Could the P681R mutation make Delta more pathogenic?

The enzyme involved in the SARS-CoV-2 genome mechanism of creating new virions makes random errors during this replication process, leading to mutations. When a mutation gives the virus an advantage, such as improved transmission effectiveness, it persists. The more a virus is transmitted, the more it reproduces, and the greater the risk of mutations. When a virus combines several mutations, we call it a variant. Numerous variants have already emerged, such as Alpha (UK), Beta (South African), Gamma (Brazilian) and, more recently, Delta (Indian). In this study, scientists have attempted to better characterise the Delta variant, which appears to be more pathogenic than the others.

A consortium of Japanese researchers (from the Universities of Miyazaki, Hokkaido, Tokyo, Kanagawa and Kumamoto) recently analysed the pathogenicity of Delta, that is, its capacity to cause illness, on a model of hamsters infected by different variants as well as the original Wuhan strain. There was more loss of weight amongst those hamsters infected with the Delta variant, and lung inflammation was more pronounced.

The scientists then looked to identify the reason for this increased pathogenicity. They carried out in vitro tests using cell culture. They observed that the Delta variant replicated more slowly than the original Wuhan strain. However, they noted that infection with the Delta variant formed larger syncytia, that is, led to the fusion of several cells to form a single one. This lysis of cells is caused by the membrane fusion activity mediated by the spike (S) surface protein of the virus. The formation of syncytia is one of the causes of the virus’ pathogenicity. But why is there greater fusion activity? The researchers showed that it is the P681R mutation, present in the S protein of the Delta variant, near to the region where the fusion activity occurs, that enables this increased membrane fusion.

Rapid characterisation of emerging variants, as is the case currently with Omicron, is essential so we can evaluate their level of risk.