A natural vaccine?

 

Geographic distribution of the G allele (TIMPRSS2), which is associated with a higher death rate from COVID-19. It’s most frequent on the Indo-Gangetic Plain, which has the longest continuous history of urban settlement in South Asia. Did that environment select for susceptibility to coronaviruses as a way to boost resistance to deadlier respiratory viruses?

 

 

The common cold is caused by over 200 strains of rhinoviruses, coronaviruses, adenoviruses, and enteroviruses. Coronaviruses differ from other respiratory viruses in one key respect: they can enter lung tissue via the ACE2 receptor. So if that receptor is altered to allow easier entry, the host would become more susceptible to the common cold but not to other respiratory diseases, including much deadlier ones that cause tuberculosis, pneumonia, or pneumonic plague.

 

The last point is important because there is evidence that a viral infection can protect against subsequent infection by respiratory viruses. When mice are infected with γherpesvirus 68, which is similar to Epstein-Barr virus, there is production of large quantities of IFN-γ and activation of macrophages that protect against Listeria monocytogenes (which causes listeriosis), Mycobacterium tuberculosis (which causes tuberculosis), and Yersinia pestis (which causes bubonic and pneumonic plague) (Barton et al., 2007; Miller et al., 2019). A cytomegalovirus infection likewise protects against Listeria monocytogenes and Yersinia pestis (Barton et al., 2007).

 

Coevolution between coronaviruses and early urban settlement

 

Beginning some 10,000 years ago, hunting and gathering gave way to farming, and nomadism to sedentism. People began to live in progressively larger settlements along the Nile in Egypt, the Tigris and the Euphrates in Mesopotamia, the Indus and the Ganges in northern India, and the Yellow and the Yangtze in China. That is where large numbers of humans first lived in close proximity to each other, and they were particularly vulnerable to the spread of respiratory diseases from one person to another. There may thus have been selection among them for increased susceptibility to coronaviruses, which are normally mild in their effects, as a means to increase resistance to deadlier respiratory viruses.

 

A recent Indian study by Pandey et al. (2022) suggests that coronavirus susceptibility may have coevolved with risk of infection by life-threatening respiratory viruses like tuberculosis, pneumonia, and pneumonic plague, at least in South Asia. People are more susceptible to infection by coronaviruses if they have the G allele of the TMPRSS2 gene. The research team found that the G allele is significantly associated with a higher fatality rate for COVID-19, apparently because it helps coronaviruses enter lung tissue via the ACE2 receptor.

 

Pandey et al. (2022) also charted the geographic distribution of the G allele in South Asia. This allele is most frequent among inhabitants of the Indo-Gangetic Plain, i.e., the fertile lowlands that border the Indus and Ganges rivers of northern India and Pakistan. This is also where urbanization has existed for the longest continuous time in South Asia, specifically since the early first millennium BCE. The Indo-Gangetic Plain has had "an uninterrupted sequence of economic development, state formation, and cultural expansion affecting the entire subcontinent as well as Central, East and Southeast Asia" (Heitzman 2008, pp. 12-13).

 

These findings are roughly consistent with an earlier finding by the same research team. Srivastava et al. (2020) found that an ACE2 allele, at rs2258666, has a negative relationship with the fatality rate for COVID-19. It is also most frequent in the northeast of India, which until recent times was sparsely populated, and whose inhabitants lived in dispersed rural settlements.

 

References

 

Barton, E.S., D.W. White, J.S. Cathelyn, K.A. Brett-McClellan, M. Engle, et al. (2007). Herpesvirus latency confers symbiotic protection from bacterial infection. Nature

447: 326-329.

https://doi.org/10.1038/nature05762

 

Frost, P. (2020). Does a commensal relationship exist between coronaviruses and some human populations? Journal of Molecular Genetics 3(2): 1-2.

https://researchopenworld.com/does-a-commensal-relationship-exist-between-coronaviruses-and-some-human-populations/

 

Heitzman, J. (2008). The City in South Asia. London: Routledge

 

Miller, H.E., K.E. Johnson, V.L. Tarakanova, and R.T. Robinson. (2019). γ-herpesvirus latency attenuates Mycobacterium tuberculosis infection in mice. Tuberculosis 116: 56-60.

https://doi.org/10.1016/j.tube.2019.04.022

 

Pandey, R.K., A. Srivastava, P.P. Singh, and G. Chaubey. (2022). Genetic association of TMPRSS2 rs2070788 polymorphism with COVID-19 case fatality rate among Indian populations. Infection, Genetics and Evolution 98 https://doi.org/10.1016/j.meegid.2022.105206

 

Shirato, K., M. Kawase, and S. Matsuyama. (2018). Wild-type human coronaviruses prefer cell-surface TMPRSS2 to endosomal cathepsins for cell entry. Virology 517: 9-15.

https://doi.org/10.1016/j.virol.2017.11.012

 

Srivastava, A., A. Bandopadhyay, D. Das, R.K. Pandey, V. Singh, N. Khanam, N. Srivastava, P.P. Singh, P.K. Dubey, A. Pathak, P. Gupta, N. Rai, G.N.N. Sultana, and G. Chaubey. (2020). Genetic Association of ACE2 rs2285666 Polymorphism with COVID-19 Spatial Distribution in India. Frontiers in Genetics. September 25

https://doi.org/10.3389/fgene.2020.564741