virulence factors and how they contribute to each step of pathogenesis.

Virulence Factors for Adhesion

As discussed in the previous section, the first two steps in pathogenesis are exposure and adhesion. Recall that an adhesin is a protein or glycoprotein found on the surface of a pathogen that attaches to receptors on the host cell. Adhesins are found on bacterial, viral, fungal, and protozoan pathogens. One example of a bacterial adhesin is type 1 fimbrial adhesin, a molecule found on the tips of fimbriae of enterotoxigenic E. coli (ETEC). Recall that fimbriae are hairlike protein bristles on the cell surface. Type 1 fimbrial adhesin allows the fimbriae of ETEC cells to attach to the mannose glycans expressed on intestinal epithelial cells. Table (PageIndex{1}) lists common adhesins found in some of the pathogens we have discussed or will be seeing later in this chapter.

Table (PageIndex{1}): Some Bacterial Adhesins and Their Host Attachment Sites
PathogenDiseaseAdhesinAttachment Site
Streptococcus pyogenesStrep throatProtein FRespiratory epithelial cells
Streptococcus mutansDental cariesAdhesin P1Teeth
Neisseria gonorrhoeaeGonorrheaType IV piliUrethral epithelial cells
Enterotoxigenic E. coli (ETEC)Traveler’s diarrheaType 1 fimbriaeIntestinal epithelial cells
Vibrio choleraeCholeraN-methylphenylalanine piliIntestinal epithelial cells

Bacterial Exoenzymes and Toxins as Virulence Factors

After exposure and adhesion, the next step in pathogenesis is invasion, which can involve enzymes and toxins. Many pathogens achieve invasion by entering the bloodstream, an effective means of dissemination because blood vessels pass close to every cell in the body. The downside of this mechanism of dispersal is that the blood also includes numerous elements of the immune system. Various terms ending in –emia are used to describe the presence of pathogens in the bloodstream. The presence of bacteria in blood is called bacteremia. Bacteremia involving pyogens(pus-forming bacteria) is called pyemia. When viruses are found in the blood, it is called viremia. The term toxemiadescribes the condition when toxins are found in the blood. If bacteria are both present and multiplying in the blood, this condition is called septicemia.

Patients with septicemia are described as septic, which can lead to shock, a life-threatening decrease in blood pressure (systolic pressure <90 mm Hg) that prevents cells and organs from receiving enough oxygen and nutrients. Some bacteria can cause shock through the release of toxins (virulence factors that can cause tissue damage) and lead to low blood pressure. Gram-negative bacteria are engulfed by immune system phagocytes, which then release tumor necrosis factor, a molecule involved in inflammation and fever. Tumor necrosis factor binds to blood capillaries to increase their permeability, allowing fluids to pass out of blood vessels and into tissues, causing swelling, or edema(Figure (PageIndex{1})). With high concentrations of tumor necrosis factor, the inflammatory reaction is severe and enough fluid is lost from the circulatory system that blood pressure decreases to dangerously low levels. This can have dire consequences because the heart, lungs, and kidneys rely on normal blood pressure for proper function; thus, multi-organ failure, shock, and death can occur.

Figure (PageIndex{1}): This patient has edema in the tissue of the right hand. Such swelling can occur when bacteria cause the release of pro-inflammatory molecules from immune cells and these molecules cause an increased permeability of blood vessels, allowing fluid to escape the bloodstream and enter tissue.


Some pathogens produce extracellular enzymes, or exoenzymes, that enable them to invade host cells and deeper tissues. Exoenzymes have a wide variety of targets. Some general classes of exoenzymes and associated pathogens are listed in Table (PageIndex{2}). Each of these exoenzymes functions in the context of a particular tissue structure to facilitate invasion or support its own growth and defend against the immune system. For example, hyaluronidase S, an enzyme produced by pathogens like Staphylococcus aureus, Streptococcus pyogenes, and Clostridium perfringens, degrades the glycoside hylauronan (hyaluronic acid), which acts as an intercellular cement between adjacent cells in connective tissue (Figure (PageIndex{2})). This allows the pathogen to pass through the tissue layers at the portal of entry and disseminate elsewhere in the body (Figure (PageIndex{2})).

Table (PageIndex{2}): Some Classes of Exoenzymes and Their Targets
GlycohydrolasesHyaluronidase S in Staphylococcus aureusDegrades hyaluronic acid that cements cells together to promote spreading through tissues
NucleasesDNAse produced by S. aureusDegrades DNA released by dying cells (bacteria and host cells) that can trap the bacteria, thus promoting spread
PhospholipasesPhospholipase C of Bacillus anthracisDegrades phospholipid bilayer of host cells, causing cellular lysis, and degrade membrane of phagosomes to enable escape into the cytoplasm
ProteasesCollagenase in Clostridium perfringensDegrades collagen in connective tissue to promote spread

Figure (PageIndex{2}): (a) Hyaluronan is a polymer found in the layers of epidermis that connect adjacent cells. (b) Hyaluronidase produced by bacteria degrades this adhesive polymer in the extracellular matrix, allowing passage between cells that would otherwise be blocked.

Pathogen-produced nucleases, such as DNAse produced by S. aureus, degrade extracellular DNA as a means of escape and spreading through tissue. As bacterial and host cells die at the site of infection, they lyse and release their intracellular contents. The DNA chromosome is the largest of the intracellular molecules, and masses of extracellular DNA can trap bacteria and prevent their spread. S. aureus produces a DNAse to degrade the mesh of extracellular DNA so it can escape and spread to adjacent tissues. This strategy is also used by S. aureus and other pathogens to degrade and escape webs of extracellular DNA produced by immune system phagocytes to trap the bacteria.

Enzymes that degrade the phospholipids of cell membranes are called phospholipases. Their actions are specific in regard to the type of phospholipids they act upon and where they enzymatically cleave the molecules. The pathogen responsible for anthrax, B. anthracis, produces phospholipase C. When B. anthracis is ingested by phagocytic cells of the immune system, phospholipase C degrades the membrane of the phagosome before it can fuse with the lysosome, allowing the pathogen to escape into the cytoplasm and multiply. Phospholipases can also target the membrane that encloses the phagosome within phagocytic cells. As described earlier in this chapter, this is the mechanism used by intracellular pathogens such as L. monocytogenes and Rickettsia to escape the phagosome and multiply within the cytoplasm of phagocytic cells. The role of phospholipases in bacterial virulence is not restricted to phagosomal escape. Many pathogens produce phospholipases that act to degrade cell membranes and cause lysis of target cells. These phospholipases are involved in lysis of red blood cells, white blood cells, and tissue cells.

Bacterial pathogens also produce various protein-digesting enzymes, or proteases. Proteases can be classified according to their substrate target (e.g., serine proteases target proteins with the amino acid serine) or if they contain metals in their active site (e.g., zinc metalloproteases contain a zinc ion, which is necessary for enzymatic activity).

One example of a protease that contains a metal ion is the exoenzyme collagenase. Collagenase digests collagen, the dominant protein in connective tissue. Collagen can be found in the extracellular matrix, especially near mucosal membranes, blood vessels, nerves, and in the layers of the skin. Similar to hyaluronidase, collagenase allows the pathogen to penetrate and spread through the host tissue by digesting this connective tissue protein. The collagenase produced by the gram-positive bacterium Clostridium perfringens, for example, allows the bacterium to make its way through the tissue layers and subsequently enter and multiply in the blood (septicemia). C. perfringens then uses toxins and a phospholipase to cause cellular lysis and necrosis. Once the host cells have died, the bacterium produces gas by fermenting the muscle carbohydrates. The widespread necrosis of tissue and accompanying gas are characteristic of the condition known as gas gangrene (Figure (PageIndex{3})).

Figure (PageIndex{3}): The illustration depicts a blood vessel with a single layer of endothelial cells surrounding the lumen and dense connective tissue (shown in red) surrounding the endothelial cell layer. Collagenase produced by C. perfringens degrades the collagen between the endothelial cells, allowing the bacteria to enter the bloodstream. (credit illustration: modification of work by Bruce Blaus; credit micrograph: Micrograph provided by the Regents of University of Michigan Medical School © 2012)

In addition to exoenzymes, certain pathogens are able to produce toxins, biological poisons that assist in their ability to invade and cause damage to tissues. The ability of a pathogen to produce toxins to cause damage to host cells is called toxigenicity.

Toxins can be categorized as endotoxins or exotoxins. The lipopolysaccharide (LPS) found on the outer membrane of gram-negative bacteria is called endotoxin (Figure (PageIndex{4})). During infection and disease, gram-negative bacterial pathogens release endotoxin either when the cell dies, resulting in the disintegration of the membrane, or when the bacterium undergoes binary fission. The lipid component of endotoxin, lipid A, is responsible for the toxic properties of the LPS molecule. Lipid A is relatively conserved across different genera of gram-negative bacteria; therefore, the toxic properties of lipid A are similar regardless of the gram-negative pathogen. In a manner similar to that of tumor necrosis factor, lipid A triggers the immune system’s inflammatory response (see Inflammation and Fever). If the concentration of endotoxin in the body is low, the inflammatory response may provide the host an effective defense against infection; on the other hand, high concentrations of endotoxin in the blood can cause an excessive inflammatory response, leading to a severe drop in blood pressure, multi-organ failure, and death.

Figure (PageIndex{4}): Lipopolysaccharide is composed of lipid A, a core glycolipid, and an O-specific polysaccharide side chain. Lipid A is the toxic component that promotes inflammation and fever.

A classic method of detecting endotoxin is by using the Limulus amebocyte lysate (LAL) test. In this procedure, the blood cells (amebocytes) of the horseshoe crab (Limulus polyphemus) is mixed with a patient’s serum. The amebocytes will react to the presence of any endotoxin. This reaction can be observed either chromogenically (color) or by looking for coagulation (clotting reaction) to occur within the serum. An alternative method that has been used is an enzyme-linked immunosorbent assay (ELISA) that uses antibodies to detect the presence of endotoxin.

Unlike the toxic lipid A of endotoxin, exotoxins are protein molecules that are produced by a wide variety of living pathogenic bacteria. Although some gram-negative pathogens produce exotoxins, the majority are produced by gram-positive pathogens. Exotoxins differ from endotoxin in several other key characteristics, summarized in Table (PageIndex{3}). In contrast to endotoxin, which stimulates a general systemic inflammatory response when released, exotoxins are much more specific in their action and the cells they interact with. Each exotoxin targets specific receptors on specific cells and damages those cells through unique molecular mechanisms. Endotoxin remains stable at high temperatures, and requires heating at 121 °C (250 °F) for 45 minutes to inactivate. By contrast, most exotoxins are heat labile because of their protein structure, and many are denatured (inactivated) at temperatures above 41 °C (106 °F). As discussed earlier, endotoxin can stimulate a lethal inflammatory response at very high concentrations and has a measured LD50 of 0.24 mg/kg. By contrast, very small concentrations of exotoxins can be lethal. For example, botulinum toxin, which causes botulism, has an LD50 of 0.000001 mg/kg (240,000 times more lethal than endotoxin).

Table (PageIndex{3}): Comparison of Endotoxin and Exotoxins Produced by Bacteria
SourceGram-negative bacteriaGram-positive (primarily) and gram-negative bacteria
CompositionLipid A component of lipopolysaccharideProtein
Effect on hostGeneral systemic symptoms of inflammation and feverSpecific damage to cells dependent upon receptor-mediated targeting of cells and specific mechanisms of action
Heat stabilityHeat stableMost are heat labile, but some are heat stable

The exotoxins can be grouped into three categories based on their target: intracellular targeting, membrane disrupting, and superantigens. Table (PageIndex{4}) provides examples of well-characterized toxins within each of these three categories.

Table (PageIndex{4}): Some Common Exotoxins and Associated Bacterial Pathogens
CategoryExamplePathogenMechanism and Disease
Intracellular-targeting toxinsCholera toxinVibrio choleraeActivation of adenylate cyclase in intestinal cells, causing increased levels of cyclic adenosine monophosphate (cAMP) and secretion of fluids and electrolytes out of cell, causing diarrhea
Tetanus toxinClostridium tetaniInhibits the release of inhibitory neurotransmitters in the central nervous system, causing spastic paralysis
Botulinum toxinClostridium botulinumInhibits release of the neurotransmitter acetylcholine from neurons, resulting in flaccid paralysis
Diphtheria toxinCorynebacterium diphtheriaeInhibition of protein synthesis, causing cellular death
Membrane-disrupting toxinsStreptolysinStreptococcus pyogenesProteins that assemble into pores in cell membranes, disrupting their function and killing the cell
PneumolysinStreptococcus pneumoniae
Alpha-toxinStaphylococcus aureus
Alpha-toxinClostridium perfringensPhospholipases that degrade cell membrane phospholipids, disrupting membrane function and killing the cell
Phospholipase CPseudomonas aeruginosa
Beta-toxinStaphylococcus aureus
SuperantigensToxic shock syndrome toxinStaphylococcus aureusStimulates excessive activation of immune system cells and release of cytokines (chemical mediators) from immune system cells. Life-threatening fever, inflammation, and shock are the result.
Streptococcal mitogenic exotoxinStreptococcus pyogenes
Streptococcal pyrogenic toxinsStreptococcus pyogenes

The intracellular targeting toxins comprise two components: A for activity and B for binding. Thus, these types of toxins are known as A-B exotoxins (Figure (PageIndex{5})). The B component is responsible for the cellular specificity of the toxin and mediates the initial attachment of the toxin to specific cell surface receptors. Once the A-B toxin binds to the host cell, it is brought into the cell by endocytosis and entrapped in a vacuole. The A and B subunits separate as the vacuole acidifies. The A subunit then enters the cell cytoplasm and interferes with the specific internal cellular function that it targets.

Figure (PageIndex{5}): (a) In A-B toxins, the B component binds to the host cell through its interaction with specific cell surface receptors. (b) The toxin is brought in through endocytosis. (c) Once inside the vacuole, the A component (active component) separates from the B component and the A component gains access to the cytoplasm. (credit: modification of work by “Biology Discussion Forum”/YouTube)

Four unique examples of A-B toxins are the diphtheria, cholera, botulinum, and tetanus toxins. The diphtheria toxin is produced by the gram-positive bacterium Corynebacterium diphtheriae, the causative agent of nasopharyngeal and cutaneous diphtheria. After the A subunit of the diphtheria toxin separates and gains access to the cytoplasm, it facilitates the transfer of adenosine diphosphate (ADP)-ribose onto an elongation-factor protein (EF-2) that is needed for protein synthesis. Hence, diphtheria toxin inhibits protein synthesis in the host cell, ultimately killing the cell (Figure (PageIndex{6})).

Figure (PageIndex{6}): The mechanism of the diphtheria toxin inhibiting protein synthesis. The A subunit inactivates elongation factor 2 by transferring an ADP-ribose. This stops protein elongation, inhibiting protein synthesis and killing the cell.

Cholera toxin is an enterotoxin produced by the gram-negative bacterium Vibrio cholerae and is composed of one A subunit and five B subunits. The mechanism of action of the cholera toxin is complex. The B subunits bind to receptors on the intestinal epithelial cell of the small intestine. After gaining entry into the cytoplasm of the epithelial cell, the A subunit activates an intracellular G protein. The activated G protein, in turn, leads to the activation of the enzyme adenyl cyclase, which begins to produce an increase in the concentration of cyclic AMP (a secondary messenger molecule). The increased cAMP disrupts the normal physiology of the intestinal epithelial cells and causes them to secrete excessive amounts of fluid and electrolytes into the lumen of the intestinal tract, resulting in severe “rice-water stool” diarrhea characteristic of cholera.

Botulinum toxin (also known as botox) is a neurotoxin produced by the gram-positive bacterium Clostridium botulinum. It is the most acutely toxic substance known to date. The toxin is composed of a light A subunit and heavy protein chain B subunit. The B subunit binds to neurons to allow botulinum toxin to enter the neurons at the neuromuscular junction. The A subunit acts as a protease, cleaving proteins involved in the neuron’s release of acetylcholine, a neurotransmitter molecule. Normally, neurons release acetylcholine to induce muscle fiber contractions. The toxin’s ability to block acetylcholine release results in the inhibition of muscle contractions, leading to muscle relaxation. This has the potential to stop breathing and cause death. Because of its action, low concentrations of botox are used for cosmetic and medical procedures, including the removal of wrinkles and treatment of overactive bladder.

Click this link to see an animation of how the cholera toxin functions.

Click this link to see an animation of how the botulinum toxin functions.

Another neurotoxin is tetanus toxin, which is produced by the gram-positive bacterium Clostridium tetani. This toxin also has a light A subunit and heavy protein chain B subunit. Unlike botulinum toxin, tetanus toxin binds to inhibitory interneurons, which are responsible for release of the inhibitory neurotransmitters glycine and gamma-aminobutyric acid (GABA). Normally, these neurotransmitters bind to neurons at the neuromuscular junction, resulting in the inhibition of acetylcholine release. Tetanus toxin inhibits the release of glycine and GABA from the interneuron, resulting in permanent muscle contraction. The first symptom is typically stiffness of the jaw (lockjaw). Violent muscle spasms in other parts of the body follow, typically culminating with respiratory failure and death. Figure (PageIndex{7}) shows the actions of both botulinum and tetanus toxins.

Figure (PageIndex{7}): Mechanisms of botulinum and tetanus toxins. (credit micrographs: modification of work by Centers for Disease Control and Prevention)

Membrane-disrupting toxins affect cell membrane function either by forming pores or by disrupting the phospholipid bilayer in host cell membranes. Two types of membrane-disrupting exotoxins are hemolysins and leukocidins, which form pores in cell membranes, causing leakage of the cytoplasmic contents and cell lysis. These toxins were originally thought to target red blood cells (erythrocytes) and white blood cells (leukocytes), respectively, but we now know they can affect other cells as well. The gram-positive bacterium Streptococcus pyogenes produces streptolysins, water-soluble hemolysins that bind to the cholesterol moieties in the host cell membrane to form a pore. The two types of streptolysins, O and S, are categorized by their ability to cause hemolysis in erythrocytes in the absence or presence of oxygen. Streptolysin O is not active in the presence of oxygen, whereas streptolysin S is active in the presence of oxygen. Other important pore-forming membrane-disrupting toxins include alpha toxin of Staphylococcus aureus and pneumolysin of Streptococcus pneumoniae.

Bacterial phospholipases are membrane-disrupting toxins that degrade the phospholipid bilayer of cell membranes rather than forming pores. We have already discussed the phospholipases associated with B. anthracis, L. pneumophila, and Rickettsia species that enable these bacteria to effect the lysis of phagosomes. These same phospholipases are also hemolysins. Other phospholipases that function as hemolysins include the alpha toxin of Clostridium perfringens, phospholipase C of P. aeruginosa, and beta toxin of Staphylococcus aureus.

Some strains of S. aureus also produce a leukocidin called Panton-Valentine leukocidin (PVL). PVL consists of two subunits, S and F. The S component acts like the B subunit of an A-B exotoxin in that it binds to glycolipids on the outer plasma membrane of animal cells. The F-component acts like the A subunit of an A-B exotoxin and carries the enzymatic activity. The toxin inserts and assembles into a pore in the membrane. Genes that encode PVL are more frequently present in S. aureus strains that cause skin infections and pneumonia.1 PVL promotes skin infections by causing edema, erythema (reddening of the skin due to blood vessel dilation), and skin necrosis. PVL has also been shown to cause necrotizing pneumonia. PVL promotes pro-inflammatory and cytotoxic effects on alveolar leukocytes. This results in the release of enzymes from the leukocytes, which, in turn, cause damage to lung tissue.

The third class of exotoxins is the superantigens. These are exotoxins that trigger an excessive, nonspecific stimulation of immune cells to secrete cytokines (chemical messengers). The excessive production of cytokines, often called a cytokine storm, elicits a strong immune and inflammatory response that can cause life-threatening high fevers, low blood pressure, multi-organ failure, shock, and death. The prototype superantigen is the toxic shock syndrome toxin of S. aureus. Most toxic shock syndrome cases are associated with vaginal colonization by toxin-producing S. aureus in menstruating women; however, colonization of other body sites can also occur. Some strains of Streptococcus pyogenes also produce superantigens; they are referred to as the streptococcal mitogenic exotoxins and the streptococcal pyrogenic toxins.

Exercise (PageIndex{2})

  1. Describe how exoenzymes contribute to bacterial invasion.
  2. Explain the difference between exotoxins and endotoxin.
  3. Name the three classes of exotoxins.

Virulence Factors for Survival in the Host and Immune Evasion

Evading the immune system is also important to invasiveness. Bacteria use a variety of virulence factors to evade phagocytosis by cells of the immune system. For example, many bacteria produce capsules, which are used in adhesion but also aid in immune evasion by preventing ingestion by phagocytes. The composition of the capsule prevents immune cells from being able to adhere and then phagocytose the cell. In addition, the capsule makes the bacterial cell much larger, making it harder for immune cells to engulf the pathogen (Figure (PageIndex{8})). A notable capsule-producing bacterium is the gram-positive pathogen Streptococcus pneumoniae, which causes pneumococcal pneumonia, meningitis, septicemia, and other respiratory tract infections. Encapsulated strains of S. pneumoniae are more virulent than nonencapsulated strains and are more likely to invade the bloodstream and cause septicemia and meningitis.

Some pathogens can also produce proteases to protect themselves against phagocytosis. As described in Adaptive Specific Host Defenses, the human immune system produces antibodies that bind to surface molecules found on specific bacteria (e.g., capsules, fimbriae, flagella, LPS). This binding initiates phagocytosis and other mechanisms of antibacterial killing and clearance. Proteases combat antibody-mediated killing and clearance by attacking and digesting the antibody molecules (Figure (PageIndex{8})).

In addition to capsules and proteases, some bacterial pathogens produce other virulence factors that allow them to evade the immune system. The fimbriae of certain species of Streptococcus contain M protein, which alters the surface of Streptococcus and inhibits phagocytosis by blocking the binding of the complement molecules that assist phagocytes in ingesting bacterial pathogens. The acid-fast bacterium Mycobacterium tuberculosis (the causative agent of tuberculosis) produces a waxy substance known as mycolic acid in its cell envelope. When it is engulfed by phagocytes in the lung, the protective mycolic acid coat enables the bacterium to resist some of the killing mechanisms within the phagolysosome.

Figure (PageIndex{8}): (a) A micrograph of capsules around bacterial cells. (b) Antibodies normally function by binding to antigens, molecules on the surface of pathogenic bacteria. Phagocytes then bind to the antibody, initiating phagocytosis. (c) Some bacteria also produce proteases, virulence factors that break down host antibodies to evade phagocytosis. (credit a: modification of work by Centers for Disease Control and Prevention)

Some bacteria produce virulence factors that promote infection by exploiting molecules naturally produced by the host. For example, most strains of Staphylococcus aureus produce the exoenzyme coagulase, which exploits the natural mechanism of blood clotting to evade the immune system. Normally, blood clotting is triggered in response to blood vessel damage; platelets begin to plug the clot, and a cascade of reactions occurs in which fibrinogen, a soluble protein made by the liver, is cleaved into fibrin. Fibrin is an insoluble, thread-like protein that binds to blood platelets, cross-links, and contracts to form a mesh of clumped platelets and red blood cells. The resulting clot prevents further loss of blood from the damaged blood vessels. However, if bacteria release coagulase into the bloodstream, the fibrinogen-to-fibrin cascade is triggered in the absence of blood vessel damage. The resulting clot coats the bacteria in fibrin, protecting the bacteria from exposure to phagocytic immune cells circulating in the bloodstream.

Whereas coagulase causes blood to clot, kinases have the opposite effect by triggering the conversion of plasminogen to plasmin, which is involved in the digestion of fibrin clots. By digesting a clot, kinases allow pathogens trapped in the clot to escape and spread, similar to the way that collagenase, hyaluronidase, and DNAse facilitate the spread of infection. Examples of kinases include staphylokinases and streptokinases, produced by Staphylococcus aureusand Streptococcus pyogenes, respectively. It is intriguing that S. aureus can produce both coagulase to promote clotting and staphylokinase to stimulate the digestion of clots. The action of the coagulase provides an important protective barrier from the immune system, but when nutrient supplies are diminished or other conditions signal a need for the pathogen to escape and spread, the production of staphylokinase can initiate this process.

A final mechanism that pathogens can use to protect themselves against the immune system is called antigenic variation, which is the alteration of surface proteins so that a pathogen is no longer recognized by the host’s immune system. For example, the bacterium Borrelia burgdorferi, the causative agent of Lyme disease, contains a surface lipoprotein known as VlsE. Because of genetic recombination during DNA replication and repair, this bacterial protein undergoes antigenic variation. Each time fever occurs, the VlsE protein in B. burgdorferi can differ so much that antibodies against previous VlsE sequences are not effective. It is believed that this variation in the VlsE contributes to the ability B. burgdorferi to cause chronic disease. Another important human bacterial pathogen that uses antigenic variation to avoid the immune system is Neisseria gonorrhoeae, which causes the sexually transmitted disease gonorrhea. This bacterium is well known for its ability to undergo antigenic variation of its type IV pili to avoid immune defenses.

Exercise (PageIndex{3})

  1. Name at least two ways that a capsule provides protection from the immune system.
  2. Besides capsules, name two other virulence factors used by bacteria to evade the immune system.

Viral Virulence

Although viral pathogens are not similar to bacterial pathogens in terms of structure, some of the properties that contribute to their virulence are similar. Viruses use adhesins to facilitate adhesion to host cells, and certain enveloped viruses rely on antigenic variation to avoid the host immune defenses. These virulence factors are discussed in more detail in the following sections.

Viral Adhesins

One of the first steps in any viral infection is adhesion of the virus to specific receptors on the surface of cells. This process is mediated by adhesins that are part of the viral capsid or membrane envelope. The interaction of viral adhesins with specific cell receptors defines the tropism (preferential targeting) of viruses for specific cells, tissues, and organs in the body. The spike protein hemagglutinin found on Influenzavirus is an example of a viral adhesin; it allows the virus to bind to the sialic acid on the membrane of host respiratory and intestinal cells. Another viral adhesin is the glycoprotein gp20, found on HIV. For HIV to infect cells of the immune system, it must interact with two receptors on the surface of cells. The first interaction involves binding between gp120 and the CD4 cellular marker that is found on some essential immune system cells. However, before viral entry into the cell can occur, a second interaction between gp120 and one of two chemokine receptors (CCR5 and CXCR4) must occur. Table (PageIndex{5}) lists the adhesins for some common viral pathogens and the specific sites to which these adhesins allow viruses to attach.

Table (PageIndex{5}): Some Viral Adhesins and Their Host Attachment Sites
PathogenDiseaseAdhesinAttachment Site
InfluenzavirusInfluenzaHemagglutininSialic acid of respiratory and intestinal cells
Herpes simplex virus I or IIOral herpes, genital herpesGlycoproteins gB, gC, gDHeparan sulfate on mucosal surfaces of the mouth and genitals
Human immunodeficiency virusHIV/AIDSGlycoprotein gp120CD4 and CCR5 or CXCR4 of immune system cells

Antigenic Variation in Viruses

Antigenic variation also occurs in certain types of enveloped viruses, including influenza viruses, which exhibit two forms of antigenic variation: antigenic drift and antigenic shift (Figure (PageIndex{9})). Antigenic drift is the result of point mutations causing slight changes in the spike proteins hemagglutinin (H) and neuraminidase (N). On the other hand, antigenic shift is a major change in spike proteins due to gene reassortment. This reassortment for antigenic shift occurs typically when two different influenza viruses infect the same host.

The rate of antigenic variation in influenza viruses is very high, making it difficult for the immune system to recognize the many different strains of Influenzavirus. Although the body may develop immunity to one strain through natural exposure or vaccination, antigenic variation results in the continual emergence of new strains that the immune system will not recognize. This is the main reason that vaccines against Influenzavirus must be given annually. Each year’s influenza vaccine provides protection against the most prevalent strains for that year, but new or different strains may be more prevalent the following year.

Figure (PageIndex{9}): Antigenic drift and antigenic shift in influenza viruses. (a) In antigenic drift, mutations in the genes for the surface proteins neuraminidase and/or hemagglutinin result in small antigenic changes over time. (b) In antigenic shift, simultaneous infection of a cell with two different influenza viruses results in mixing of the genes. The resultant virus possesses a mixture of the proteins of the original viruses. Influenza pandemics can often be traced to antigenic shifts.

For another explanation of how antigenic shift and drift occur, watch this video.

Exercise (PageIndex{4})

  1. Describe the role of adhesins in viral tropism.
  2. Explain the difference between antigenic drift and antigenic shift.

Virulence factors contribute to a pathogen’s ability to cause disease. Exoenzymes and toxins allow pathogens to invade host tissue and cause tissue damage. Exoenzymes are classified according to the macromolecule they target and exotoxins are classified based on their mechanism of action. Bacterial toxins include endotoxin and exotoxins. Endotoxin is the lipid A component of the LPS of the gram-negative cell envelope. Exotoxins are proteins secreted mainly by gram-positive bacteria, but also are secreted by gram-negative bacteria. Bacterial pathogens may evade the host immune response by producing capsules to avoid phagocytosis, surviving the intracellular environment of phagocytes, degrading antibodies, or through antigenic variation. Viral pathogens use adhesins for initiating infections and antigenic variation to avoid immune defenses. Influenza viruses use both antigenic drift and antigenic shift to avoid being recognized by the immune system.


  • Nina Parker, (Shenandoah University), Mark Schneegurt (Wichita State University), Anh-Hue Thi Tu (Georgia Southwestern State University), Philip Lister (Central New Mexico Community College), and Brian M. Forster (Saint Joseph’s University) with many contributing authors. Original content via Openstax (CC BY 4.0; Access for free at

Moonlighting Proteins: Novel Virulence Factors in Bacterial Infections

Moonlighting Proteins: Novel Virulence Factors in Bacterial Infections is a complete examination of the ways in which proteins with more than one unique biological action are able to serve as virulence factors in different bacteria.

The book explores the pathogenicity of bacterial moonlighting proteins, demonstrating the plasticity of protein evolution as it relates to protein function and to bacterial communication. Highlighting the latest discoveries in the field, it details the approximately 70 known bacterial proteins with a moonlighting function related to a virulence phenomenon. Chapters describe the ways in which each moonlighting protein can function as such for a variety of bacterial pathogens and how individual bacteria can use more than one moonlighting protein as a virulence factor. The cutting-edge research contained here offers important insights into many topics, from bacterial colonization, virulence, and antibiotic resistance, to protein structure and the therapeutic potential of moonlighting proteins.

Moonlighting Proteins: Novel Virulence Factors in Bacterial Infections will be of interest to researchers and graduate students in microbiology (specifically bacteriology), immunology, cell and molecular biology, biochemistry, pathology, and protein science.

Virulence Factors for Adhesion

As discussed in the previous section, the first two steps in pathogenesis are exposure and adhesion. Recall that an adhesin is a protein or glycoprotein found on the surface of a pathogen that attaches to receptors on the host cell. Adhesins are found on bacterial, viral, fungal, and protozoan pathogens. One example of a bacterial adhesin is type 1 fimbrial adhesin, a molecule found on the tips of fimbriae of enterotoxigenic E. coli (ETEC). Recall that fimbriae are hairlike protein bristles on the cell surface. Type 1 fimbrial adhesin allows the fimbriae of ETEC cells to attach to the mannose glycans expressed on intestinal epithelial cells. Table 1 lists common adhesins found in some of the pathogens we have discussed or will be seeing later in this chapter.

Table 1. Some Bacterial Adhesins and Their Host Attachment Sites
Pathogen Disease Adhesin Attachment Site
Streptococcus pyogenes Strep throat Protein F Respiratory epithelial cells
Streptococcus mutans Dental caries Adhesin P1 Teeth
Neisseria gonorrhoeae Gonorrhea Type IV pili Urethral epithelial cells
Enterotoxigenic E. coli (ETEC) Traveler’s diarrhea Type 1 fimbriae Intestinal epithelial cells
Vibrio cholerae Cholera N-methylphenylalanine pili Intestinal epithelial cells

Clinical Focus: Pankaj, Part 3

The presence of bacteria in Pankaj’s blood is a sign of infection, since blood is normally sterile. There is no indication that the bacteria entered the blood through an injury. Instead, it appears the portal of entry was the gastrointestinal route. Based on Pankaj’s symptoms, the results of his blood test, and the fact that Pankaj was the only one in the family to partake of the hot dogs, the physician suspects that Pankaj is suffering from a case of listeriosis.

Listeria monocytogenes, the facultative intracellular pathogen that causes listeriosis, is a common contaminant in ready-to-eat foods such as lunch meats and dairy products. Once ingested, these bacteria invade intestinal epithelial cells and translocate to the liver, where they grow inside hepatic cells. Listeriosis is fatal in about one in five normal healthy people, and mortality rates are slightly higher in patients with pre-existing conditions that weaken the immune response. A cluster of virulence genes encoded on a pathogenicity island is responsible for the pathogenicity of L. monocytogenes. These genes are regulated by a transcriptional factor known as peptide chain release factor 1 (PrfA). One of the genes regulated by PrfA is hyl, which encodes a toxin known as listeriolysin O (LLO), which allows the bacterium to escape vacuoles upon entry into a host cell. A second gene regulated by PrfA is actA, which encodes for a surface protein known as actin assembly-inducing protein (ActA). ActA is expressed on the surface of Listeria and polymerizes host actin. This enables the bacterium to produce actin tails, move around the cell’s cytoplasm, and spread from cell to cell without exiting into the extracellular compartment.

Pankaj’s condition has begun to worsen. He is now experiencing a stiff neck and hemiparesis (weakness of one side of the body). Concerned that the infection is spreading, the physician decides to conduct additional tests to determine what is causing these new symptoms.

  • What kind of pathogen causes listeriosis, and what virulence factors contribute to the signs and symptoms Pankaj is experiencing?
  • Is it likely that the infection will spread from Pankaj’s blood? If so, how might this explain his new symptoms?

We’ll conclude Pankaj’s example later on this page.


Pancreatic cancer is considered as one of the deadliest cancers, since its onset is occult and the early symptoms are not typical (Kamisawa et al., 2016). Although the detection and treatment of pancreatic cancer has progressed, the 5-year survival rate of pancreatic cancer is only 9%, which is the lowest among all cancers (Siegel et al., 2019). Worldwide, the incidence of pancreatic cancer is increasing year by year. There are 458,918 new cases in 2018, which means more than 1,250 people are told to have pancreatic cancer every day. In the same year, 432,242 patients died of pancreatic cancer, therefore, it has become the seventh leading cause of cancer-related deaths (Rawla et al., 2019). The reason for this situation is that researchers do not know enough about the pathogenesis of pancreatic cancer.

According to the 2018 International Agency for Research on Cancer (IARC) 縘% of cancers are associated with infectious diseases caused by bacteria, viruses and parasites (Rawla et al., 2019). Bacterial infections promote the formation of inflammatory microenvironment, which is a critical regulator of carcinogenesis (Coussens and Werb, 2002). Persistent infections will induce epigenetic modification of the somatic cells and lead to the production of a large amount of reactive oxygen species (ROS) and reactive nitrogen (RNS), that eventually cause DNA damage, oncogene activation or tumor suppressor genes inactivation (Cuevas-Ramos et al., 2010 Sahan et al., 2018).


The ability of pathogenic bacteria to exploit their hosts depends upon various virulence factors, released in response to the concentration of small autoinducer molecules that are also released by the bacteria 1, 2, 3, 4, 5. In vitro experiments suggest that autoinducer molecules are signals used to coordinate cooperative behaviors and that this process of quorum sensing (QS) can be exploited by individual cells that avoid the cost of either producing or responding to signal 6, 7. However, whether QS is an exploitable social trait in vivo, and the implications for the evolution of virulence 5, 8, 9, 10, remains untested. We show that in mixed infections of the bacterium Pseudomonas aeruginosa, containing quorum-sensing bacteria and mutants that do not respond to signal, virulence in an animal (mouse) model is reduced relative to that of an infection containing no mutants. We show that this is because mutants act as cheats, exploiting the cooperative production of signal and virulence factors by others, and hence increase in frequency. This supports the idea that the invasion of QS mutants in infections of humans 11, 12, 13 is due to their social fitness consequences 6, 7, 14 and predicts that increased strain diversity will select for lower virulence.

Kiwi disease study finds closely related bacterial strains display different behaviors

Over the last decade, severe outbreaks of bacterial canker have caused huge economic losses for kiwi growers, especially in Italy, New Zealand, and China, which are among the largest producers. Bacterial canker is caused by the bacterial pathogen Pseudomonas syringae pv. actinidiae (Psa) and more recent outbreaks have been particularly devastating due to the emergence of a new, extremely aggressive biovar called Psa3.

Due to its recent introduction, the molecular basis of Psa3's virulence is unknown, making it difficult to develop mitigation strategies. In light of this dilemma, a group of scientists at the University of Verona and University of Rome collaborated on a study comparing the behavior of Psa3 with less-virulent biovars to determine the basis of pathogenicity.

They found that genes involved in bacterial signaling (the transmission of external stimuli within cells) were especially important, especially the genes required for the synthesis and degradation of a small chemical signal called c-di-GMP, that suppresses the expression of virulence factors. Compared to other biovars, Psa3 produces very low levels of c-di-GMP, contributing to an immediate and aggressive phenotype at the onset of infection before the plant can corral a defense response.

"It was exciting to discover this diversified arsenal of pathogenicity strategies among closely related bacterial strains that infect the same hosts but display different behaviors," said Elodie Vandelle, one of the scientists involved with this study. "Although their 'small' genomes mainly contain the same information, our research shows that bacterial populations within a pathovar are more complex than expected and their pathogenicity may have evolved throughout different strategies to attack the same host."

Their research highlights the importance of working on a multitude of real-life pathogenic bacterial strains to shed light on the diversity of virulence strategies. This approach can contribute to the creation of wider pathogenicity working models. In terms of kiwi production, Vandelle hopes their findings can help scientists develop new mitigation methods. In the long-term, their research could lead to the identification of key molecular switches responsible for the transition between high and low bacterial virulence phenotypes.

"This identification would allow, at industrial level, to develop new targeted strategies to control phytopathogenic bacteria, weakening their aggressiveness through switch control, instead of killing them," Vandelle explained. "This would avoid the occurrence of new resistances among bacterial communities, thus guaranteeing a sustainable plant protection."

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

PhD in Cellular Biology and host-pathogen interactions

Team “Immunomodulation by Mycobacterial Lipids and Glycoconjugates”, headed by Jérôme Nigou, IPBS, CNRS / Université de Toulouse, Toulouse.

Constraints and risks

The student will be trained to perform level 2 and 3 safety laboratory experiments.

Additional Information:

This thesis project is funded by a grant from the ANR. Motivated candidates with a Master's degree in Cell Biology or Immunology must provide a CV, an official transcript of their Master's grades, a letter of motivation and the e-mail contact of referees who supervised their work in the laboratory.

Scientific Responsible : Layre Emilie

Description of the thesis topic:

“Role of extracellular vesicles in host-pathogen interactions and virulence of Mycobacterium tuberculosis”

Tuberculosis is one of the 10 leading causes of death in the world (WHO, 2018) (1). The etiological agent, Mycobacterium tuberculosis (Mtb), infects alveolar macrophages and establishes a chronic infection in humans through its ability to adapt to intracellular conditions and host immune responses (2). A better understanding of the host-pathogen interactions of this infection is necessary for the development of more effective means of control. Every living cell releases extracellular vesicles (EV) that shuttle diverse molecules (lipids, proteins, nucleic acids) and play important roles in intercellular communication, regulation of immune responses or bacterial virulence (3). Similarly, infected cells as well as the bacillus release EV during Mtb infection. If the host-pathogen interaction of this infection is essentially studied at the direct interface between the 2 organisms, the diffusion of bacterial and eukaryotic factors within EV most likely contribute significantly to these interactions at the infection site and beyond (4, 5). However, the characterization of the composition and immunomodulatory properties of these EV remains largely incomplete.

In this context, the aim of this project is to better characterize the interactions of these vesicles with the preferred target of Mtb: the macrophages. Their capacity to regulate the inflammatory and microbicide properties of macrophages. In particular, we will study the capacity of EV to activate and induce cytokine production and autophagy, via their interaction with innate immunity receptors or Pattern Recognition Receptors (PRRs), such as Toll Like Receptors (TLRs) or C-type lectins. Their intracellular trafficking, which conditions their immunomodulatory properties, will be analysed by super-resolution microscopy. The vesicles released in presence of mycobacteria of variable virulence will be studied comparatively in these different assays. In order to decipher the molecular basis of their immunomodulatory properties, we will undertake to characterize their content in PRR ligands using omic-type methods, among others.
Given their relevance for the study of host-pathogen interactions, a better characterization of EV will provide important insights into Mtb pathogenesis.

Methods: cell and mycobacterial culture, vesicle purification (density gradient, exclusion chromatography), TEM and super-resolution microscopy, activation assays of reporter and functional bioassay on primary cells, flow cytometry, Western blot, ELISA, mass spectrometry.

References: (1) WHO. Global Tuberculosis Report 2020. (2) Ernst J. D. Mechanisms of M. tuberculosis Immune Evasion as Challenges to TB Vaccine Design. Cell Host Microbe 2018, 24(1):34-42. (3) Robbins PD, Morelli AE. Regulation of immune responses by extracellular vesicles. Nat Rev Immunol. 2014, 14(3):195-208. (4) Prados-Rosales R, et al. Mycobacteria release active membrane vesicles that modulate immune responses in a TLR2-dependent manner in mice. J Clin Invest. 2011, 121(4):1471-83. (5) Layre E. Trafficking of Mycobacterium tuberculosis Envelope Components and Release Within Extracellular Vesicles: Host-Pathogen Interactions Beyond the Wall. Front Immunol. 2020, 11:1230.

Work Context

This project will be carried out in the team "Immunomodulation by lipids and mycobacterial glycoconjugates" led by Dr. J. Nigou, in the "Tuberculosis and Infection Biology" department of the Institute of Pharmacology and Structural Biology (IPBS, joint research unit CNRS-Paul Sabatier University, Toulouse, France). The student will work under the supervision of Drs. Emilie Layre (CR, CNRS) and Jérome Nigou (DR, CNRS). The IPBS offers a stimulating research environment and benefits from several state-of-the-art facilities on site, including proteomics and mass spectrometry, macromolecular crystallography, liquid and solid state NMR, high resolution imaging of tissues and cells imaging of tissues and cells, flow cytometry and cell sorting in standard in standard or level 3 security laboratories and animal facilities.
The IPBS is located on the main campus of the University Toulouse III-Paul Sabatier. which offers multidisciplinary education in the fields of science health, engineering and technology, and is developing one of the most important scientific research centers in France. Founded in 1996, the IPBS is today composed of 16 internationally recognized research groups, which bring together more than 250 scientists, including numerous post-doctoral fellows and national and international PhD students.


The demonstration that the flagellar export apparatus can also function as a protein secretion system will open new areas of research in interactions between bacteria and their hosts. Many pathogenic bacteria possessing a TTSS are also known to be motile and so a re-examination of extracellular proteins using flagellar mutants may reveal new virulence factors. Furthermore, as the authors note, the study of flagellum biosynthesis is highly developed, and a vast array of biochemical and genetic tools are available that could be used to investigate the dual function of protein secretion.

Part 2: Arabidopsis thaliana-Pseudomonas syringae interaction: The effect of climate in plant disease

00:00:0722 Hello.
00:00:0822 I'm Sheng Yang He.
00:00:0923 I am a professor at Michigan State University and an Investigator at the Howard Hughes Medical Institute.
00:00:1524 This is Part 2 of my iBiology talk.
00:00:1908 In this part of my talk, I want to tell you some of our work involving Arabidopsis and
00:00:2706 the Pseudomonas syringae interactions.
00:00:2906 Particularly, I want to highlight one aspect of our research, illustrating how environmental conditions
00:00:3424 could profoundly influence disease development in plants.
00:00:3921 So, as you know, when you look at a plant growing in nature, outside, they not only are,
00:00:4707 you know, exposed to potential pathogens, but they are also experiencing a lot of different conditions:
00:00:5224 temperature fluctuation, you know, from morning to evenings light, as you can see here
00:00:5920 and temperature humidity and microbiome, even.
00:01:0323 We know that all of these factors actually influence pathogen and plant interactions.
00:01:0909 The molecular bases of this are not well understood.
00:01:1224 And so some famous scientist said, you know, without understanding environmental conditions,
00:01:1626 we will never understand the immunity in plants. you know, in the plant system.
00:01:2304 So, I'll just give you a couple of examples of how important the climate conditions could be
00:01:2800 for plant disease outbreak in the field.
00:01:3211 This is the bacterial fire blight disease in apple.
00:01:3611 This is in Switzerland.
00:01:3711 This is a 12-year span of disease incidents from 1995 to 2007.
00:01:4518 So, apples are always growing in, you know, Switzerland, and pathogens are always in these orchards,
00:01:5020 but you don't see the disease every year.
00:01:5315 And the reason is for disease to occur you need a lot of humidity and the right temperature, right?
00:02:0110 So, in 2007, in that year you have heavy rain and high humidity in the spring,
00:02:0523 when the apple was flowering, and these bacteria tend to infect the flowering parts.
00:02:1119 And so everything kind of came at the same time, and then have very severe disease.
00:02:1617 So, that's one example.
00:02:1908 Another example is called fusarium head blight of wheat.
00:02:2307 This is actually a very huge global disease right now.
00:02:2811 It's also favored by high humidity and warm temperatures in the spring.
00:02:3122 So, you can see that. you know, normally you see a nice green top of the wheat.
00:02:3803 In this image, you can see, basically, bleached grains.
00:02:4315 And there were four very severe epidemics in China in the last five years,
00:02:4728 so almost every year has very severe disease.
00:02:4925 This disease, also, is very serious, because the fungus actually produces a toxin
00:02:5611 which makes us sick.
00:02:5711 And so. not only reducing yield, but also causing sickness in the human population.
00:03:0515 So, I want to tell you that plant diseases are really, you know, problems in modern agriculture.
00:03:1119 They're really major threats to food security, globally, right now.
00:03:1619 Some of these diseases are very old.
00:03:1828 On the left is a disease called rice blast, a disease I actually grew up, when in China
00:03:2504 I lived in a village with 200 people or so.
00:03:2904 So, you know, I saw this rice blast when I was a really small little child.
00:03:3501 When I go back right now, 40 years later, and talk to my parents, and this is
00:03:4104 still the number one disease locally, but also globally, in rice production.
00:03:4506 So, many old diseases continue to really pose major problems.
00:03:4910 Now, you also have new diseases coming up.
00:03:5220 One example I'm giving to you here is a kiwi bacterial canker, which is caused by
00:03:5714 a bacterial pathogen called Pseudomonas syringae, and I'm going to tell you a little bit about that today.
00:04:0212 So, this is despite all the chemical input -- you know, pesticides, you have to spray them,
00:04:0809 farms have to use them, because otherwise you won't have, you know, really high yield --
00:04:1120 but also all the breeding efforts, that many scientists try to breed resistant cultivars.
00:04:1821 You know, from wheat to rice, based on these so-called disease resistant genes.
00:04:2503 But this is not enough.
00:04:2603 So. because we have disease every year still.
00:04:2818 One of the problems, as we've realized, is that we really don't understand
00:04:3205 the basic process of disease, okay?
00:04:3416 So, this is an area that we really want to push ahead.
00:04:3902 So, in the last 15 years or so, you know, many laboratories including us are
00:04:4511 really concentrating on trying to work out why disease occurs.
00:04:4922 And so this is an overview of different kind of pathogens that can cause disease in plants.
00:04:5419 So, we have fungus we have bacteria we have nematode, worms, you know and viruses.
00:05:0302 Many of these pathogens also cause problems in our human bodies also.
00:05:0625 And so one. so, they look very different, but one of the common things they do is to
00:05:1018 deliver these virulence factors -- collectively, we call them effectors -- into the plant cell.
00:05:1627 And. and so, they use different ways of delivering these virulence proteins.
00:05:2120 In the case of bacteria, they use a secretion system called the type III secretion system.
00:05:2602 You can see on the right a syringe-like structure, here.
00:05:3108 If you knock out this delivery system, bacteria become non-pathogenic, okay?
00:05:3522 So, that illustrates how important these virulence factors are to causing diseases.
00:05:4106 So, because of that, studying how effectors work really can provide great progress into
00:05:4825 the molecular basis of disease susceptibility.
00:05:5227 And interestingly, these molecules, microbial molecules, also can be very powerful probes
00:05:5819 into the fundamental biology of the host -- and that can be plants or it could be humans --
00:06:0313 because they usually find very intriguing RNAs or proteins or DNAs to manipulate the host physiology.
00:06:0927 Okay, so in a sense, this is a really great, you know, probe into the biology of the host itself.
00:06:1608 Obviously, discovering the target of these virulence factors could offer new leads into
00:06:2124 innovative disease control we really desperately need right now.
00:06:2525 So, how do we understand disease susceptibility?
00:06:2807 Which approaches?
00:06:2923 We and others are really following this very simple diagram, here.
00:06:3224 We want to understand the host target of all these bacterial virulence proteins.
00:06:3817 So, in the case of the bacteria we study, it has about, you know, 30 or so effectors.
00:06:4304 What we want to do -- we means us and the many other laboratories -- is really to identify
00:06:4812 these host proteins or RNAs or DNAs that are being targeted by these virulence factors,
00:06:5412 and we want to associate these host targets to these particular pathways.
00:06:5805 You know, I listed the five of them -- A, B, C, D, E -- but it could be 30, right?
00:07:0228 So, we don't know how many pathways are being targeted by bacterial virulence factors.
00:07:0800 What we hope to do is to. once we identify these pathways, we could genetically
00:07:1400 perturb these pathways in the host, in this case, in the plant.
00:07:1725 And if we're successful, then if we understood everything about the disease process,
00:07:2313 we can create a poly mutant of the host in which these pathways are basically either
00:07:2916 activated or inactivated to simulate the collective activity of these virulence factors.
00:07:3603 And then if we really understood the process then, then the poly mutant of the host
00:07:4005 would be susceptible to a bacteria that is not able to produce effectors.
00:07:4422 In other words, if we manipulate the host already, genetically, to simulate the
00:07:5017 action of the virulence factors, you don't need these virulence factors to start with, right?
00:07:5328 Until then, we will never know we understood the disease, okay?
00:07:5627 So, that's the goal.
00:07:5806 It's very challenging, but by the end of these twenty minutes, I want to show you that
00:08:0205 we have made progress towards that goal.
00:08:0428 So, we use this very simple model system involving Arabidopsis, which is a model plant,
00:08:1204 and a bacterial pathogen called Pseudomonas syringae.
00:08:1421 It's a very common pathogen.
00:08:1613 It infects virtually all crop plants in the field, okay?
00:08:2025 Each individual string of this species, Pseudomonas syringae, infects a very narrow range of hosts.
00:08:2702 So for instance, strain DC3000 in the field only infects tomato.
00:08:3224 In the laboratory, you can also make it infect Arabidopsis, okay?
00:08:3705 So. so because Arabidopsis is a very, you know, powerful model for plant research.
00:08:4205 so we have been working on Arabidopsis-Pseudomonas model system for many years now.
00:08:4800 Pseudomonas can actually live on the surface of the bacteria. of the plants as an epiphyte.
00:08:5415 But in order to cause disease, it has to go into the interior of the leaf, in this case, okay?
00:09:0020 They go into the leaves through so-called stomata.
00:09:0316 So, these are microscopic pores on the leaf epidermis that allow plants to take up
00:09:0915 the CO2 to make food for us, okay?
00:09:1202 So, photosynthesis.
00:09:1302 It's very important, okay?
00:09:1522 And once bacteria go into the. inside the leaf, it lives in between the cells, okay?
00:09:2109 So, these are called mesophyll cells.
00:09:2312 So, these are extracellular pathogens, okay?
00:09:2521 So, this space is called the apoplast.
00:09:2706 Now, I want to tell you the apoplast is normally filled with air.
00:09:3113 It's not filled with liquid.
00:09:3213 This is very important, because CO2 has to go into the. goes through to the stomata
00:09:3718 into the apoplast, but it has to diffuse into the mesophyll cell and the chloroplast.
00:09:4204 So, it's a long distance for the CO2 to go in there.
00:09:4503 You don't want water in there, because there will be very high resistance to CO2.
00:09:5100 So, the plant has a way of keeping that space mostly filled with air.
00:09:5504 I'll come back to this.
00:09:5604 It's actually very relevant to pathogenesis.
00:09:5822 So, what we do in the laboratory to kind of have a disease assay is really to grow plants
00:10:0408 in a pot.
00:10:0525 You probably do this at home.
00:10:0714 Not this style, but in another way.
00:10:1001 And then, when they are four or five weeks old, we would dip the plants entirely
00:10:1519 into the bacterial suspension and wait for, basically, three days, okay?
00:10:1911 You will see disease symptoms, as shown here.
00:10:2115 So, I'm gonna play a movie which shows you the time-lapse video of the infection process.
00:10:2805 On the left are the mock.
00:10:2919 I mean, are the bacterially infected plants.
00:10:3304 On the right is a mock infection, this is water, okay?
00:10:3524 So, what you can see, now. eventually, you can see the yellowing on the plants that are infected.
00:10:4200 And on the right are the ones that are moving, you know, they are alive, okay?
00:10:4517 You can see there are some plants that are kind of dancing, of this thing you can see.
00:10:5012 But the infected plants are basically paralyzed, okay?
00:10:5302 So, we actually don't know why plants are motionless very early on in the disease.
00:10:5800 This is one of the things we are trying to understand in the. in the next few years.
00:11:0218 So, we have worked on several aspects of this disease process.
00:11:0814 For instance, we have, a few years ago, figured out that entry process, right?, how bacteria
00:11:1507 enter the plant tissues through the stomata.
00:11:1825 For a long time, scientists think they are passive, because the stomata pores are
00:11:2411 quite big and bacteria are kind of small.
00:11:2526 They can. the pore has to be open for photosynthesis during the day, so we always thought bacteria
00:11:3111 can just take advantage of that and go into the tissue, like, passively, right?
00:11:3417 That doesn't turn out to be the case.
00:11:3700 It turns out these guard cells -- there are two guard cells to form one stomata pore --
00:11:4218 they actually can sense bacteria.
00:11:4503 And so once they sense the bacteria, they close it as the first line of defense,
00:11:5002 to prevent any microbes entering the tissue.
00:11:5227 So, plants are very smart, okay?
00:11:5412 So, that's about. a very intriguing mechanism defending against pathogen invasion.
00:12:0023 We discovered one of the. so, that's bad for the bacterial pathogen, right?
00:12:0400 It cannot even start the infection.
00:12:0512 So, in the case of Pseudomonas syringae, it figured out a way to prevent that from happening
00:12:1002 by producing a toxin called coronatine, which prevents stomata from closing.
00:12:1507 And so the bacteria can massively infect to start an infection.
00:12:2014 Once the bacteria get into the mesophyll space. as I mentioned before, it's an extracellular pathogen,
00:12:2513 but it makes a type III secretion system injecting more virulence effectors
00:12:3001 into the plant cell as a major weapon of pathogenesis.
00:12:3228 So, we're working on this area as well.
00:12:3528 So, we knew a little bit of these basic steps of this infection involving stomata entry,
00:12:4113 involving a toxin that prevents the stomata from closing, and involving these effectors
00:12:4617 that we think, now, are suppressing immune responses in plants, okay?
00:12:5107 Work in the past few years, from us and many other groups, has deepened our understanding
00:12:5626 of these basic steps, but also. in our case, we realized that we're missing two dimensions
00:13:0221 in the last, you know, many years, actually.
00:13:0500 One dimension involves the profound effect of environmental conditions on the host-pathogen interactions.
00:13:1019 So, that's under the left circle, here.
00:13:1413 We also started to realize the endogenous microbiome -- the plant also has a microbiome --
00:13:1900 has tremendous effect on host-pathogen interactions.
00:13:2121 So, these are new directions.
00:13:2227 I'm gonna highlight one particular area, which is involving how environmental conditions
00:13:2817 could influence the disease interactions, okay?
00:13:3124 So, we are focusing on two areas.
00:13:3427 One is the temperature, how elevated temperatures could influence disease.
00:13:3909 This is actually very relevant right now with climate change.
00:13:4216 The globe is warming.
00:13:4411 But also, more importantly, the heat waves we're experiencing in different countries
00:13:4906 are very severe right now. and how these short periods of heat waves could influence infection.
00:13:5526 Okay, so this is one of my students, Bethany Huot, who recently published a paper
00:14:0020 just showing very simply. you can see under. we grow plants the same way, okay?,
00:14:0515 but during infection we put the plants in 23 degrees, which is the normal temperature, or you shift
00:14:1104 5 degrees up, to 28 degrees, you can see dramatic differences already.
00:14:1508 At the warm temperature, you see much more severe disease, okay?
00:14:1920 She discovered this is based on two mechanisms.
00:14:2221 One is the warm temperature actually enhances greatly the virulence expression.
00:14:2628 So, the effector secretion into the plants is greatly enhanced.
00:14:3205 But also, she discovered that the immune signaling in the host is completely shut down.
00:14:3721 So, this is actually very important in the field, you know.
00:14:4021 The immune pathway that she was working on is called salicylic acid signaling,
00:14:4528 which is mimicking, like, the aspirin we take sometimes.
00:14:4800 It's a similar chemical.
00:14:4914 It boosts the immune response.
00:14:5117 This response is shut down by warm temperature.
00:14:5415 This could have a profound influence in the field, crop resistance, because most of the
00:14:5828 crop resistance is based on their signaling cascades.
00:15:0112 So, we don't know the details of this pathway.
00:15:0324 This is something we're gonna work out in the next few years.
00:15:0524 What I'm going to talk to you about in more detail is humidity's effect on plant disease,
00:15:1102 okay?
00:15:1202 This became, actually, obvious in our disease reconstitution experiment I mentioned in the
00:15:1512 beginning of my talk.
00:15:1621 We tried to figure out how many pathways are being manipulated by the bacterial pathogen.
00:15:2118 And ultimately, we want to create a poly mutant of the plant to see whether we can
00:15:2621 rescue the pathogenesis of a bacteria that does not, you know, deliver any of these effectors,
00:15:3112 okay?
00:15:3212 So, that's a very daunting task, but we. as scientists, we want to, you know,
00:15:3708 face the challenge and try to work it out.
00:15:3922 So, there are 30 of so effectors, I told you, in this particular bacterium, so we and others
00:15:4503 are systematically going through to identify the host target of each of these effectors,
00:15:4916 okay?
00:15:5016 A model that we and others have developed in the last, you know, 15 years or so about
00:15:5525 the function of these effectors is this, in a simple way.
00:15:5827 So, you're seeing a bacteria sitting on the plant cell wall.
00:16:0210 So, a plant cell, unlike an animal cell, has a cell wall surrounding it.
00:16:0518 But in the plasma membrane, which you can see, there are receptors.
00:16:0917 They're called immune receptors, that perceive these patterns from microbes, in this case,
00:16:1416 flagella, these wavy things, very common for bacteria.
00:16:1807 And once they sense these molecules, it then triggers a signal transduction pathway
00:16:2220 -- this is a very simple diagram -- eventually leading to a form of immunity called pattern-triggered immunity.
00:16:2906 So, this is bad for bacteria, so what bacteria are doing is to send these effectors
00:16:3406 into the plant cell to attack different steps of this signaling cascade, to shut down
00:16:3824 this form of immunity.
00:16:3924 It's a major mechanism of disease.
00:16:4305 And so, I'll just give you one example from a collaborative work from Cyril Zipfel's group
00:16:4811 and my laboratory, also, involving a particular effector called HopAO1.
00:16:5301 HopAO1 biochemically is a phosphatase, which removes phosphate from proteins.
00:16:5922 And it turns out these immune receptors are phosphorylated, normally, during activation
00:17:0414 at a tyrosine residue of the protein.
00:17:0711 And this effector actually removes the phosphate from tyrosine to shut down this immune activation.
00:17:1202 So, this is a very cute way of. you know, bacteria figured out how to kind of sabotage
00:17:1714 the immune signaling.
00:17:1818 And there are many studies to support this, very strong evidence that this is really true.
00:17:2310 So, one of the major functions of these virulence factors is to shut down the plant immune response, right?
00:17:2910 If there's no immunity response in the host then you can, you know, infect the plants.
00:17:3216 And this is very similar to human pathogenesis.
00:17:3503 And many of the bacterial pathogens are human pathogens that actually do the same thing.
00:17:3902 They're shutting down the immune system in our body, then infect.
00:17:4222 Okay, so our question is this.
00:17:4420 Are all these 30 or so effectors involved in immune suppression?
00:17:4806 If they're all attacking, you know, immune suppression, then we can reconstitute the disease
00:17:5323 by using the immune compromised plants, right?
00:17:5627 So, I'm coming back to point. that point later.
00:17:5913 I've introduced you to two bacterial strains, now.
00:18:0210 I'm talking about the wild type strain, DC3000.
00:18:0517 It secretes these 30 or so effectors into the plant cell.
00:18:0813 There's a mutant called delta-28E, which has 28 of these 30 effectors deleted.
00:18:1427 It has involved a lot of work done by Alan Collmer's lab at Cornell University,
00:18:2102 but they did it, so it's a very useful mutant, and we take advantage of this mutant.
00:18:2520 Because this mutant has essentially no effectors that are delivered into the plant cell,
00:18:3004 it's not pathogenic.
00:18:3104 So, if you put into a wild type plant. you can see that on the left is infection by DC3000.
00:18:3612 It causes disease-like symptoms.
00:18:3809 But on the right is green it's a healthy plant.
00:18:4028 So, this mutant cannot cause disease in the wild type plants.
00:18:4522 If, as I said, all effectors are attacking the immune signaling, then if we start with
00:18:5122 immune defective plants, if there's no immunity in the plants, then this mutant, delta-28E,
00:18:5827 should be able to infect the plants, right?
00:19:0122 Okay, so that's the experiment we did.
00:19:0323 You can see that, unfortunately, the delta-28E mutant was unable to cause disease.
00:19:0914 You know, the plants are still kind of green after infection, okay?
00:19:1304 The mutants we used, fec and bbc, these are defective immune responses in the plants.
00:19:1816 So, the answer is no.
00:19:1928 Okay?
00:19:2028 So, you can also look at the bacterial population.
00:19:2221 So, when the plants are infected by Pseudomonas syringae, it multiplied really high.
00:19:2717 So, this is. the bar is in the logarithm. log-type scale, so each step is a tenfold increase.
00:19:3604 You can see that DC3000 aggressively multiplied inside the leaf.
00:19:4020 Versus the delta-28E in wild type and in mutant leaves, they are unable to achieve
00:19:4710 a very high population.
00:19:4810 So, there's no disease, so the answer is no.
00:19:5005 So, the question is, what are we missing?, right?
00:19:5226 So, some effectors must be attacking something other than immunity as a part of their mechanism.
00:19:5902 So, I'm gonna pull you away from my. our own results to tell you something about a website.
00:20:0522 So, if you're growing plants in your garden, this is actually for master gardeners,
00:20:1009 so anything written on this website must be true because you have to follow that.
00:20:1408 Okay, so you can see that I just took a few sentences out.
00:20:1805 It says, bacterial diseases are most intense in warm and humid conditions like Florida,
00:20:2326 okay?
00:20:2426 So, Florida actually has a lot of diseases compared to California.
00:20:2626 California is dry.
00:20:3002 You can recapitulate. this is actually famous idea called the "disease triangle" dogma.
00:20:3417 For a disease to occur, you not only need a planet which is susceptible genetically
00:20:3806 and a pathogen which would is virulent genetically, but you also need a conducive environment.
00:20:4226 One of the main factors is high humidity, okay, rains and things like that.
00:20:4727 This was formulated by a very famous plant pathologist, RB Stevens, 50 years ago.
00:20:5214 We actually don't know the molecular basis by which humidity is required for disease
00:20:5603 very much.
00:20:5808 You can recapitulate the humidity requirement in the laboratory.
00:21:0107 Basically, you can grow plants, you know, for four weeks.
00:21:0412 But during the infection period of three days, we either place the plants under high humidity,
00:21:0913 like 95% percent, which simulates the disease outbreak condition in the field, or you,
00:21:1502 you know, set up the plants at [30%], which is a low humidity.
00:21:1920 You can see that at high. and only at high humidity you have disease.
00:21:2216 At low humidity, plants look healthy.
00:21:2511 And you can look at the disease bacterial population, also.
00:21:2908 High humidity has a very high population, and under lower humidity you have very low.
00:21:3420 Okay, so it's a dramatic difference, okay?
00:21:3624 Now, if you go back to this website, you can also see a term called water soaking.
00:21:4202 This is describing the symptom of the disease of many bacterial diseases.
00:21:4524 Normally, if you look at leaves in your backyard you will see kind of, you know, green, okay?
00:21:5115 There's no spots, right?
00:21:5315 In this picture, you can see there's a lot of dark spots.
00:21:5518 These dark spots are caused by liquid in the leaf.
00:22:0017 And plants don't like that.
00:22:0117 I just how you been beginning, for photosynthesis to occur, for CO2 to diffuse into the mesophyll cell,
00:22:0610 you want to keep the apoplast air-filled.
00:22:0920 And in these dark spots, there's liquid in there.
00:22:1212 It's really bad for plants.
00:22:1321 But bacteria seems to be able to do this for a purpose.
00:22:1700 We are actually. so, phenomenon has been observed for many decades.
00:22:2022 We don't know whether it's needed for pathogenesis, okay?
00:22:2407 So, we were intrigued by this.
00:22:2611 This only occurred under high humidity, also.
00:22:2813 So, you can simulate this process in the laboratory.
00:22:3124 This is our Arabidopsis, again, infected by Pseudomonas syringae.
00:22:3610 You can see dark spots, here, on the right leaf, which is infected.
00:22:3919 On the left, that was not infected.
00:22:4125 This also occurred in tomato, because this bacteria also infected tomato.
00:22:4501 So, under high humidity, you have this so-called water soaking symptom.
00:22:4925 Now we can label bacteria to see where the bacteria are in the infected tissue by
00:22:5518 loading it with a luc. you know, lucs emit light. allow bacteria to emit light.
00:23:0028 So, you can catch the light emitted from bacteria in the infected tissue and then overlay this
00:23:0725 with the water soaking symptom that you capture with regular light.
00:23:1026 And if you see, in the bottom of the left leaf, we can see extensive overlap
00:23:1618 between the luc -- the light indicating bacteria -- and the water soaking spots, suggesting that
00:23:2417 the water soaked area is where bacteria multiply really highly, okay?
00:23:2723 So, that is really spatially kind of indicating water soaking is quite important.
00:23:3223 So, what causes the water soaking?
00:23:3502 Okay, I told you this bacteria produces 30 or so effectors.
00:23:3814 We actually screened each individual effector to see which one can cause water soaking.
00:23:4314 In this experiment, we show that two of them can cause water soaking.
00:23:4716 And the names are not very important, but I can show you that one is localized to
00:23:5120 the plant plasma membrane, here.
00:23:5401 One is localized to, actually, the endomembrane system in the plant cell, called the endosome,
00:23:5826 which is involved in recycling all the proteins to and off the plasma membrane of the plant cell.
00:24:0503 So, they're two. these two effectors are doing something to the plasma membrane
00:24:0806 of the plant cell to cause water soaking.
00:24:1124 We actually know a little bit more about one of these effectors.
00:24:1401 They actually attack a protein in the plants that regulates the vesicle traffic.
00:24:1902 So, it's a really intriguing phenomenon, also, because a lot of human pathogens also do that,
00:24:2504 attack proteins that are involved in vesicle trafficking in our human cells as a way to
00:24:2923 shutting down the immune system.
00:24:3201 Okay.
00:24:3301 So, now we have. in addition to the immune suppression process, we discovered a new process
00:24:3814 we called aqueous apoplast, which is the inside of the leaf accumulating, basically,
00:24:4317 water and other things.
00:24:4511 Okay?
00:24:4611 So, in order to cause water soaking, you need the so-called water soaking effectors
00:24:5026 from bacteria.
00:24:5126 But that's not sufficient.
00:24:5226 You also need high humidity in the air.
00:24:5523 The reason is that in the low humidity, even if the bacteria are producing water soaking symptoms,
00:25:0105 it will be evaporated out through stomata, because stomata are open during the
00:25:0424 day for. to take up CO2.
00:25:0722 And because of that, if you have low humidity, the water just comes right out.
00:25:1118 And because there's no water, then the bacteria will not benefit.
00:25:1416 So, here's an example where we need variance factors in the bacteria and we need
00:25:1818 the external environment to be humid, okay?
00:25:2005 So, this is kind of interesting.
00:25:2228 So now, the question.
00:25:2328 The next question we want to ask is. okay, we have two processes now.
00:25:2711 We know that immune suppression is not sufficient for pathogenesis.
00:25:3100 Now we have two. are they sufficient, now, for pathogenesis?
00:25:3500 So, this is a disease reconstitution experiment we always wanted to do.
00:25:3915 So, we can simulate the suppression of the immune response in the plant by using
00:25:4614 this mutant of Arabidopsis that is unable to mount an immune response.
00:25:5000 We can also mimic the water accumulation in the apoplast by using this new mutant
00:25:5506 that we have, called min7, okay?
00:25:5708 The idea is to combine these two process by genetically manipulating the two pathways.
00:26:0307 Using CRISPR/Cas9 technology, we created quadruple mutants, basically affecting both immunity
00:26:0926 and water homeostasis.
00:26:1127 So, the question is that, in these quadruple mutants, would bacteria that normally
00:26:1725 cannot deliver any effectors. is going to multiply or not, okay?
00:26:2202 So, this is the experiment we did.
00:26:2409 So, the bacterial mutant we use is the bacteria that are unable to secrete any of these effectors,
00:26:2825 that's defective in type III secretion, okay?
00:26:3106 In the wild type plants, they don't cause disease.
00:26:3406 It's green plants.
00:26:3527 In these immune-defective mutants, it still does not cause disease, as I showed you before,
00:26:4106 okay?
00:26:4206 So, it's not sufficient.
00:26:4313 In a min7 plant, also, it does not cause disease.
00:26:4617 In the quadruple mutants, now, you can see disease-like symptoms.
00:26:5011 And this is actually when we're seeing a non-pathogenic bacteria cause any disease on a plant system.
00:26:5619 So this is pretty exciting to us.
00:26:5824 If you look at the bacterial population in these leaves, you can see that the red bars
00:27:0310 are indicating the quadruple mutants.
00:27:0515 Only in these two quadruple mutants, you can start to see the multiplication of an otherwise
00:27:1011 non-pathogenic bacteria, okay?
00:27:1217 So, it's not to the extent of the totally wild type infection, so we have some distance to go,
00:27:1608 but this is a quite significant step.
00:27:1825 So, summarizing this part of my talk, we have identified a new pathogenic process involving
00:27:2527 what we called aqueous living space.
00:27:2904 We know bacteria loves water because, you know, human pathogens and plant pathogens
00:27:3405 all love water, right?
00:27:3513 So. but this is a case where bacteria actually create water conditions in an otherwise air-filled space.
00:27:4322 And if you think about whether this is relevant to, you know, other diseases,
00:27:4709 including human diseases like a lung infection and the respiratory system, which is normally filled with the air.
00:27:5312 so, we will see whether this principle will go beyond plant diseases, okay?
00:27:5717 We were able to reconstitute the basic features of a bacterial infection within
00:28:0302 exclusively host mutants, okay?
00:28:0503 So, that's also the first time we've done this.
00:28:0802 Of course, we're getting some insight into why humidity could have profound influence
00:28:1208 on the disease interactions.
00:28:1513 In this case, because it's required for the virulence factors to function as virulence factors.
00:28:2104 So now, I'd like to acknowledge the people that actually did the work.
00:28:2407 Of course, my lab members at Michigan State.
00:28:2801 And I also want to acknowledge a number of collaborators: Jeff Chang, Cyril Zipfel.
00:28:3425 Also other investigators that I collaborated with for the other part of my talk.
00:28:4024 Funding are from HHMI, Gordon and Betty Moore Foundation, NIH, DOE, USDA,
00:28:4624 and the National Science Foundation.
00:28:4902 Thank you.

  • Part 1: Introduction to Plant-Pathogen Interactions

Horiguchi Lab /Division of Infectious Disease Department of Molecular Bacteriology

Some pathogenic bacteria cause specific disease symptoms including flaccid/spastic paralyses, paroxysmal coughing, skin exfoliation, and osteogenesis imperfecta, besides general symptoms such as fever and inflammation. Our major questions are as to how these specific symptoms appear in response to bacterial infections or what kinds of bacterial virulence factors are involved in them. We hope that we will understand the nature of bacterial infections by answering these questions.

To understand the mechanism of infection

Bordetella pertussis, which is one of our research subjects is a representative pathogenic bacteria of Bordetella and causes whooping cough. In addition to B. pertussis, B. parapertussis and B. bronchiseptica are categorized in the genus Bordetella. Although these pathogenic organisms share homologous virulence factors and commonly cause respiratory infections with characteristic coughing, their host specificities and the course of disease manifestation are quite different: B. pertussis is a strict human pathogen causing the acute disease whereas B. bronchiseptica infects a wide range of mammals and causes chronic infections. We are trying to understand what determines host specificities and distinct disease manifestations in Bordetella infections. Understanding the molecular mechanism by which the bacteria cause coughing in hosts is our another goal of the Bordetella research.

Analyzing the structure-function relationship of bacterial protein toxins.

Bacterial protein toxins cause a variety of specific symptoms manifested in bacterial infections. Many bacterial protein toxins are essentially multifunctional biomolecules, which travel in a host body, bind to target molecules or cells, and modify target molecules with high specificity. Some bacterial toxins are known as the most poisonous substances on the earth. We are analyzing the structure-function relationship of these bacterial protein toxins to understand how they exert such powerful toxicities on target cells and intoxicated animals. We believe that these results should give an insight into the mechanism causing specific symptoms observed in bacterial infections.

To achieve the above-mentioned goals, we are conducting the research work by using every experimental technique based on bacteriology, molecular and cellular biology, biochemistry, medical and veterinary science.

Watch the video: ΠΑΘΟΓΟΝΟΙ ΜΙΚΡΟΟΡΓΑΝΙΣΜΟΙ (January 2022).