How does your body know when it is infected so it can invoke a fever?

How does your body know when it is infected with a virus or bacteria so it can invoke a fever or ramp up the immune system?

During infection certain macromolecules present in the pathogens (pathogen associated molecular patterns) such as lipopolysaccharide launch the innate immune response, through toll like receptors. This leads to production of pro-inflammatory cytokines and also other inflammatory mediators like prostaglandins, thereby causing inflammation and fever.

An opinion by non-technical observer.

If you know the function of a hive, you know that bees communicate with each other, touching and rubbing chemical information. In a few minutes the information reaches the center of the hive and returns to individuals which are caring of it. It is widely accepted that a hive is a unique individual, composed of thousands of insects each with its own function.

I believe that we can make the observation reverse. The man (and animals) are agglomerations of cells that pass chemically information to each other. Information reaches the central system, which responds by activating the necessary functions.

In case of infection, viral or bacterial, blood flow to the affected place very quickly, scrolling faster and thus raising the temperature. Similarly in the blood activates the necessary antibodies, which communicate with each other chemically referring where necessary. Pile up in the affected areas, resulting in swelling.

Other functions, such as sweating, vomiting or pus, are ways to excrete toxins (such should not be blocked). If we imagine the human body as a great hive where each cell is a member that transmits information and responds to stimulation of central system, acting in cooperation, the operation according to me is very clear.

How do the bees know that they are dying, if not passing to collecting companions honey too thick? Sorry for non-technical opinion, if not useful delete it.

COVID-19, the illness caused by the coronavirus, starts with droplets from an infected person’s cough, sneeze, or breath. They could be in the air or on a surface that you touch before touching your eyes, nose, or mouth. That gives the virus a passage to the mucous membranes in your throat. Within 2 to 14 days, your immune system may respond with symptoms including:

  • Fever
  • A cough
  • Shortness of breath or trouble breathing
  • Fatigue
  • Chills, sometimes with shaking
  • Body aches
  • Headache
  • A sore throat
  • Congestion or a runny nose
  • Loss of taste
  • Loss of smell
  • Nausea or vomiting
  • Diarrhea

The virus moves down your respiratory tract. That’s the airway that includes your mouth, nose, throat, and lungs. Your lower airways have more ACE2 receptors than the rest of your respiratory tract. So COVID-19 is more likely to go deeper than viruses like the common cold.

Your lungs might become inflamed, making it tough for you to breathe. This can lead to pneumonia, an infection of the tiny air sacs (called alveoli) inside your lungs where your blood exchanges oxygen and carbon dioxide.

If your doctor does a CT scan of your chest, they’ll probably see shadows or patchy areas called “ground-glass opacity.”

For most people, the symptoms end with a cough and a fever. More than 8 in 10 cases are mild. But for some, the infection gets more severe. About 5 to 8 days after symptoms begin, they have shortness of breath (known as dyspnea). Acute respiratory distress syndrome (ARDS) begins a few days later.


ARDS can cause rapid breathing, a fast heart rate, dizziness, and sweating. It damages the tissues and blood vessels in your alveoli, causing debris to collect inside them. This makes it harder or even impossible for you to breathe.

Many people who get ARDS need help breathing from a machine called a ventilator.

As fluid collects in your lungs, they carry less oxygen to your blood. That means your blood may not supply your organs with enough oxygen to survive. This can cause your kidneys, lungs, and liver to shut down and stop working.

Not everyone who has COVID-19 has these serious complications. And not everyone needs medical care. But if your symptoms include trouble breathing, get help right away.

Fever Increases Immune System Defense, Study Shows

A new study adds more reason to why our bodies employ fevers as a defense against sickness.

Researchers from Roswell Park Cancer Institute found that a higher body temperature can help our immune systems to work better and harder against infected cells. The finding was published in the Journal of Leukocyte Biology.

"Having a fever might be uncomfortable, . but this research report and several others are showing that having a fever is part of an effective immune response," John Wherry, Ph.D., deputy editor of the Journal of Leukocyte Biology, said in a statement.

Before, researchers thought that fevers worked by hindering dangerous microbes from multiplying, Wherry said.

But "this new work also suggests that the immune system might be temporarily enhanced functionally when our temperatures rise with fever," he said in the statement, though he noted that the finding should only prompt people to reconsider how they treat mild fevers, and not fevers that are dangerously high.

The secret is in a kind of immune cell, or lymphocyte, called a CD8+ cytotoxic T-cell. This kind of lymphocyte is able to destroy cells infected with viruses and even tumor cells, researchers said. Researchers found that a higher body temperature (like one achieved in a fever) raises the number of these CD8+ cytotoxic T-cells, which means a greater body response against infection.

To find this, researchers injected mice with an antigen and saw how the CD8+ cytotoxic T-cells activated to react to the antigen. Then, they raised the body temperatures of half the mice by 2 degrees centigrade, while leaving the temperatures of the other = mice alone. They found that the mice whose body temperatures were raised had more of the CD8+ cytotoxic T-cells than the mice without raised body temps.

The rise in mouse's body temperature is "similar to that that happens in fever," study researcher Elizabeth Repasky told the Toronto Star.

University of Pittsburgh Medical Center clinical associate professor Dr. Amesh A. Adalja, who wasn't involved with the study, told MSNBC that the finding shouldn't mean a fever should never be treated because too-high fevers can lead to brain cell damage. Parents should still take care to lower fevers in children, particularly if the fever is above 102 degrees Fahrenheit, since high fever can lead to seizures, Adalja told MSNBC.

Adalja also warns it"s also not worth the risk to your own health if you have heart disease, have suffered a stroke or endure other medical complications. "This is not a blanket recommendation," he says. "Secondary consequences to the fever can cause other conditions in the patient to occur or worsen. If someone has a persistent fever of 104, it's a sign of infection, and it"s not just some viral thing you are going to get over."

This is certainly not the first research to suggest that fevers ramp up our body's immune responses. Discover magazine reported in 2007 on another Roswell Park Cancer Institute mouse study, which showed that mice that were heated up produced more immune cells to fight disease than mice that weren't heated.

What is pneumonia?

Pneumonia is an acute inflammatory response deep in the lungs, in the alveoli. When a tissue is infected or injured, there is an inflammatory response that is, in the simplest sense, an accumulation of pus. When the deep lungs are injured or infected, pus accumulates there. Pus in the alveoli is pneumonia.

Pneumonia is caused by an infection, and a wide variety of microbes can infect the lungs. Most of the time, pneumonia is caused by viruses or bacteria, but fungi and other microbes can be responsible. SARS-CoV-2 emerged in 2019 and became pandemic in 2020 and is currently an especially pressing cause of pneumonia, COVID-19. Other viral causes include influenza viruses, respiratory syncytial viruses, and more. The most common cause of community-acquired bacterial pneumonia is the pneumococcus (Streptococcus pneumoniae). Hospital-acquired pneumonia often results from other bacteria including Klebsiella pneumoniae, Pseudomonas aeruginosa, E. coli, or Staphylococcus aureus.

In a healthy lung, inhaled air flows through the airways and alveolar ducts to the alveoli. The alveoli are air sacs surrounded by very thin walls containing blood. At this site, gases (oxygen and carbon dioxide) exchange between air and blood.

The response to infection – the pus accumulating in the lungs – is crucial to outcome. This pus contains blood elements, white blood cells (particularly a group of cells called neutrophils) and plasma proteins (particularly a group of proteins called opsonins). These cells and proteins are essential to killing the microbes and overcoming infection. Therefore, when we have pneumonia, we have to get these cells and proteins to where the microbes are, in the lungs, or we may succumb to the infection. However, this same pus is dangerous. Neutrophils make toxic and degradative products that are useful in killing microbes, but they can also damage the lungs. An example is hypochlorite, the active chemical in bleach, which is synthesized by neutrophils in pneumonic lungs – good for killing bacteria, but not so great for lung cells. In addition, the accumulation of plasma proteins results in a fluid build-up in the lungs, called pulmonary edema. Pulmonary edema makes it harder to breathe and harder for oxygen and carbon dioxide to pass between blood in the lungs and inhaled air, as these gases need to do for the body to function. Therefore, regulation of this accumulation of pus is critical we need enough to fight the microbes, but not so much that our lungs have trouble working properly.

There's no way to avoid breathing in spores. But you can do a few things to lower your chances of mucormycosis. It's especially important if you have a health condition that raises your risk.

Stay away from areas with a lot of dust or soil, like construction or excavation sites. If you have to be in these areas, wear a face mask like an N95.

Avoid infected water. This can include floodwater or water-damaged buildings, especially after natural disasters like hurricanes or floods.

If you have a weakened immune system, avoid activities that involve dust and soil, like gardening or yard work. If you can't, protect your skin with shoes, gloves, long pants, and long sleeves. Wash cuts or scrapes with soap and water as soon as you can.

If you get mucormycosis, be sure to take your medications as directed. If side effects cause problems or the infection doesn't get better, let your doctor know right away.


CDC: “About Mucormycosis,” “People at Risk & Prevention,” “Mucormycosis statistics,” “Diagnosis and Testing for Mucormycosis,” “Symptoms of Mucormycosis,” “Treatment for Mucormycosis.”

National Organization for Rare Disorders: “Mucormycosis.”

Journal of Medical Cases: “Rhinocerebral Mucormycosis and COVID-19 Pneumonia.”

Evaluation of Fever in Adults

Usually, a doctor can determine that an infection is present based on a brief history, a physical examination, and occasionally a few simple tests, such as a chest x-ray and urine tests. However, sometimes the cause of fever is not readily identified.

When doctors initially evaluate people with an acute fever, they focus on two general issues:

Identifying other symptoms such as headache or cough: These symptoms help narrow the range of possible causes.

Determining whether the person is seriously or chronically ill: Many of the possible acute viral infections are difficult for doctors to diagnose specifically (that is, to determine exactly which virus is causing the infection). Limiting testing to people who are seriously or chronically ill can help avoid many expensive, unnecessary, and often fruitless searches.

Warning signs

In people with an acute fever, certain signs and characteristics are cause for concern. They include

A change in mental function, such as confusion

A headache, stiff neck, or both

Flat, small, purplish red spots on the skin (petechiae), which indicate bleeding under the skin

Rapid heart rate or rapid breathing

Shortness of breath (dyspnea)

A temperature that is higher than 104° F (40° C) or lower than 95° F (35° C)

Recent travel to an area where a serious infectious disease such as malaria is common (endemic)

Recent use of drugs that suppress the immune system (immunosuppressants)

When to see a doctor

People who have any warning signs should see a doctor right away. Such people typically need immediate testing and often admission to a hospital.

People without warning signs should call the doctor if the fever lasts more than 24 to 48 hours. Depending on the person's age, other symptoms, and known medical conditions, the doctor may ask the person to come for evaluation or recommend treatment at home. Typically, people should see a doctor if a fever lasts more than 3 or 4 days regardless of other symptoms.

What the doctor does

Doctors first ask questions about the person's symptoms and medical history. Doctors then do a physical examination. What they find during the history and physical examination often suggests a cause of the fever and the tests that may need to be done.

A doctor begins by asking a person about present and previous symptoms and disorders, drugs currently being taken, any blood transfusions, exposure to infections, recent travel, vaccinations, and recent hospitalizations, surgeries, or other medical procedures. The pattern of the fever rarely helps the doctor make a diagnosis. However, a fever that returns every other day or every third day is typical of malaria. Doctors consider malaria as a possible cause only if people have traveled to an area where malaria is common.

Recent travel may give the doctor clues to the cause of a fever because some infections occur only in certain areas. For example, coccidioidomycosis (a fungal infection) occurs almost exclusively in the southwestern United States.

Recent exposures are also important. For example, people who work in a meatpacking plant are more likely to develop brucellosis (a bacterial infection spread through contact with domestic animals). Other examples include unsafe water or food (such as unpasteurized milk and milk products, and raw or undercooked meat, fish, and shellfish), insect bites (such as ticks or mosquitoes), unprotected sex, and occupational or recreational exposures (such as hunting, hiking, and water sports).

Pain is an important clue to the possible source of fever, so the doctor asks about any pain in the ears, head, neck, teeth, throat, chest, abdomen, flank, rectum, muscles, and joints.

Other symptoms that help determine the cause of the fever include nasal congestion and/or discharge, cough, diarrhea, and urinary symptoms (frequency, urgency, and pain while urinating). Knowing whether the person has enlarged lymph nodes or a rash (including what it looks like, where it is, and when it appeared in relation to other symptoms) may help the doctor pinpoint a cause. People with recurring fevers, night sweats, and weight loss may have a chronic infection such as tuberculosis or endocarditis (infection of the heart's lining and usually the heart valves).

The doctor may also ask about the following:

Contact with anyone who has an infection

Any known conditions that predispose to infection, such as HIV infection, diabetes, cancer, organ transplantation, sickle cell disease, or heart valve disorders, particularly if an artificial valve is present

Any known disorders that predispose to fever without infection, such as lupus, gout, sarcoidosis, an overactive thyroid gland (hyperthyroidism), or cancer

Use of any drugs that predispose to infection, such as cancer chemotherapy drugs, corticosteroids, or other drugs that suppress the immune system

Use of illicit drugs that are injected

The physical examination begins with confirmation of fever. Fever is most accurately determined by measuring rectal temperature. Then the doctor does a thorough examination from head to toe to check for a source of infection or evidence of disease.


The need for testing depends on what the doctor finds during the medical history and physical examination.

Otherwise healthy people who have an acute fever and only vague, general symptoms (for example, they feel generally ill or achy) probably have a viral illness that will go away without treatment. Therefore, they do not require testing. Exceptions are people who have been exposed to an animal or insect that carries and transmits a specific disease (called a vector), such as people with a tick bite, and people who have recently been in an area where a particular disorder (such as malaria) is common.

If otherwise healthy people have findings that suggest a particular disorder, testing may be needed. Doctors select tests based on those findings. For example, if people have a headache and stiff neck, a spinal tap (lumbar puncture) is done to look for meningitis. If people have a cough and lung congestion, a chest x-ray is done to look for pneumonia.

People who are at increased risk of infection, people who appear seriously ill, and older people often need testing even when findings do not suggest a particular disorder. For such people, doctors often do the following:

A complete blood count (including the number and proportion of different types of white blood cells)

An increase in the white blood cell count usually indicates infection. The proportion of different types of white blood cells (differential count) gives further clues. For example, an increase in neutrophils suggests a relatively new bacterial infection. An increase in eosinophils suggests the presence of parasites, such as tapeworms or roundworms. Also, blood and other body fluids may be sent to the laboratory to try to grow the microorganism in a culture. Other blood tests can be used to detect antibodies against specific microorganisms.

Fever of unknown origin (FUO)

A fever of unknown origin may be diagnosed when

People have a fever of at least 101° F (38.3° C) for several weeks

Extensive investigation does not detect a cause

In such cases, the cause may be an unusual chronic infection (such as tuberculosis, bacterial infection of the heart, HIV infection, cytomegalovirus, or Epstein-Barr virus) or something other than an infection, such as a connective tissue disorder (such as lupus or rheumatoid arthritis) or cancer (such as lymphoma or leukemia). Other causes include drug reactions, blood clots (deep vein thrombosis), inflammation of organ tissues (sarcoidosis), and inflammatory bowel disease. In older people, the most common causes of FUO are giant cell arteritis, lymphomas, abscesses, and tuberculosis.

Doctors usually do blood tests, including a complete blood cell count, blood cultures, liver blood tests, and tests to check for connective tissue disorders. Other tests, such as chest x-ray, urinalysis, and urine culture, may be done.

Ultrasonography, computed tomography (CT), or magnetic resonance imaging (MRI), particularly of areas that are causing discomfort, may help a doctor diagnose the cause. Radionuclide scanning, done after white blood cells labeled with a radioactive marker are injected into a vein, may be used to identify areas of infection or inflammation.

If these test results are negative, doctors may need to take a sample of tissue from the liver, bone marrow, or another site of suspected infection for biopsy. The sample is then examined under a microscope, cultured, and analyzed.

The treatment of FUO is focused on treating the disorder causing the fever if it is known. Doctors may give drugs to lower the body temperature (see treatment of fever).

Sexually Transmitted Bacterial Infections

Many sexually transmitted diseases (STDs) are caused by harmful bacteria. Sometimes, these infections aren't associated with any symptoms but can still cause serious damage to the reproductive system. Common STDs caused by bacterial infections include:

  • Chlamydia is an infection in men and women caused by an organism called Chlamydia trachomatis. Chlamydia increases the risk of pelvic inflammatory disease (PID) in women.
  • Gonorrhea, also known as "clap" and "the drip," is caused by Neisseria gonorrhoeae. Men and women can be infected. Gonorrhea also increases the risk of pelvic inflammatory disease (PID) in women.
  • Syphilis can affect men and women and is caused by the bacteria Treponema pallidum. Untreated, syphilis is potentially very dangerous and can even be fatal.
  • Bacterial vaginosis, which causes an overgrowth of pathogenic bacteria in the vagina (the CDC does not consider this a STD see second text reference).

Much more than just the flu

When the coronavirus first hit the United States early this year, public health officials insisted that influenza was a bigger danger, killing at least 12,000 Americans a year.

But the new virus quickly revealed itself to be so much worse.

COVID-19, the disease caused by the coronavirus, is exponentially more complex and deadlier than the seasonal flu. In just seven months, more than 170,000 Americans have died of the novel infection.

Initially, experts thought COVID-19 was primarily a respiratory illness, infecting the nose, throat, and lungs, like flu viruses.

Now, it’s clear that this new germ can harm the brain, heart, circulatory system, liver, pancreas, and kidneys, as well as the lungs.

Here is an organ-by-organ tour of what the coronavirus can do to the human body.

The respiratory system

The coronavirus first takes hold in the upper respiratory tract — the nose, mouth, throat — and can provoke the same symptoms seen in other respiratory infections, notably fever and cough.

But the virus can also work its way deep into the lungs’ tiny air sacs. Those air sacs are loaded with ACE2, the protein that the coronavirus uses as a gateway into cells, where it replicates and emerges to infect adjacent cells.

Severe infection can lead to pneumonia as the lung tissue fills with fluid and pus, reducing the air sacs’ ability to transfer oxygen into the blood. This can progress to acute respiratory distress that requires treatment with mechanical ventilation.

COVID-19 pneumonia is distinct from other viral pneumonias. One study found that COVID-19 patients have characteristic “ground glass” opaque spots on their chest CAT scans, and are more likely to have pneumonia in both lungs rather than one. Often, their lab tests point to abnormalities in other organs, particularly the liver.

The lungs can also be damaged by two other uniquely awful features of COVID-19: the immune system overreaction, or cytokine storm. And excessive blood clotting.

The circulatory system

The cells that line blood vessels throughout the body help regulate blood pressure, inflammation, and clotting. These “endothelial” cells also produce ACE2, the surface protein that the coronavirus uses to break in.

This viral invasion sets off a cascade of destruction, as researchers explained in May in Nature Reviews Immunology. Vessels become leaky, the lungs fill with fluid, and the blood thickens and clots. All of this is intensified by inflammation — normally the immune system’s healing response to injury.

Some scientists now view COVID-19 as primarily a vascular disease, not a respiratory illness. That could explain some of the strange complications, particularly blood clots that have caused heart attacks, strokes, and limb tissue death that led to amputations, even in previously healthy young adults. Circulatory problems could also help explain why preexisting hypertension, diabetes, and heart disease raise the risk of severe COVID-19. It might even explain reddish-purplish toe rashes, dubbed “COVID toes.”

The heart

Blood clots generated by the coronavirus can block a heart vessel, triggering a heart attack.

But there is mounting evidence that COVID-19 can damage the heart, sometimes fatally, in a completely different way: by causing inflammation of the heart muscle, or myocardium.

The condition, called myocarditis, is a recognized complication of some other viral infections, and it usually goes away with rest. But it can also cause temporary or permanent heart problems, including abnormal rhythms, progressive heart failure, even sudden cardiac death.

In hospitalized COVID-19 patients, myocarditis is relatively common — affecting 7% to 23% of intensive-care patients, studies suggest — and dramatically increases the risk of death.

But in rare, unpredictable cases, myocarditis develops in elite athletes, even though they appear to have recovered from a coronavirus infection. That’s one reason sports leagues at all levels have debated whether to suspend competition during the pandemic. A recent cautionary case was Michael Ojo, 27, a former Florida State University basketball player who collapsed and died while training in Serbia. He had reportedly tested positive for COVID-19 and recuperated.

The brain and central nervous system

When a coronavirus-related blood clot blocks or bursts a vessel in the brain, the severing of the blood supply — better known as a stroke — begins to kill brain cells in minutes. This may impair speech, movement, and thinking, depending on the location and severity of the stroke.

But the virus can also interfere with brain signaling, in ways that are not yet understood. An early clue to this insidious effect: COVID-19 often causes temporary loss of smell and taste, usually without nasal congestion.

Recent studies and surveys have tied more serious, long-lasting psychiatric and neurological complications to COVID-19, including psychosis, PTSD, depression, dizziness, nerve damage, and a dementia-like syndrome.

However, the link is not clear-cut many of these complications are also aftereffects of intensive-care and life-supporting devices.

The renal system

Initial reports from China, where the coronavirus first emerged, suggested that kidney damage was rare, and found mostly in people with underlying kidney problems due to diabetes or other chronic illnesses.

But researchers mining more recent data from New York City found that more than a third of patients admitted to the hospital developed acute kidney injury. Among those who needed intensive care, 78% had kidney damage, and 35% needed dialysis.

Why are these vital blood-filtering organs so vulnerable? Johns Hopkins University nephrologist C. John Sperati explains that research points to four possibilities: The virus can directly invade kidney cells. Low levels of oxygen in the blood, an inevitable part of severe COVID-19, can damage the kidneys. Clots generated by the virus can clog the kidneys. And fallout from the immune system overreaction (cytokine storm) can trigger kidney failure.

The liver

What the coronavirus does to this organ is a particular mystery. Some hospitalized COVID-19 patients have abnormally high levels of liver enzymes, indicating at least temporary damage.

However, it is not clear whether this is related directly to the infection, or to other factors, according to the U.S Centers for Disease Control and Prevention.

And while it’s reasonable to assume that COVID-19 patients who already have chronic liver diseases such as cirrhosis or hepatitis B would be at higher risk of serious liver damage, the CDC says “more research is needed” to prove it.

The gastrointestinal system

Doctors have come to realize that nausea, vomiting, and diarrhea — although not the usual symptoms of COVID-19 — may be part of the disease. What’s more, numerous studies have found at least circumstantial evidence that the coronavirus can infect the digestive system, including the pancreas, which regulates blood sugar.

The evidence includes finding viral RNA in human feces, imaging scans showing bowel abnormalities, a correlation between digestive symptoms and a positive stool test, a review of 52 COVID-19 cases that found 17% had pancreatic injury, and a case report of a woman diagnosed with pancreatitis (sudden inflammation of the pancreas) who turned out to have COVID-19.

“Our understanding of clinical manifestations of COVID-19 continues to progress, and this case illustrates that [the coronavirus] can precipitate acute pancreatitis,” wrote the authors, led by Mark M. Aloysius of Geisinger Commonwealth School of Medicine in Scranton.

Scientific understanding of the coronavirus is evolving at warp speed (which is also the name of the federal government’s vaccine initiative). An avalanche of studies have been published in the past seven months, reshaping assumptions and advice. We now know the virus can be spread by infected people with no symptoms. It can hang in the air, like pollen, and be inhaled. Its transmission can be reduced by wearing masks.


Your immune system will kick into action should you show symptoms of COVID-19 in fact, a fever, one of the telltale signs, is a product of your body trying to fight the virus.

The Rx: Don't miss these 13 Early Signs You've Caught Coronavirus so you know when to ask for help. As for yourself: To get through this pandemic at your healthiest, don't miss these 35 Places You're Most Likely to Catch COVID .

How the strep bacterium hides from the immune system

The graphical abstract: pathogen Group A Streptococcus camouflaging as red blood cells. Credit: Dorota Wierzbicki

A bacterial pathogen that causes strep throat and other illnesses cloaks itself in fragments of red blood cells to evade detection by the host immune system, according to a study publishing December 3 in the journal Cell Reports. The researchers found that Group A Streptococcus (GAS) produces a previously uncharacterized protein, named S protein, which binds to the red blood cell membrane to avoid being engulfed and destroyed by phagocytic immune cells. By arming GAS with this form of immune camouflage, S protein enhances bacterial virulence and decreases survival in infected mice.

"Our study describes a completely novel mechanism for immune evasion," says corresponding author David Gonzalez of the University of California, San Diego. "We believe the discovery of this previously overlooked virulence factor, S protein, has broad implications for development of countermeasures against GAS."

GAS is a human-specific pathogen that can cause many different infections, from minor illnesses to very serious and deadly diseases. Some of these conditions include strep throat, scarlet fever, a skin infection called impetigo, toxic shock syndrome, and flesh-eating disease. An estimated 700 million infections occur worldwide each year, resulting in more than half a million deaths. Despite active research, a protective vaccine remains elusive.

To date, penicillin remains a primary drug of choice for combatting GAS infections. But the rate of treatment failures with penicillin has increased to nearly 40% in certain regions of the world. "Due to the high prevalence of GAS infection and the decreasing efficacy of the available set of countermeasures, it is critical to investigate alternative approaches against GAS infection," Gonzalez says.

One alternative approach is to develop novel anti-virulence therapeutics. To avoid immune clearance, GAS expresses a wide variety of molecules called virulence factors to facilitate survival during infection. But the function of many of these proteins remains unknown, hindering the development of alternative pharmacological interventions to combat widespread antibiotic resistance.

To address this gap in knowledge, Gonzalez and co-first authors Igor Wierzbicki and Anaamika Campeau of the University of California, San Diego, used a nanotechnology-based technique called biomimetic virulomics to identify proteins that are secreted by GAS and bind to red blood cells. This approach revealed a previously uncharacterized protein, which the researchers named S protein, because this type of protein is limited to members of the Streptococcus genus.

The researchers found that a mutant bacterial strain lacking S protein was less able to grow in human blood, and less able to bind to red blood cells, compared to the non-mutated strain. The mutant strain was also more readily captured and killed by phagocytic immune cells called macrophages and neutrophils. In addition, the absence of S protein vastly reshaped the bacterial protein landscape, decreasing the abundance of many known virulence factors.

Moreover, mice infected with GAS cells coated with red blood cells showed a 90% mortality rate, compared to 40% of mice infected with uncoated GAS cells. Infection with coated GAS cells also caused a more rapid decrease in body weight. "These findings suggest that S protein co-opts red blood cell membranes for molecular mimicry, or imitation of host molecules, to evade the immune response," Gonzalez says.

Additional experiments showed that infection with GAS caused a progressive decline in the body weight of mice and a 90% mortality rate. By contrast, all mice infected with mutant GAS lacking S protein survived infection, and their body weight stabilized and remained constant after a slight initial decline. Infection with mutant GAS also resulted in a lower concentration of bacteria in the bloodstream and organs, and promoted a robust immune response and immunological memory.

"Taken together, the results suggest that inactivation of S protein function makes GAS vulnerable to host immunity," Gonzalez says. "S protein influences virulence by capturing lysed red blood cell membranes to cloak the bacterial cell surface, which allows bacteria to circumvent host immunity. This novel evasion mechanism can be targeted for anti-streptococcal therapies."

Currently, Gonzalez and his team are examining the mechanism by which S protein binds to red blood cells. They are also studying the role that S protein plays in other important human pathogens, including Streptococcus pneumoniae, which causes pneumonia and other illnesses, as well as Group B Streptococcus or S. agalactiae—a bacterium that is a common cause of severe infections in newborns during the first week of life.

"Ultimately, the findings could lead to the development of a novel vaccine candidate," Gonzalez says. "Because of its pivotal roles in pathogenesis and immune evasion, and its conserved nature in Streptococci, S protein shows promising clinical potential as a target for the development of anti-virulence pharmacological interventions."