Eligible Student Poster 49th Lorne Conference on Protein Structure and Function 2024

How some of us remain asymptomatic after COVID-19  (#146)

Lawton D Murdolo 1 , Danillo G Augusto 2 , Dimitra Chatzileontiadou 1 , Jill A Hollenbach 2 3 , Stephanie Gras 1 4
  1. Infection and Immunity Program, La Trobe Institute for Molecular Science (LIMS), La Trobe University, Bundoora, Victoria, Australia
  2. Weill Institute for Neurosciences, University of California San Francisco, San Francisco, California, United States of America
  3. Infection and Immunity Program, La Trobe Institute for Molecular Science (LIMS), La Trobe University, Bundoora, Victoria, Australia
  4. Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia

The rapid emergence of SARS-CoV-2 and the ensuing pandemic shifted research focus towards severe COVID-19 cases, with relatively little attention given to understanding why about 20% of infected individuals remain asymptomatic. Our study unravelled the natural immunity that shields asymptomatic individuals from COVID symptoms.

T lymphocyte activation is driven by the recognition of Human Leukocyte Antigens (HLA) on the surface infected cells. HLAs present viral peptides to T cells, which then recognize them as antigens via their T cell receptor (TCR). However, the polymorphic nature of HLA molecules leads to variations in the adaptive immune response. We discovered a link between asymptomatic COVID infection and a specific HLA, HLA-B*15:01, which is present in approximately 3% of the global population. We sought to understand how HLA-B*15:01 provided protection against SARS-CoV-2.

We examined four SARS-CoV-2-derived epitopes that could be presented by HLA-B*15:01 using samples collected in the 90’s before the COVID-19 pandemic. These individuals were unexposed to the virus, not vaccinated, and not even exposed to SARS-CoV-1. One epitope, NQK-Q8, from the spike protein, triggered a robust memory T cell response in unexposed individuals. Interestingly a homologous peptide, NQK-A8, from human seasonal coronaviruses, was recognized by the same T cells. I showed that HLA-B*15:01 was able to present the two peptides with similar stability and using X-ray crystallography, we found that the residue difference at position 8 of the peptides were solvent-exposed and could be a contact point for T cells.

We show that both epitopes efficiently activate T cells and assessed the affinity of T cell receptors (TCRs) isolated from COVID-recovered, vaccinated, and unexposed HLA-B*15:01+ individuals exhibited. The TCRs had a high and similar affinity for both peptides. and facilitate viral recognition and protection in HLA-B*15:01+ individuals.

This discovery not only enhances our understanding of the immunological factors behind the potential rapid viral clearance but also provides a foundation for developing therapeutics that would mimic such a protective immune response as observed in HLA-B*15:01+ individuals.

This work has been published in Nature (Augusto et al. 2023)

  1. Augusto, D.G., Murdolo, L.D., Chatzileontiadou, D.S.M. et al. A common allele of HLA is associated with asymptomatic SARS-CoV-2 infection. Nature 620, 128–136 (2023). https://doi.org/10.1038/s41586-023-06331-x