New study finds why some population may be more susceptible to COVID-19

April 13, 2020 0 By FM

A rapid study by a team of scientists in India and the US under the aegis of genetics research and data company MedGenome Inc and science education trust SciGenom Research Foundation (SGRF) led by genomics researcher Dr Sekar Seshagiri has identified that the natural ACE2 variants that are predicted to alter the virus-host interaction makes some people more susceptible to the infection of coronavirus, while others are not. 

The study, which throws light on what made the spread of COVID-19 infection wider and more severe in certain population, may turn out to be an important breakthrough to assess why the outbreak was more severe in the West compared to the East. This finding may also help in various rapid research projects, currently in progress worldwide, to develop an effective treatment for the infection.    

The preliminary report of this new finding published in bioRxiv says the viral spike (S) coat protein engages the human angiotensin-converting enzyme2 (ACE2) cell surface protein to invade the host cell.  

ACE2 is an enzyme attached to the outer surface of cells in the lungs, arteries, heart, kidney, and intestines. This enzyme which helps lowering blood pressure by catalysing the cleavage of angiotensin II into angiotensin, also serves as the entry point into cells for some coronaviruses.  

Critically supporting this new findings, a parallel study in Italy had also almost established that ACE2 variants underlie interindividual variability and susceptibility in Italian population. Italy was the most affected country by COVID-19 with the total number of confirmed cases crossing 1,60,000 and about 20,000 deaths so far.   

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease (COVID-19), has resulted in the current global pandemic and it has already affected more than 1.8 million people across some 210 countries around the world. SARS-CoV-2 is a highly contagious positive strand RNA virus and its clinical presentation includes severe to critical respiratory disease that appears to be fatal in about 3% to 5% of the cases.

The study states that SARS-CoV-2 S-protein has acquired mutations that increase its affinity to human ACE2 by ~10-15-fold compared to SARS-CoV S-protein, making it highly infectious. 

“In this study, we assessed if ACE2 polymorphisms might alter host susceptibility to SARS-CoV-2 by affecting the ACE2 S-protein interaction,” said the authors of the bioRxiv report. 
According to the authors, their comprehensive analysis of several large genomic datasets that included over 290,000 samples representing >400 population groups identified multiple ACE2 protein-altering variants, some of which mapped to the S-protein-interacting ACE2 surface. 

“Using recently reported structural data and a recent S-protein-interacting synthetic mutant map of ACE2, we have identified natural ACE2 variants that are predicted to alter the virus-host interaction and thereby potentially alter host susceptibility. In particular, human ACE2 variants S19P, I21V, E23K, K26R, T27A, N64K, T92I, Q102P and H378R are predicted to increase susceptibility. The T92I variant, part of a consensus NxS/T N-glycosylation motif, confirmed the role of N90 glycosylation in immunity from non-human CoVs,” they said in the report. 

Other ACE2 variants K31R, N33I, H34R, E35K, E37K, D38V, Y50F, N51S, M62V, K68E, F72V, Y83H, G326E, G352V, D355N, Q388L and D509Y are putative protective variants predicted to show decreased binding to SARS-CoV-2 S-protein. Overall, ACE2 variants are rare, consistent with the lack of selection pressure given the recent history of SARS-CoV epidemics, however, are likely to play an important role in altering susceptibility to CoVs, the report said.