The body's immune response plays a crucial role in the course of a
SARS-CoV-2 infection. In addition to antibodies, the so-called T-killer
cells, are also responsible for detecting viruses in the body and
eliminating them. Scientists from the CeMM Research Center for Molecular
Medicine of the Austrian Academy of Sciences and the Medical University of
Vienna have now shown that SARS-CoV-2 can make itself unrecognizable to the
immune response by T-killer cells through mutations.
The findings of the research groups of Andreas Bergthaler, Judith Aberle and
Johannes Huppa provide important clues for the further development of
vaccines and were published in the journal Science Immunology.
After a year of the pandemic, an increasingly clear picture is emerging for
science and medicine of how the immune response protects people from
SARS-CoV-2. Two protagonists play central roles: antibodies and T-killer
cells (also called cytotoxic CD8 T cells). While antibodies dock directly
onto viruses to render them harmless, T-killer cells recognize viral protein
fragments on infected cells and subsequently kill them to stop virus
production.
More and more studies show that SARS-CoV-2 can evade the antibody immune
response through mutations and thus also impair the effectiveness of
vaccines. Whether such mutations also affect T-killer cells in their
function had not been clarified so far. Benedikt Agerer in the laboratory of
Andreas Bergthaler (CeMM), Maximilian Koblischke and Venugopal Gudipati in
the research groups of Judith Aberle and Johannes Huppa (both Medical
University of Vienna) have now worked together closely to investigate the
effect of viral mutations in so-called T cell epitopes, i.e., in regions
recognized by T-killer cells.
For this purpose, they sequenced 750 SARS-CoV-2 viral genomes from infected
individuals and analyzed mutations for their potential to alter T cell
epitopes. "Our results show that many mutations in SARS-CoV-2 are indeed
capable of doing this. With the help of bioinformatic and biochemical
investigations as well as laboratory experiments with blood cells from
COVID-19 patients, we were able to show that mutated viruses can no longer
be recognized by T-killer cells in these regions," says Andreas Bergthaler.
Focus on spike protein might be too narrow
In most natural infections, several epitopes are available for recognition
by T-killer cells. If the virus mutates in one place, it is likely that
other epitopes indicate the presence of the virus.
Most of the current vaccines against SARS-CoV-2 are directed exclusively
against the so-called spike protein, which is one of 26 virus proteins. This
also reduces the number of epitopes that are available for recognition by
T-killer cells. "The spike protein has, on average, one to six of these T
cell epitopes in an infected person.
If the virus mutates in one of these regions, the risk that the infected
cells will not be recognized by the T-killer cells increases," explains
Johannes Huppa. Judith Aberle emphasizes: "Especially for the further
development of vaccines, we therefore have to keep a close eye on how the
virus mutates and which mutations prevail globally. Currently, we see few
indications that mutations in T killer cell epitopes are increasingly
spreading."
The study authors see no reason in their data to believe that SARS-CoV-2 can
completely evade the human immune response. However, these results provide
important insights into how SARS-CoV-2 interacts with the immune system.
"Furthermore, this knowledge helps to develop more effective vaccines with
the potential to activate as many T-killer cells as possible via a variety
of epitopes. The goal are vaccines that trigger neutralizing antibody and T
killer cell responses for the broadest possible protection," the study
authors say.
Reference:
Agerer B, Koblischke M, Gudipati V, et al. SARS-CoV-2 mutations in
MHC-I-restricted epitopes evade CD8+ T cell responses. Sci. Immunol.
2021;6(57). doi:
10.1126/sciimmunol.abg6461