Variances in critical protein may guide fate of those infected with SARS
CoV-2

Date:
March 23, 2021
Source:
Arizona State University
Summary:
Why does COVID-19 seem to strike in such a haphazard way, sometimes
sparing the 100-year-old grandmother, while killing healthy young
men and women in the prime of life? A new study may offer some
tentative clues.

The research explores MHC-I, a critical protein component of the
human adaptive immune system.



FULL STORY ==========================================================================
Of the many perplexing questions surrounding SARS CoV-2, a mysterious
new pathogen that has killed an estimated 2.6 million people worldwide,
perhaps the most insistent is this: why does the illness seem to strike
in such a haphazard way, sometimes sparing the 100 year old grandmother,
while killing healthy young men and women in the prime of life?

==========================================================================
A new study by Karen Anderson, Abhishek Singharoy and their colleagues
at the Biodesign Institute at Arizona State University, may offer some tentative clues. Their research explores MHC-I, a critical protein
component of the human adaptive immune system.

The research suggests that certain variant forms of MHC-I can help
protect the body, by stimulating a strong immune response, while others
may leave an individual susceptible to viral assault, severe illness
and possibly, death.

"The implication of our findings is that the capacity to mount a
strong and diverse T cell response to SARS-CoV-2 may be important to
limit disease severity," Anderson says. "The key to this work is using
protein structure to predict individual MHC-I peptide binding capacity." Anderson is researchers at the Biodesign Virginia G. Piper Center for Personalized Diagnostics and professor at ASU's School of Life Sciences.

Singharoy is a researcher in the Biodesign Center for Applied Structural Discovery and assistant professor at ASU's School of Molecular Sciences.

Cellular police Humans, like all vertebrates, carry MHC-I molecules in
all nucleated cells. A central role of MHC-I is to help the body clear infections from viruses and other pathogens. It does this by gathering fragments of the virus, ferrying them to the cell surface and presenting
them to immune agents known as CD8+ T cells, which ceaselessly patrol
the body.



========================================================================== MHC-I however, is a polymorphic molecule, meaning that it occurs in a
wide variety of forms, which differ markedly in their ability to bind
viral fragments and present them for interrogation by T cells. Depending
on which MHC-I variants or alleles are present, the body may mount a
successful immune response to SARS CoV-2, or may fail to do so, leaving
the body vulnerable.

In new research appearing in the journal Cell Reports Medicine, Anderson, Singharoy and their colleagues describe a sophisticated algorithm known as EnsembleMHC, designed to predict which MHC-I alleles are best at binding
viral fragments and presenting them to T cells. They also identify 108
viral peptides derived from SARS CoV-2 structural proteins, believed to
be potent stimulators of the immune response.

"This is one of the first examples of molecular epidemiology with the
SARS-CoV2 spike," says Singharoy. The scaling from molecular properties
to population properties, developed by (first author) Eric Wilson is
quite novel." Wilson is a researcher at the Biodesign Institute and
ASU's School of Molecular Sciences.

Range of effects The research examines 52 common MHC-I alleles and finds significant disparities in their ability to bind viral fragments derived
from the full SARS CoV- 2 genome as well as fragments derived from a
key subset of structural components believed to be the most important
viral proteins for generating robust immune responses. These essential
proteins help the virus assemble 4 critical structures and are known as
the S (Spike), N (Nucleocapsid), M (Membrane), and E (Envelope) proteins.



==========================================================================
CD8+ T cells are able to recognize docking regions on these structural proteins, known as epitopes. When these patrolling immune cells encounter
S, N, M and E proteins, they will usually target the infected cell
for destruction.

When the researchers compared COVID-19 figures from 23 countries, they
found that mortality rates from the disease were closely associated with
the distribution of MHC-I variants. Specifically, populations rich in
MHC-I alleles ranked as strong binders of SARS CoV-2 peptide fragments
showed reduced rates of death from COVID-19, suggesting these favorable
MHC-I alleles generate a robust immune response when they encounter the
novel coronavirus.

The work has important implications for monitoring vulnerability to
COVID-19 in both individuals and populations and can also help researchers ferret out the essential pieces of the SARS CoV-2 pathogen that best
stimulate the immune response, a critical component in future vaccines.

Defensive measures MHC-I molecules are generated by the MHC gene,
which is the most polymorphic part of the entire human genome. MHC is
known to encode over 160 proteins of diverse function, half of which are directly involved in immune responses. The enormous diversity of MHC-I
proteins provide the body with a formidable early warning defense system, capable of binding a broad range of pathogen fragments and fine-tuning
the immune response. The rich diversity of MHC-I molecules also makes
it difficult for a foreign invader like a virus to stealthily outwit
all of the potential binding molecules.

The CD8+ T cells conducting their surveillance have an uncanny ability to distinguish self from non-self. If the T cells don't like what they see,
when antigen-presenting MHC-I molecules display the fragments they have acquired, the CD8+ T cells will terminate the infected cell.

Previous research has shown that even slight amino acid variances in
MHC- I composition can have profound effects. On the one hand, some
MHC-I forms may promote inflammatory and autoimmune diseases, such as
Graves's disease, psoriasis, rheumatoid arthritis, or multiple sclerosis,
in which healthy tissues are recognized as foreign. On the other hand,
MHC-I variants may be structurally unequipped to bind the proper fragments
of a virus or other pathogen and fail to mount an immune response. For
this reason, MHC genotype is considered a critical determinant of patient outcomes following a range of viral infections.

MHC-I also plays an important role in cases of tissue transplantation,
as its full name -- major histocompatibility complex -- suggests. If
donated tissue is not compatible with the recipient, MHC-I molecules
present fragments from the donor tissue, which are recognized as foreign
and attacked by T cells, a phenomenon known as graft-host rejection,
another form of autoimmunity.

Following the trail of protection In the current study, researchers
examined 52 common alleles of the MHC- I protein, using a custom-designed algorithm known as EnsembleMHC to predict their binding affinities for
SARS CoV-2 protein fragments. Two sets of data were compiled, the first, measuring each allele's binding affinity for the complete repertoire
of proteins in the SARS CoV-2 genome. The second data set examines the
binding affinities of each allele to just the S, N, M and E structural
viral peptide candidates.

The researchers then mined a massive data bank of protein alleles,
matching the prevalence of the 52 alleles in the study with 23
counties. Each country received a population-wide score, which combines
the MHC-I binding capacity with MHC-I allele frequencies.

A compelling correlation was found between countries with lower mortality
rates during the January-April, 2020 study period and high population-wide percentages of alleles identified by EnsembleMHC as strong binding
molecules for SARS CoV-2 proteins.

Further, when only those alleles exhibiting high binding affinity for
the S, N, M, and E proteins were compared, the association between
low COVID-19 mortality and this suite of favorable MHC-I alleles was
strongest, again suggesting that the virus's structural proteins are
the most effective in producing an immune response.

The findings suggest that patients who have MHC-I alleles capable of
engaging with SARS-CoV-2 structural protein peptides may stimulate an
enhanced CD8+ T cell response, with improved post-infection outcomes
and lower mortality.

The powerful technique described in the new study further unveils the
subtle relationship of MHC-I alleles and immune response and will help researchers pinpoint the most important immunogenic viral fragments from
SARS CoV-2, aiding future vaccine development. Combining such information
with patient clinical data and genetic profiles may help identify those
at greatest risk for this still-elusive disease.

========================================================================== Story Source: Materials provided by Arizona_State_University. Original
written by Richard Harth. Note: Content may be edited for style and
length.


========================================================================== Journal Reference:
1. Eric A. Wilson, Gabrielle Hirneise, Abhishek Singharoy, Karen S.

Anderson. Total predicted MHC-I epitope load is inversely associated
with population mortality from SARS-CoV-2. Cell Reports Medicine,
2021; 2 (3): 100221 DOI: 10.1016/j.xcrm.2021.100221 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/03/210323103838.htm

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