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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https://gseasyrecipes.blogspot.com. feel free to view for easy, simple and healthy recipes    
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How to ease the pain of heartache

The reality of how painful a broken heart could be first hit me many years ago. I know the term we use is heartbroken but, when my relationship ended, I just felt broken, punched in the gut. I had been at that dangerous juncture of being completely loved-up and utterly unprepared. And almost worse than the shock was how embarrassed I felt. My inner voice kept telling me to put this in perspective and somehow rally round. But new findings on heartbreak show it is a physiological and mental state. Rather than something to belittle, heartbreak is a profound form of grief. I wasn’t being silly; I was experiencing the proven impact of romantic loss.

One of the first reassuring pieces of research I read, when trying to grapple with the confusing aftermath of my own miserable breakup, was a major review of studies on heartbreak by the psychologist Tiffany Field at the University of Miami. She had pulled together findings from a host of other researchers showing that the symptoms of heartbreak resembled those of bereavement: sleep disturbance, compromised immune function, digestive problems, body aches, depression, anxiety, all the way to something called ‘broken-heart syndrome’ where the shock from loss can induce a heart attack-style episode. At least I knew I wasn’t regressing to my melodramatic teenage self; someone had vanished and the loss hit me hard. If, like me, you have been confused by the force of the blow, it might help to consider heartbreak in this way.

Not only did I feel sad and lost and confused and weepy, I also felt physically ill. I remember sitting in a brightly lit diner with my best friend, a few days after my breakup, staring at my plate of food unable to eat. The smell of food, even the idea of it, was completely off-putting. I am not someone who ever misses a meal, but here I was feeling sick to my stomach like I had gastric flu. I thought we just talked about being lovesick: I didn’t think I was literally going to rush to the bathroom to throw up.

One of the main reasons we feel so ill in the aftermath of a breakup is the stress of rejection, betrayal and loss, leading to the release of the stress hormone cortisol. Extra cortisol in moments of danger is incredibly useful. It activates our bodies and gets us ready to defend ourselves or flee the scene. The fight-or-flight response (also known as the acute stress response) is where a kind of domino effect occurs inside us, our mind perceives a threat, our body hears the cry for help and releases stress hormones in reaction to this danger. But if we don’t need to literally fight or run for our lives, then we can be left with some unpleasant side-effects. Our muscles (if not used to ward off that grizzly bear) can end up tense and taut, producing aches and pains. If you feel like you’ve been hit by a truck right now, then this might be why.

Cortisol and other hormones also instruct our bodies to divert blood away from our digestive system in order to make sure that our muscles have adequate blood supply to fuel our fight-or-flight state. This diversion can hugely upset our digestive system, triggering stomach aches, diarrhoea or loss of appetite. The broken-hearted feel like they are falling apart, but they are just having a normal physical reaction to the flood of cortisol induced by the stress.

The broken-hearted also crave the neurotransmitter and hormone dopamine, generated by the body when we’re ‘in love’. Dopamine is produced in the brain’s reward centre, the area that generates pleasure and motivation. Dopamine not only produces the sensation of ecstasy but also energy, drive and focus, propelling us to keep trying to get a little more – more dopamine, more romantic giddiness, more hits of reward and pleasure.

One theory proposed by the anthropologist Helen Fisher at the Kinsey Institute is that love is not exactly an emotion in the same way that we might talk about fear or sadness or joy but is in fact a mammalian drive that is designed to make us focus on pursuing a mate. This is why, she theorises, being in love is so intertwined with these hits of dopamine. There is a kind of evolutionary reason that we get these pleasurable rewards in the brain, we are being pushed to pair up and rewarded with this hormone. But when we are first heartbroken, the regions of the brain previously being stimulated to produce dopamine do not instantly calm down or decrease arousal: they remain activated. Part of the initial struggle of being heartbroken is that, within the brain at least, the regions activated by love are still working away. Brain scans of rejected lovers show that the brain’s reward centre is still lit up after a breakup, as is the region of the brain linked to feelings of deep attachment. We are still in a state that is energised and driven to find ways to activate those hits of pleasure, even when the person previously triggering it is no longer there. There is a great deal of writing about the addictive quality of love, which can make a lot of sense when you are first hit by a breakup and reeling from being cut off. We have the unpleasant side-effects of the stress hormone cortisol and the confusing signals in our brain’s reward centre to keep trying to get those hits of pleasure, and this combination is likely to make us feel not only physically awful but totally confused.

I know for me ‘confused’ was a bit of an understatement. My mind was more of a scrambled mess. I felt like I was wandering through a surrealist film, with walls and floors and ceilings all suddenly interchangeable. The shock of suddenly being out of that relationship was an incredibly destabilising experience. I’d not only lost that person, but all the things that went along with them. In such a situation, we can all find ourselves questioning our very identity. What does it mean if you’re no longer the duo who were into kayaking or the couple who always brought the good dip? There’s a common feeling after a breakup of not only losing that person but your very identity and the whole world attached to that. This is often referred to as ‘self-concept change’. When we enter a relationship, we form a kind of new identity with that person, and when we break up that identity is confused. The difficulty is that the change we go through when entering the relationship is full of positivity and hope. In their book Interpersonal Relationships and the Self-Concept (2020), the psychologist Gary Lewandowski Jr at Monmouth University in New Jersey and colleagues explain that one of the most well-developed theories for self-concept change in relationships is based on our desire to maximise our goals and our future. We are driven to forge something new and positive when we pair up with someone, and part of the comfort in having this partner is that they not only validate and support our view of ourselves (which is very reassuring) but also help to shape a sort of ‘best-version’ view of ourselves for the future.

According to this theory, once you’re in a couple, you believe that you can be your ideal self in the relationship. How distressing for that inspiring idea to suddenly vanish. You had signed up to this new thing, this exciting, improved version of your life. Perhaps, before the relationship, you had not believed you could move to Paris or go for that new job, and yet, within your couple-identity, you believed so much more was possible. It is naturally going to feel confusing to have that world suddenly taken away, and at first you are going to feel very lost, shocked and distressed.

There are things you can do to ease your stress, calm your mind and help you process what has happened. This initial kick in the head, however unpleasant, will eventually start to ease. You will not be heartbroken forever. Although it is miserable being heartbroken, the silver lining is that you are heartbroken now, in the 21st century, surrounded by scientific insights that can help guide you towards ways of feeling better and allowing you to be proactive about your recovery. You don’t just have to endure these first few hard days and weeks – there are things you can actively do to take the edge off and start to feel a little better once again.

What to do

Accept your feelings

One soothing practice you can try in these first few confusing weeks is a little acceptance of how you feel. This is a strategy taken from acceptance and commitment therapy (ACT) and is based on the idea  that, if we give ourselves permission to feel however we feel, without self-judgment, it can help us to process something we are struggling with.

The idea is to focus your mind on a simple statement that articulates your feelings. This could be ‘It’s okay to feel sad,’ or ‘You are not alone in being heartbroken,’ or ‘It’s ok to love someone you’re no longer with.’ In these moments, we accept our feelings as legitimate, not silly or detrimental. A recent study from the Neurocognition of Emotion and Motivation Lab at the University of Missouri-St Louis that used this method on heartbroken participants found that concentrating on these types of sentences a few seconds at a time decreased motivated attention for the ex-partner, meaning that the participants were less captivated by their heartbreaker and potentially a little more free to move on. It wasn’t that these people were no longer sad or heartbroken, but they were less captivated by the ex. This can be incredibly helpful if you are fixated on that person who has just rejected you.

This method allows you to focus on the present without trying to conquer anything. It can help to simply accept your current state. This can be done as a kind of meditative exercise, starting your days with a few minutes in which you allow yourself to be kind to yourself and honest about how you feel. Find a quiet spot, give yourself this peaceful moment and concentrate on a simple, real feeling, without critiquing it, simply allowing it to sink in, and rest there for a moment.

Give yourself permission to grieve

It can be tempting to try to ‘hold it together’ when you are in shock or struggling with bad news. If you are able to view this heartbreak as a form of grief, then letting yourself cry and mourn this loss can be an important way to release some of the sadness you are feeling.

How many times have you heard the saying that ‘grief comes in waves’? These waves are likely to drift in and out and, although I understand that you might not want to burst into tears when chairing a meeting or travelling home on a busy commuter bus, you are likely to feel so much worse if you try to keep this sadness inside. When you feel those waves of grief hit you, the best thing you can do is to let yourself cry or let yourself be open about how terrible you are feeling. You don’t want to try to hold this in by bottling up sadness or answering every ‘How are you doing?’ with a high-pitched ‘I am totally fine!’

This is a time to reach out for support, be honest about how terrible you feel, and give yourself permission to treat this seriously. Maybe your inner voice is kinder than mine was, but I know I would often battle a terribly British stiff-upper-lip mentality in that period. Cry if you need to cry, and be honest about how you feel. Reach out to friends when you need them.

Get some exercise

There is a poster in my gym that says: ‘When your body is busy, your mind isn’t.’ Not groundbreaking, I know, but it so simply summarises my experience of exercise. I can feel my mind clear and the stress ease as I exercise. I would say it was magical if I didn’t know there was a huge amount of research in this area. A major review of these studies looked at data from nearly 20,000 participants, and found strong associations between physical activity and reduced psychological distress, with even mild exercise such as cleaning or gardening making a difference. Even if you know all this deep down, it can be hard to motivate yourself to get active when you are at your most heartbroken. It is tempting to curl up and hibernate at first, and naturally you might find that your motivation is low. This is not a time to beat yourself up or to set unrealistic goals. Even just setting simple, gentle targets – maybe trying to get out for a 10-minute walk a day – can help. Taking some baby steps towards increasing your exercise will help. When you exercise and increase your heart rate, your cortisol levels go down, and, even if this is just by a small amount at a time, it can help ease the unpleasant effects of stress you are experiencing.

Spend time in nature

The natural world can be a kind of medicine. The idea of ‘forest bathing’ might sound like a modern trend but in many cultures immersing in nature to reduce stress or sadness is nothing new. In Japan, it has been used for many years and, over the past 40 years, research there has shown that walking in a forest can not only help when you are feeling low but also decrease stress levels, improve concentration and even boost the immune system. If you do not live next to a beautiful Japanese forest, then do not fear. Recent studies that tracked groups of participants walking in open, green spaces recorded that those walking out in nature, as opposed to those in an urban environment, had a greater increase in endorphins and greater decrease in cortisol levels. Just walking in green areas can help us, and if we want to help our low mood then having a lift from endorphins – a chemical produced by the body that relieves stress and pain and can create a feeling of euphoria – is worth the diversion away from busy streets to natural environments.

Distract yourself

One way of easing your mind after a breakup is through the technique of distraction. The aforementioned study from the University of Missouri-St Louis took heartbroken men and women and tested the use of distraction to ease distress. Participants were asked to actively distract their minds from thoughts of their heartbreak, by concentrating on topics unrelated to their breakup, such as their favourite music or movies, or where they might like to travel next. The results showed that, after using this technique, their well-being scores were higher and the exercise had a positive impact on their emotions and moods. The distraction techniques used in this experiment were mostly about moving the mind to other, happier topics so as not to dwell on negative thoughts, but distraction can be about throwing yourself into an activity too, or watching a film. This is not to say you shouldn’t think about your past relationship at all. Distraction techniques are not about suppressing memories or burying your feelings but instead redirecting your thoughts when something is repeating on a loop in your mind. Of course, you will still think about that person and the relationship, but if these thoughts are overwhelming, as they often can be initially, then it can be soothing to give your mind a rest.

It is common to experience some form of depression following a breakup, with some studies showing that as many as 40 per cent of heartbroken people do so. However, if this depression starts to become overwhelming, then a low mood that can follow loss could tip into something more serious. You want to try to alleviate this as much as possible by stopping your mind from dwelling too much on the breakup.

Key points

• Heartbreak is a form of grief. You have lost someone significant, and that loss has a powerful impact, even when that person is still alive. The loss triggers a stress response, and in the initial aftermath of a breakup, you can be left reeling from the impact of this shock.
• The impact of cortisol, a key stress hormone, can be incredibly disruptive. It can create unpleasant side-effects, such as digestive problems, aches and pains.
• Reducing cortisol levels can help to ease these symptoms. You can do this by increasing your exercise, spending time in nature, and widening your social support.
• Distraction techniques can help to mitigate the tendency to dwell on negative thoughts or upsetting memories after a breakup occurs.
• Heartbreak can trigger depression. You need to be aware of how low your mood is, and seek professional help if necessary. No breakup is too small to make one depressed.

Learn more

Sadness is a natural emotion associated with loss, and so feeling sad when heartbroken is completely normal. What can be difficult, though, is if this natural sadness tips into depression. We know that many people recovering from a broken heart experience some form of depression. If this depression lasts too long or becomes more severe, it can become more serious, eg clinical depression. This slide is not uncommon, with one recent study showing that around 13 per cent of those recovering from a breakup experienced severe clinical depression. The degree of depression might hinge not only on how serious the relationship was or how long you were with that other person; loss can affect us all in different ways and, for some people, any breakup at all can result in a crash. It is sometimes hard to identify exactly how sad or low you feel, so, if you are unsure, then it is best to ask for a professional opinion, or try an online survey that takes you through an assessment.

Getting out into nature, increasing your exercise or getting more social support are incredibly helpful tools, but they might not be effective or sufficient for everyone. If you find these strategies don’t make a significant difference, you are not failing, and you are not alone; you are just one of the many people who needs a little more help. Whether you contact a therapist, a doctor or a support group, finding professional support is always an option to consider.

There is no one-size-fits-all answer to this process. We are complex, emotional beings, and the way we recover from the loss of love is going to vary. The important thing is that you try to begin the recovery process in some form, however small those steps might be, so that you can start to heal and to feel like yourself again.

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

https://gscrochetdesigns.blogspot.com. one can see my crochet creations  
https://gseasyrecipes.blogspot.com. feel free to view for easy, simple and healthy recipes    
https://kneereplacement-stickclub.blogspot.com. for info on knee replacement