Genetic resistance to COVID-19 could present a previously untapped resource in the fight against the virus, international experts say in a new report. Genes conferring natural resistance have been identified in other infections, including HIV and norovirus, and could provide an opportunity to better understand COVID-19 and develop improved treatments and vaccines.

Published today in Nature Immunology, the perspective draws on the wealth of knowledge already out there to consider factors that could influence an individual’s susceptibility to severe outcomes, as well as factors that could give rise to inborn resistance. The team present several targets for future research and provide a comprehensive strategy detailing how this research be conducted.

As has become apparent in the 22 months since the COVID-19 pandemic began, infections are incredibly variable, ranging from asymptomatic to life-threatening, with all the varying degrees in between. Some suffer mildly, some are hospitalized, and some continue to suffer for months after infection. Secondary attack rates – the probability that an infection occurs among susceptible people within a specific group – can reach up to 70 percent in some households, and there are numerous reports of individuals resisting infection despite the rest of their families succumbing. This is not, however, the result of a malevolent virus cherry-picking its targets – the authors of this new study suggest that, perhaps, the clinical variability of COVID-19 could be explained by genetic factors.

“Our study pertains to the intriguing enigma of humans who have not been infected with SARS-CoV-2 despite repeated and intense exposure to the virus. We propose that these cases are ‘genetic’ and explain how we intend to crack this enigma by means of human genetics,” study author Dr András N. Spaan told IFLScience.

The first of these “genetic” causes that the team considers relates to innate susceptibility to the virus. A deficiency of type I interferons (IFNs), for example, has been linked to around 20 percent of critical COVID-19 cases. Type I IFNs are proteins that play an integral role in the body’s antiviral immune response, so perhaps unsurprisingly, inborn errors in their genes have been linked to severe COVID-19. Errors at eight locations in two type I IFN genes were reported in 23 critically ill people by the COVID Human Genetic Effort. Subsequent studies have found that more than 10 percent of people with severe COVID-19 have pre-existing autoantibodies against type I IFNs, further suggesting that a lack of the proteins could increase one’s susceptibility to infection.

As for innate resistance, only three known examples currently exist – Plasmodium vivax, HIV-1, and norovirus infections. All these mechanisms are deficiencies of receptors or coreceptors which are exploited by the pathogen to enter host cells. Following this line of research, the authors suggest that those with O-type blood groups may be slightly more resistant. ABO blood groups may play a direct role in infection by serving as coreceptors for SARS-CoV-2. 

Further candidate SARS-CoV-2 resistance genes that the team suggest include those for the ACE2 receptor, which the virus uses for cell entry. A rare mutation was found to safeguard against infection, possibly by reducing ACE2 expression, while different forms of the receptor are known to bind the virus’s spike protein with different affinities.

Another protein, TMEM41B, which is required for viral entry in flaviviruses – a viral family that includes the dengue, yellow fever, and Zika viruses – could be of interest, the authors say. Its impact on SARS-CoV-2 infection is yet to be established, but it has been identified as a requirement for permissive infection with the virus. In flavivirus studies, an allele common in East and South Asians has been linked with a lower capacity to support flavivirus infection.

In order to test these potential resistance targets, the authors suggest a four-step strategy, which begins by focusing on uninfected individuals in the same household as people with symptomatic COVID-19. Next up are individuals exposed to the virus without personal protection equipment, followed by those with negative PCR and serological tests following exposure. Finally, T cell – a type of immune cell – response in “resistant” individuals are to be compared with those of the infected. In fact, the team are currently recruiting for a dedicated resistance study. So far, 400 individuals are enrolled.

The results of this study, the team hopes, could lead to the development of new COVID therapies; “Our study has the potential to pave the way for the development of rationally novel drugs blocking infection with SARS-CoV-2,” Spaan added to IFLScience.

“The emergence of viral variants partly capable of escaping immunity serves as a warning that COVID-19 is likely to persist as a global health problem for years. Given the lack of specific and effective drugs for treating COVID-19, the need to unravel mechanisms of inborn resistance to SARS-CoV-2 infection has become more urgent than ever.”