University Of California Study Confirms That Human Genetics Determines Host Immunity To COVID-19
Genetics and COVID-19
: A new study by researchers from the University of California-San Diego School of Medicine confirms that human genetics plays a critical role in determining immunity to COVID-19.
The SARS-CoV-2 neutralizing antibodies develop within two weeks of a SARS-CoV-2 infection, but their durability and intensity can vary by individual, prompting concerns about the prospects of long-lasting immunity and efficacy of COVID-19 vaccines while also raising concerns about whether antibody responses will provide protection upon re-exposure.
The study team focused their attention on T-B cooperation as a prerequisite for effective and durable neutralizing antibody responses centered on a mutationally constrained RBM B cell epitope. T-B cooperation requires co-processing of B and T cell epitopes by the same B cell and is subject to MHC-II restriction.
The study team evaluated MHC-II constraints relevant to the neutralizing antibody response to a mutationally-constrained B cell epitope in the receptor binding motif (RBM) of the spike protein. Examining common MHC-II alleles, the team found that peptides surrounding this key B cell epitope are predicted to bind poorly, suggesting a lack MHC-II support in T-B cooperation, impacting generation of high-potency neutralizing antibodies in the general population.
Furthermore, the team found that multiple microbial peptides had potential for RBM cross-reactivity, supporting previous exposures as a possible source of T cell memory.
The study findings were published in the peer reviewed journal : PLOS ONE. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246731
The study team report that individual immune response to SARS-CoV-2, the virus that causes COVID-19, may be limited by the major histocompatibility complex or MHC, a set of variable genes that code for cell surface proteins essential for the adaptive immune system.
The study team led by senior authors Dr Maurizio Zanetti, MD, professor of medicine and Dr Hannah Carter, Ph.D., associate professor of medicine examined how the MHC interacts with two kinds of lymphocytes or immune cells called T and B.
Dr Zanetti told Thailand Medical News, "The immune system responds to invading pathogens by producing antibodies aimed at intercepting and neutralizing the pathogen. The production of antibodies against proteins requires productive cooperation between the T lymphocyte and the B lymphocyte, which must both recognize adjacent antigen sequences initiated by the MHC on B cells. Peptide sequences in close proximity engage the two cells preferentially and non-randomly. The MHC serves as the link between the T and B lymphocytes in this process."
Focusing on this hypothesis, the study team computationally analyzed all possible fragments of the spike protein RBM, which is a trigger for both the human immune response and for vaccine activity, in connection with the more than 5,000 different MHC molecules represented in the global human population.
Surprisingly the team found that the average propensity of the MHC to display RBD-derived peptides is low. Since MHC binding is an indirect
measure of the probability that the T cell will be activated and stimulate the B lymphocyte into producing antibodies against the RBM, the authors said it follows that the production of RBM-specific antibodies could be hampered by the poor fitting of these portions of the virus to the MHC.
First author Dr Andrea Castro, a member of Dr Carter's lab said,"This then could lead to poorer neutralizing antibody responses," "And in the case of SARS-CoV-2, the poor presentation of key RBD fragments by many MHC alleles could stand as an obstacle to the production of neutralizing antibodies targeting the RBM."
The study team suggests that the immunological history of individuals may play a role in T cell response and subsequent activation of B lymphocytes that can produce robustly targeted neutralizing antibodies.
Dr Carter said that the potential implications of the study are twofold, "One is that the ability to generate antibodies with potent neutralization activity may vary considerably from individual to individual within the general population, reflecting the large genetic diversity of the MHC. The other is that lack of effective cooperation between T and B lymphocytes may affect the longevity of neutralizing antibody responses in infected people."
The study team notes that multiple studies have reported that neutralizing antibodies in infected persons (hospitalized patients, health care workers and convalescent individuals) drop within three months.
Dr Zanetti further added, "To these considerations, one may add the impact of the newly discovered mutations in the RBM, such as those in the UK, South African and Brazilian variants of the virus. The topology of the mutations in these new variants is indicative of further potential breakdown of the immunological relay between T and B lymphocytes, with additional negative impact on the ability of individuals in the global population to generate high quality and long-lived neutralizing antibody responses against SARS-CoV-2."
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