SARS-CoV-2 mutant outbreaks and nature’s balancing mechanisms

SARS-CoV-2 mutant outbreaks and nature’s balancing mechanisms

Insights from the molecular world of virus and host interactions

With the emergence of new lineages of SARS-CoV-2, every moment seems terrifying. The rapid surge in Covid-19 cases in India is thought to be driven mainly by these new variants, coupled with the complacency that set in after we thought we had dodged the first wave. We deluded ourselves into believing that the virus is not going to haunt us again. But the virus showed up again in its new avatars, with increased transmissibility and mortality rate, particularly the Indian strain of SARS-CoV-2 double mutant B.1.617 and triple mutant B.1.618 with mutations E484Q, L452R and E484K (the letters represent names of amino acids which form the proteins and the numbers represent the positions of amino acids).
While vaccines offer a ray of hope, there is substantial skepticism on the efficacy of vaccines against these new variants of SARS-COV2, as none of the vaccines that have been approved until now take into account these newly emerged variants. Furthermore, there is no sufficient data to suggest if either COVAXIN or CO-VISHIELD are effective against mutants forms of the virus. Although a recent study published by National Institute of Virology (NIV, Pune) has shown that both convalescent sera harvested from patients who were infected with the prototype strain and sera from patients administered COVAXIN could confer heterolo-gous immunity against the new variants. These results are still at laboratory adapted stage and do not validate whether in vivo they do possess the same capability. One important question is if this is going to be a perpetual vicious cycle in which mutants will emerge and devour millions of human lives or is there something hopeful within this process. In this article I will discuss the biological and molecular mechanisms involved in virus-host interactions and the answers and hopes it holds for the current crises.
Understanding virus-host interaction at molecular/atomic scale unravels the mystery of SARS-CoV-2 virus lineages and the better fit of mutant viruses in terms of transmissi-bility, pathogenecity and resistance. The answers lie deep in the science of natural defence of humans against infections and within evolution of these processes that reflect the fundamental tenet of life, ‘survival of the fittest’. Our immune system has a way of dealing with frequently mutating antigenic structures of pathogens (for example, the famous Spike protein in SARS_CoV2) by churning out antibodies of increasingly higher affinity from a broad-based repertoire of antibodies produced against the antigen.
In immunology is a concept called ‘affinity maturation’: the antibodies that destroy pathogens assaulting our body need to be specifically precise and accurate or else they will wreck havoc in our body (e.g. rheumatoid arthritis in which antibodies also react to our own body and destroy it). This precision and accuracy towards these infectious creatures is developed gradually within a few days by fine tuning antibodies to have measured calibrated response. This fine tuning ensures that there is no mistake in mounting surgical strike against invading enemy and is with pinpoint accuracy with maximum damage to the enemy lines.
The reason for the evolution of affinity maturation process is that our immune system doesn’t have an intrinsic capacity to respond to the enemies it has to deal with. Had that been the case, it would have been an enormous burden on immune system to remember all different varieties and types of enemies we encounter on daily basis. This allows our immune system to develop antibodies outweighing with complete acumen the entire diversity of life forms on earth. Should we not be baffled that our immune system somehow defends us from anything from inert dust, to chemicals in drugs, to pollens, to venoms, etc.? This reflects the diversity of our immune system to tackle anything that is not a component of our own body.
Although entirely a different process, the coronavirus at molecular level somehow mutates in a manner to precisely and perfectly bind its receptor angiotensin converting enzyme 2 (ACE2) on lung cells. The more avidity the viral spike binds to the ACE2 receptor the more it will penetrate inside the lung cells and concomitantly increased pathogenecity will be displayed. In near future, given the mutation potential of SARS-CoV-2 there are chances that newer range of mutants will continuously be added to the pool of hundreds of thousands of mutants. These mutants may have a survival advantage over the parent virus or reduced survival range. These mutants are developed not merely by chance flips and replacements in viral nucleic acid positions but are monitored under the extreme restrictive environment of host immune system and sometimes in the presence of antiviral drugs (similar to antibiotics which generate multi drug-resistant forms in bacterial infection) called immune escape mutants and drug resistant forms, respectively. The antibodies that are raised in viral infection pose tremendous selection pressure to the virus and set the stage for survival vs death of the virus. In this tug of war, viruses change themselves by virtue of their mutation potential and completely transform themselves into a form that is not recognised by antibodies due to their stringent mechanisms of precision in recognising and binding pathogens as described above. The battle is however completely at the molecular level. If there is development of completely protective antibody response against virus, or in other terms antibodies effectively binding to virus, it results us in a pool of convalescent patients (recovered) and in majority of them the virus has been effectively eliminated by this mechanism.
Sometimes, there is lack of completely effective antibody response and the result is mild to severe symptoms and in extreme case death of the infected subject. Antibodies are the key players mediating overall and prolonged protection. In the battle of immune system vs. virus infection process, antibody generation vs. virus multiplication, highly specific antibody response vs mutating virus, mutations are key mechanisms at atomic scale level as viral factors thwarting or evading immune effector responses. These mutations called escape mutations give escape mutant viruses selective advantage compared to their parents in the presence of antibodies. These mutations in a somewhat different manner than immune selection pressure are also responsible for emergence of drug mutant or resistant forms as mentioned earlier. These phenomena are intrinsic to the whole functioning and development of intricate mechanisms of development of antibody diversity as well as viral mutation potential being controlled by extremely leaky enzymes synthesising viral nucleic acids. For this reason there is no direct target in either of the two mechanisms to give any predictable controllable switch or target to turn it on or off or modify. It also explains unpredictable nature of vaccine against mutants or whether vaccine recipients shall be categorically identified as completely resistant to SARS-CoV-2 infection.
However, one satisfying thing is that although the virus is mutating, so are our antibodies, thanks to affinity maturation. Our immune system will sooner cope up with learned antibodies against mutants. Scientists will study these antibodies and will mimic them in laboratories and more strict means of producing vaccines will be in pipeline. My own simulation and molecular modelling of the SARS-CoV-s spike suggests that convalescent people (who have previously recovered from SARS-CoV-2) may have antibodies not effective against Indian mutants. The emergence of immune escape mutant means it has escaped even the most effective antibody available. While analysing the antibody binding regions and the frequency of mutations on spike protein, most of the antibodies potent and broadly neutralising are rendered ineffective against the mutants. Those people who recover from the mutant infections will tremendously help to find new features in binding sites of these antibodies and will help us to recognise new prone and vulnerable targets. So, we have to wait for evolution and natural processes to guide us towards understanding mutants and their vulnerability.

P.S. I would like to thank Dr. Raees-ul-Hameed, Scientist at PGIMER Chandigarh, for statistics on current COVID crisis as well as for moderation of the article.

The writer is an Assistant Professor and has worked extensively on molecular virology, Immunology and Vaccinology at NYU, ISMMS and NIH USA. He is currently working on SARS-CoV-2 immune escape mechanism in collaboration with Icahn School of Medicine (ISMMS) NY, USA. muzijan@gmail.com, @drmuzafarjan (twitter)

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