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The NQK-Q8 peptide (light color), a piece of the SARS-CoV-2 spike protein that the virus uses to enter cells, binds to the HLA-B*15:01 groove (orange). The illustration is based on the crystal structure of HLA-B*15:01 in complex with the peptide derived from the NQKLIANQF peak of the SARS-CoV-2 virus (PDB Entry – 8ELH) published by Augusto et al., 2023 (Nature). Credit: André Luiz Lourenço
New study shows that common genetic variation among people is responsible for mediating Have you ever wondered why some people never get sick because of
The role of human leukocyte antigens (HLA)
The study focuses on a group of genes called human leukocyte antigens (HLA). These HLA genes encode proteins used by the immune system to identify healthy cells and distinguish them from those infected by bacteria and viruses. The HLA system is critical for the immune response and is also highly variable between individuals. Due to the role of HLA in fighting infection, researchers wondered whether there were specific variants that would make us more protected or susceptible to SARS-CoV-2. 
Danillo Augusto, assistant professor of Biological Sciences at UNC Charlotte. Credit: UNC Charlotte
Research results and methodology
Hollenbach led the data collection, which began at the beginning of the pandemic. First, 29,947 unvaccinated individuals were screened using a mobile app specifically designed to monitor COVID-19 symptoms, and 1,428 reported testing positive for the virus. All individuals had their
Insights into immune response
“We hypothesized that their immune system could react so quickly and powerfully that the virus was eliminated before it caused any symptoms. It’s like having an army that already knows what to look for and can tell from the uniform that these are the bad guys”, according to Hollenbach.
HLA molecules display pieces of the virus to immune system effector cells for inspection. The study used cells from individuals with HLA-B*15:01 who donated blood several years before the pandemic. The results showed that these individuals had memory T cells against a specific SARS-CoV-2 particle. Individuals who have never had contact with SARS-CoV-2 have already had some type of previous exposure to other viruses and developed immunological memory against a SARS-CoV-2 particle.
Their immunological memory would trigger a much faster response and explain why these individuals remained asymptomatic. Still, it remained intriguing how they could develop immunological memory against SARS-CoV-2 without ever being exposed to this virus.
Cross-reactive immune responses
“It has been widely known that other types of coronavirus have been causing seasonal colds for decades. We hypothesize that these individuals were exposed to seasonal coronaviruses in the past and somehow individuals specifically carrying HLA-B*15:01 could quickly kill SARS-CoV-2-infected cells due to cross-reactive immune responses. . So even if the bad guys changed their uniform, the army would still be able to identify them by their boots or perhaps a tattoo on their arms. This is how our immunological memory works to keep us healthy”, said Augusto.
After carefully analyzing the genomic sequences of all coronaviruses, the study showed that this SARS-CoV-2 particle recognized by HLA-B*15:01 in unexposed individuals is very similar to viral particles from other previous coronaviruses. The research demonstrated that T cells from pre-pandemic individuals could identify viral particles from previous coronaviruses and SARS-CoV-2 with the same efficiency, showing crystal structures and affinity assays. This means that these individuals have created immunological memory for previous coronaviruses, but due to the high similarity of this viral particle, their memory T cells can also recognize and kill SARS-CoV-2 very quickly.
Implications and future research
The results show a mechanism for how individuals can avoid becoming sick with SARS-CoV-2, and the research group plans to continue learning about the response against this virus, which will result in a better understanding of COVID-19 therapeutics and vaccines. 19.
For more information about this research, see Uncovering the Secret of the COVID-19 “Super Dodgers.”
Reference: “A common allele of HLA is associated with asymptomatic SARS-CoV-2 infection” by Danillo G. Augusto, Lawton D. Murdolo, Demetra SM Chatzileontiadou, Joseph J. Sabatino Jr, Tasneem Yusufali, Noah D. Peyser, Xochitl Butcher, Kerry Kizer, Karoline Guthrie, Victoria W. Murray, Vivian Pae, Sannidhi Sarvadhavabhatla, Fiona Beltran, Gurjot S. Gill, Kara L. Lynch, Cassandra Yun, Colin T. Maguire, Michael J. Peluso, Rebecca Hoh, Timothy J. Henrich, Steven G. Deeks, Michelle Davidson, Scott Lu, Sarah A. Goldberg, J. Daniel Kelly, Jeffrey N. Martin, Cynthia A. Vierra-Green, Stephen R. Spellman, David J. Langton, Michael J. Dewar-Oldis, Corey Smith, Peter J .Barnard, Sulggi Lee, Gregory M. Marcus, Jeffrey E. Olgin, Mark J. Pletcher, Martin Maiers, Stephanie Gras, and Jill A. Hollenbach, July 19, 2023, Nature.
DOI: 10.1038/s41586-023-06331-x
