By: Ariella Zadrima, PharmD Candidate c/o 2026

Since coronavirus disease 2019 (COVID-19) first made its appearance in December of 2019, its pathology has been a topic of research for many years. COVID-19 is a respiratory illness that can be spread through droplets. It is known that COVID-19 is caused by infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As time passed, research done on the basic route of infection for this virus began to provide more insight into who can be affected by the disease and how some of the common side effects individuals experienced came to be. It has been found that SARS-CoV-2 infects our body through the expression of angiotensin-converting enzyme 2 (ACE2), the main host receptor of this virus. ACE2 is found on the surface of cells found in our airways, including type II alveolar epithelium.¹ From there, the virus continues to spread and cause damage to the alveolar spaces as well as the rest of the body in multiple stages. Stage 1, or the exudative stage, entails forming a hyaline membrane along the alveolar wall coupled with inflammatory cell infiltration.¹ At stage 2, or the organizing stage, lesions continue to spread through the alveolar space and a more defined hyaline membrane can be seen. In this stage, we can observe the detachment of alveolar epithelial cells, hyperplasia of type II alveolar epithelial cells, and congestion and hemorrhage in the alveolar space.¹ Finally, stage 3, or the fibrotic stage, consists of the proliferation of fibroblasts, worsening of lesions, and collagen fiber deposit, leading to the obstruction of alveolar space and modification of alveolar structure.¹

Human Leukocyte Antigens and Their Role in COVID-19 Response

Not only has the pathology of COVID-19 been uncovered but through new research, it has also been found that specific genotypes play a significant role in pre-determining which individuals are more susceptible to contracting this virus, as well as the severity this virus may have on this person.² More specifically, human leukocyte antigen (HLA) alleles are used by our immune system to differentiate foreign cells in our body by encoding for the expression of cell surface glycoproteins that help present antigens to T cells. In the case of COVID-19, specific HLA alleles contain a varying binding affinity to certain viral peptides expressed on the surface of SARS-CoV-2.² Therefore, depending on an individual’s specific allele of these HLA proteins, one may have a higher or lower binding affinity to SARS-CoV-2 cells compared to others, leading to varying degrees of immune system response.

Literature Review

To test these theories, Nguyen et al. ran an in silico analysis of the binding affinity between multiple alleles of HLA and SARS-CoV-2 peptides. By pairing certain HLA genotypes with SARS-CoV-2 proteins, such as the spike glycoprotein (S protein) and open reading frame 1ab (ORF1ab) polyprotein, the researchers of this study were able to examine the potential relationship between viral presentation and type of HLA allele. This was a first-of-its-kind study that demonstrated genotype variability may be associated with severity of viral infection. From the results gathered, it was seen that the presence of the HLA-B*46:01 gene could be associated with the development of a more severe COVID-19 illness. However, it was also revealed that this gene had the ability to present highly conserved SARS-CoV-2 peptides that are shared among other coronaviruses, suggesting that it could enable cross-protective T-cell-based immunity.³

Furthermore, another study conducted by Charonis et al. involved a similar simulation, testing the binding affinities of 61 common HLA class I alleles to epitopes from the S protein and ORF1ab polyprotein.⁴ These proteins play a crucial role in the antigenic effect of SARS-CoV-2.⁴ It was concluded that all 61 alleles showed good binding affinities to both proteins assessed. Though there were no major differences in binding affinities between the two proteins, it was observed that a difference existed among the various HLA genotypes. HLA gene A (HLA-A) was the most effective at binding to the S protein and ORF1ab epitopes compared to gene B (HLA-B) and C (HLA-C). It was noted that this result may not apply to all populations around the world, and further studies must be done to truly narrow down how HLA genotypes affect viral susceptibility.⁴

When it comes to asymptomatic patients, genotyping also plays a prevalent role in determining who is affected by SARS-CoV-2 and to what degree. As shown by a study done by Augusto et al., a specific variant of HLA, the HLA-B*1501 genotype, can allow for some individuals to be asymptomatic while having COVID-19. Over 1,400 participants were included in the cohort study due to being unvaccinated and reporting a positive SARS-CoV-2 test. The results of this study demonstrated that there was a high frequency of carrying the HLA-B*15:01 genotype among those who were asymptomatic (20%) as compared to those who were symptomatic (9%) after SARS-CoV-2 infection.⁴ Upon this observation, the investigators then decided to observe how this specific gene variant affects the ability of T-cells to recognize SARS-CoV-2. It was seen that T-cells not only recognized these SARS-CoV-2 segments, or more specifically the NQK-Q8 peptide companied with the virus, but also other coronavirus segments containing a similar peptide, NQK-A8, which causes seasonal colds.⁵  Therefore, it was concluded that because these two viral peptide segments bound to the HLA-B*15:01 protein in a similar manner, the T-cells of these individuals with the HLA-B*15:01 mutation can learn to recognize these segments and attack immediately, eliminating the threat of the virus before symptoms can develop. Therefore, this study concluded that a majority of asymptomatic individuals contain the HLA-B*15:01 genotype mutation, which grants them almost immediate protection against an invading viral peptide segment, further preventing any symptoms of infection to occur in the body and allowing an individual to appear and feel seemingly healthy as compared to those missing this HLA gene.

Conclusion

Many factors can contribute to how one reacts to an illness like COVID-19, including age, social support, and comorbidities. However, our genes play a major role in dictating our personal immune responses to SARS-CoV-2. Although not every individual who presents asymptomatically possesses this HLA genetic mutation, the discovery of this mutation provides insight into how an individual may become asymptomatic and fight off COVID-19  differently than others.

References

1. Iida S, Arashiro T, Suzuki T. Insights into Pathology and Pathogenesis of Coronavirus Disease 2019 from a Histopathological and Immunological Perspective. JMA J. 2021;4(3):179-186. doi:10.31662/jmaj.2021-0041
2. Augusto DG, Hollenbach JA. HLA variation and antigen presentation in COVID-19 and SARS-CoV-2 infection. Curr Opin Immunol. 2022;76:102178. doi:10.1016/j.coi.2022.102178
3. Nguyen A, David JK, Maden SK, et al. Human Leukocyte Antigen Susceptibility Map for Severe Acute Respiratory Syndrome Coronavirus 2. J Virol. 2020;94(13):e00510-20. Published 2020 Jun 16. doi:10.1128/JVI.00510-20
4. Charonis SA, Tsilibary EP, Georgopoulos AP. In silico investigation of binding affinities between human leukocyte antigen class I molecules and SARS-CoV-2 virus spike and ORF1ab proteins. Explor Immunol. 2021;1:16-26. https://doi.org/10.37349/ei.2021.00003
5. Augusto DG, Murdolo LD, Chatzileontiadou DSM, et al. A common allele of HLA is associated with asymptomatic SARS-CoV-2 infection. Nature. 2023;620(7972):128-136. doi:10.1038/s41586-023-06331-x

Published by Rho Chi Post