Certain intestinal bacteria induce cross-reactive IgA responses to the SARS-CoV-2 spike RBD

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the virus responsible for the coronavirus disease 2019 (COVID-19), infects the human host cell via its spike antigen. Most neutralizing antibodies against SARS-CoV-2 that have been thus far discovered interact with sites on this spike glycoprotein, especially the receptor-binding domain (RBD).

A new study published finds that human gut bacteria can induce antibodies of the immunoglobulin A (IgA) subtype that cross-react with the SARS-CoV-2 spike RBD.

Antibody response to SARS-CoV-2

The SARS-CoV-2 spike antigen mediates attachment to the angiotensin-converting enzyme 2 (ACE2) receptor that is present on the surface of human cells. The interactions between SARS-CoV-2 and ACE2 primarily occur at the RBD; therefore, this protein is a vital target for viral neutralizing antibodies. Monoclonal antibodies to the RBD have been shown to protect the host against target cell infection.

The antibody response to the virus includes IgA, IgG, and IgM, all of which are found throughout the host system. These antibodies suppress the spread of the virus from infected cells. Mucosal antibodies such as IgA2, IgA2, and IgM can also effectively neutralize viral entry at the point of contact with the host, thus preventing productive infection.

Patients with severe COVID-19 have been shown to lack SARS-CoV-2-specific IgA2 antibodies, thereby suggesting that these antibodies are protective against severe disease. However, SARS-CoV-2-naïve individuals have also been found to have detectable levels of antibodies that bind to the RBD.

The antigens of commensal microflora

One potential explanation for this observation is that prior endemic seasonal human coronavirus infection induced the production of these antibodies. However, further studies are needed to confirm this hypothesis.

Previous studies have indicated that gastrointestinal (GI) commensals induce mucosal IgA responses. These microbiota contain millions of genes and, as a result, several million antibody-binding regions. Some of these regions, which are otherwise known as epitopes, may be similar or almost identical to host proteins, which can potentially induce autoimmunity.

Other epitopes may be cross-reactive to protein antigens from other pathogenic or non-pathogenic microbes, thereby inducing immunity to these microbes upon subsequent exposure. In fact, the gp41 of human immunodeficiency virus-1 (HIV-1) is a target of cross-reactive antibodies elicited by gut microbes.

Such microbial cross-reactive immunity has been established to protect the host against many pathogens including Clostridium difficile, Pseudomonas aeruginosa, and the influenza virus. Several different mechanisms have been postulated, including toning of the innate immune system by interferon I (IFN I) production or by cross-reactive antibody production.

What were the study findings?

In the current study, the researchers identified two individuals out of 12 healthy uninfected donors who were previously unexposed to SARS-CoV-2 as identified by the lack of anti-SARS-CoV-2 IgG antibodies in their sera. Despite the lack of antibodies present within their sera, these individuals were found to have fecal IgA antibodies that were reactive to the RBD of SARS-CoV02.

An additional 10 out of 21 donors with a history of severe COVID-19 were found to contain SARS-CoV-2 RBD-specific IgA in their stool. Interestingly, the anti-RBD IgA titer negatively correlated with the age of the donor.

Upon purification of the fecal IgA antibodies, the researchers found that the neutralizing activity was low. In fact, complete inhibition of ACE2-RBD binding was not observed, even at equimolar concentrations.

Notably, the IgA antibodies from some healthy donors with anti-RBD antibodies did not suppress ACE2-RBD interactions. Thus, uninfected individuals may have neutralizing and non-neutralizing IgA antibodies to the virus. Interestingly, while healthy donors had RBD-directed IgA2 antibodies in feces, those with severe COVID-19 lacked these antibodies.

Among the two groups of healthy donors with IgA1 and IgA2 antibodies coating the intestinal mucosa, only one group had anti-RBD IgA in stool. These two groups of patients showed IgA binding to two different sets of bacteria, indicating that RBD-IgA plays a major role in commensal recognition by mucosal IgA.

The researchers also found that most of the purified neutralizing anti-RBD antibodies in this study were bound to different commensal bacteria. The most commonly recognized was Bacteroides, with others binding to Clostridia, Streptococci, Escherichia, and Bifidobacteria. The bacteria Parabacteroides and Bilophila were also bound by anti-RBD IgA and RBD-specific IgG antibodies.

Salivary IgA of high titers bound to streptococcal and bacillary species was also identified. Thus, commensal microbes express protein antigens that cross-react with some neutralizing anti-RBD antibodies.

Bacteria induce RBD-targeting IgA

Following these observations, the authors then aimed to understand whether these bacteria could induce a cross-reactive antibody response to the viral RBD. To this end, many of these bacteria were, in fact, found to elicit anti-RBD IgG antibodies in mice. When challenged with the bacteria orally, the production of fecal IgA directed against the RBD was also induced.

The fecal supernatants from the latter mice were also found to successfully prevent ACE2-RBD binding. In fact, two bacterial species including B. pseudocatenulatum and S. salivarius elicited antibodies to the receptor-binding motif (RBM) of the RBD, which accounted for this inhibition.

In rabbits, the anti-RBD and the human IgA antibody CV07-200 showed overlapping peptide recognition patterns, with similar peptide sequences within the RBM.

“These data show that oral supplementation with S. salivarius K12 and B. pseudocatenulatum can induce antibodies cross-reactive against the RBM motif of the spike protein of SARS-CoV-2.”

The commensal population of the oral cavity in severe COVID-19 is quite different from that of healthy subjects, those with mild COVID-19, or those with symptoms of the flu. In healthy individuals, the number of bacterial species is significantly reduced, especially the Veillonella and Streptococcus genera, while sparing Bifidobacteria genera.

However, genera like Enterococcus, Staphylococcus, and Escherichia/Shigella were increased. This difference could not be the result of antibiotic treatment, since all patients in the group had not received antibiotics.

Intestinal microbiota also reflected the same changes. Thus, severe COVID-19 is linked to the growth of opportunistic bacterial genera like Enterococci and Staphylococci, with others being lost or reduced.

Mucosal infection with SARS-CoV-2 induces inflammation and sometimes fatal COVID-19. The risk of severe COVID-19 is considerably higher in individuals with autoantibodies against IFN I, certain specific genes, older age, as well as those with underlying health conditions like obesity or diabetes.

Cross-reactive but low-avidity T-cells generated by earlier microbes but specific for SARS-CoV-2 may not only fail to neutralize the virus but instead enhance SARS-CoV-2 binding and disease severity. In this case, however, uninfected individuals showed high titers of pre-existing mucosal IgA targeting the viral RBD that were capable of neutralizing the virus.

What are the implications?

The GI microbiota helps to protect the host by reducing ACE2 receptor expression and inducing IFN I responses in a tonic manner. These microorganisms also modulate antibody switching to IgA via transforming growth factor β1 (TGF-β1), both locally and systemically.

In the current study, the investigators identified the specific oral bacteria that have cross-reactive antigenic epitopes on their surfaces that are capable of inducing cross-reactive antibodies to SARS-CoV-2 RBD. This allows these bacteria to both be recognized by anti-RBD antibodies that are elicited by the virus, and capable of inducing anti-RBD neutralizing antibodies against the virus.

Taken together, healthy donors with these bacteria appear to have mucosal IgA that recognizes SARS-CoV-2 RBD and inhibits RBD-ACE2 binding, despite their negative history of infection with the virus. Further studies will be required to understand the underlying mechanism of cross-reactivity and the direction of causality for the altered microbiota seen in acute severe COVID-19.

In immunocompromised patients with poor immune responses to COVID-19 vaccination, the researchers propose: “Bacteria supplementation, in particular with S. Salivarius K12, may enhance the titers of anti-RBD IgA antibodies at the mucosal surfaces, prophylactically or therapeutically, or even in the context of vaccination.”

However, this requires research to understand whether such antibodies will protect against SARS-CoV-2 infection or severe COVID-19.

This is only for your information, kindly take the advice of your doctor for medicines, exercises and so on.   

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Can coronavirus damage the brain?

The full spectrum of the symptoms experienced by those infected with the SARS-CoV-2 is not fully known yet. Recently, research has pointed towards the neurological symptoms witnessed in COVID-19 patients.

Now, in an investigation of hospitalised COVID-19 patients in Wuhan, researchers have recorded the neurological manifestations of the disease. Their findings were published in the journal JAMA Neurology on April 10. They conclude that neurological symptoms can be noticed in a “notable proportion” of the patients and are not uncommon.

Neurological manifestations of the coronavirus (COVID-19)

In their investigation, researchers studied 214 COVID-19 patients between January 16 and February 19 and noted that over 36.4 per cent of them showed neurologic symptoms, more commonly in patients with severe infection.

They have categorised the symptoms into three categories — central nervous system manifestations which include dizziness, headache, impaired consciousness, acute cerebrovascular disease, ataxia (loss of full control of body movements) and seizures; peripheral nervous system manifestations which include taste and smell impairment, vision impairment and nerve pain; and skeletal muscular injury manifestations.
 
How can the coronavirus (COVID-19) affect the brain?

The SARS-CoV-2 virus binds itself to a receptor in the human cells called ACE2. This is also the receptor for SARS-CoV. ACE2 is present in other human organs as well, including the nervous system and skeletal muscles. Therefore, it is possible that the virus can lead to the person showing neurological symptoms through direct or indirect mechanisms using the ACE2 receptor.

Even so, it is not yet clear if the virus affects the skeletal muscles by binding with the ACE2 receptors or through some other route.

Further, the autopsy report of some COVID-19 patients showed that the brain tissue was hyperemic (congestion of blood in an organ), edematous (accumulation of watery fluids in cells or tissues) and some neurons showed degeneration.

Even so, such symptoms are not exclusive to the SARS-CoV-2 virus, neurological injury has also been reported in patients of SARS and MERS. An editorial in JAMA Neurology notes that in the case of SARS, the reports of neurological complications were limited and they appeared in patients two to three weeks into the course of illness.

So does COVID-19 affect the brain?

The researchers note that out of the 214 patients they studied, 126 had a nonsevere infection and 88 patients had severe infection. Overall, 78 patients showed neurological manifestations of the disease.

Compared to the nonsevere cases, the severe cases were older and had more comorbidities such as hypertension. Such patients also showed fewer “typical symptoms” of the disease such as fever and cough, while they were more likely to have neurological symptoms such as acute cerebrovascular disease, impaired consciousness and skeletal muscle injury.

Further, these neurological symptoms were seen early in the illness in COVID-19 patients, as opposed to similar manifestations seen in the case of some SARS patients.

Significantly, some of these patients reported themselves to the hospitals without any typical symptoms of the disease such as fever and cough, and presented themselves only with neurological symptoms. “Therefore, for patients with COVID-19, we need to pay close attention to their neurologic manifestations, especially for those with severe infections, which may have contributed to their death,” the researchers note.

An article in The New York Times said that specialists have observed neurological symptoms in COVID-19 patients in Germany, France, Austria, Italy and Holland. The report says, “Some doctors have reported cases of patients who were brought in for treatment because of their altered mental state, and who ultimately tested positive for Covid-19, although they had none of the classic symptoms like fever or cough,”, which is in line with what the researchers have observed in some patients in Wuhan as well.

Even so, further research needs to be done to understand why certain symptoms such as loss of smell or taste occur, to see if they are clinical manifestations of the disease itself or occur due to an inflammatory response in some patients.

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What makes this novel coronavirus the scariest so far for humans

If you do not know what you are fighting, you are unlikely to know how to fight it. When it comes to the coronavirus, however, the more we get to know about the virus, the more we realise how badly the odds are stacked against us.

Viruses, to begin with, have not been easy to take on. Their invisibility gives them a wide edge even before the fight begins, which is before they enter our bodies. Covid-19, which we have been trying to scrub off our hands, clothes, paper and poly bags, is one-thousandth the width of an eyelash.

Viruses, it seems, can bide their time to attack humans with the patience of a monk. Till the time viruses do not get a human body, they are not even technically alive. They can remain in that state for eternity. In 2014, a virus frozen in permafrost for 30,000 years was still able to infect an amoeba after being revived in a laboratory. Coronavirus is far from frozen.

This coronavirus that causes Covid-19, the SARS-Cov-2, is a novel virus. There is not one thing which scientists can say with certainty about its behaviour. We do not know of the exact way in which it is entering us. Droplet infection is definitely a way. So let’s look at how it works.

Droplet infection

When an infected person sneezes or coughs, she releases droplets in the air. A person who happens to inhale these droplets becomes the next victim. The virus can also stick to surfaces and stay put, waiting for its next target. This is called a fomite-mediated transmission.

Many experts have been assigning varying periods for which the virus can survive on a surface - on cardboard for up to 24 hours, and on plastic and stainless steel for up to three days. The shocker on that front came when US public health institute Centers for Disease Control and Prevention found that the virus on surfaces of the Diamond Princess cruise ship was potent up to 17 days after passengers disembarked. So, it can’t be conclusively said as to how long Covid-19 can stay alive on surfaces.

What happens when the virus finds its way into our system?
Once in our body, the virus spreads to the back of the nasal passage and to mucous membranes in the throat. The viral particles attach themselves onto the outer walls of the host’s cells.

The genetic material that the virus has, then breaches the cell membrane of the host cell. The novel coronavirus then hijacks the cell and comes to life. The virus uses the hijacked cell to make more copies of itself.

Numerous copies are created. These copies then break out of the cell the virus attached itself to, and begin infecting other cells in the body.

It would not be unfair to say that the only purpose the virus has in mind is to make copies of itself and multiply its race.

Peter Kolchinsky, virologist and author of The Great American Drug Deal, in a Twitter thread brings out the sly nature of the virus strikingly – also scarily. He says viruses, they may not be technically alive, but are evil geniuses.

Before a cell dies, it can churn out millions of copies of the virus. Professor Hugh Montgomery, director of the Institute for Human Health and Performance at University College London, has illustrated that 10 infected people can pass on the novel coronavirus to 59,000 people.

The R-naught, which is basically the rate at which an infected person can pass on the infection for most viral infections is 1.3 to 1.4 people. This means an infected person can infect another 1.3 or 1.4 people. The R-naught for Covid-19 is three.

So what makes Covid-19 more infectious than others?

So, now we know that viruses like to multiply and for that, they need a human cell. They need to enter a human cell to produce more of their kind. The SARS-Cov-2 isn’t too good at entering cells. But it has other advantages that make it more dangerous than other viruses.

A Lancet research has shown that the novel coronavirus sneaks in by attaching itself to a protein called ACE2. ACE2 is present on the surface membrane of human cells.

So what does the ACE2 do lying on the surface of the cells? Its job is to bind to a hormone (ACE2 hormone). This combination guides the body’s stress response. The ACE2 hormone plays a role in constricting blood vessels. When blood vessels are constricted, blood pressure rises.

When the SARS-Cov-2 sneaks in, it finds that the part that creates antibodies that help identify foreign elements in the body quickly, doesn’t know what this coronavirus looks like.

SARS-Cov-2 then assumes control of the cell’s genetic reproduction tools and begins to fulfil its life’s mission – which is to create more of its kind. This relentless duplication allows the virus to burst through the cell membrane.

It is the ACE2 which could be making the virus deadlier for those suffering from diabetes or high blood pressure. Such patients are given ACE inhibitors to limit the constriction of blood vessels.

So such people have more ACE2 receptors in the body and hence the SARS-Cov-2 can multiply faster in their bodies.

What about healthy individuals?

ACE2 is found in abundance in our body otherwise too. They exist on our tongue and oesophagus, the part of the digestive tract that connects the throat to the stomach. They are also on the heart, kidney and gastrointestinal tract.

This is perhaps the reason why many patients report a loss of appetite and diarrhea if suffering from a coronavirus infection.

Most worryingly, ACE2 receptors are present on the alveoli in our lungs.

What happens to the lungs when SARS-Cov-2 reaches them?

The alveoli is the most vulnerable part of our lungs. The alveoli are responsible for the exchange of oxygen and carbon dioxide molecules to and from the bloodstream. And this is the reason why Covid-19 patients are reporting coughs and/or trouble in breathing.

The inflammation in the lungs, and their reduced efficacy, can cause them to fill with fluids, pus and dead cells, and cause an infection, leading to pneumonia.

According to The Guardian, pneumonia caused by the novel coronavirus appears to be more severe than most cases of the disease. It also affects a larger portion of the lungs.

Delayed symptoms

One person in South Korea, known as Patient 31, transmitted the virus to over 1,100 people as she went about her life. Similar cases are being reported from across the world.

It takes about five days to two weeks for symptoms to show in an infected person. All this while, the person can pass on the infection to other people without anyone knowing.

People can be asymptomatic for different reasons. One reason is that the person’s immune system is strong. The body is not completely defenceless against the virus.

One person in South Korea, known as Patient 31, transmitted the virus to over 1,100 people as she went about her life. 

Our immune system comes into action the moment we contract a new infection. Infected cells do not surrender without giving a fight to the virus. The system tries to limit the spread of the virus by eliminating infected cells. This human body, which is at war with a virus inside, is also a carrier. The person who houses this body could suffer mild infection or may show no symptom at all.

SARS and MERS, two other diseases caused by the coronavirus, made people so badly sick and so rapidly, that they couldn’t go undetected. So, while the virus wasn’t visible, it was possible to see which body was carrying the virus. The mildness with which Covid-19 is treating some of us is perhaps its biggest weapon.

Spread through body fluids

The virus has also been found in blood and stool specimens. It is, however, unclear whether it can spread through any bodily fluids.

We do not know if the coronavirus, like the Human Immunodeficiency Virus (HIV), can spread through blood transfusion or while having sex. Now, HIV didn’t spread through kissing, but this novel coronavirus could very well, since it could bind itself to the ACE2 receptors on the tongue.

Social distancing, with your mask on, so far seems to be the best remedy to avoid infection.

As more data emerges, hopefully, silver linings on tackling it will also come forth.

This is only for your information, kindly take the advice of your doctor for medicines, exercises and so on.     

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