Within-host evolutionary dynamics and tissue compartmentalization during acute SARS-CoV-2 infection

Abstract

The global evolution of SARS-CoV-2 depends in part upon the evolutionary dynamics within individual hosts with varying immune histories. To characterize the within-host evolution of acute SARS-CoV-2 infection, we deep sequenced saliva and nasal samples collected daily from immune and unvaccinated individuals early during infection. We show that longitudinal sampling facilitates high-confidence genetic variant detection and reveals evolutionary dynamics missed by less-frequent sampling strategies. Within-host dynamics in both naive and immune individuals appeared largely stochastic; however, we identified clear mutational hotspots within the viral genome, consistent with selection and differing between naive and immune individuals. In rare cases, minor genetic variants emerged to frequencies sufficient for forward transmission. Finally, we detected significant genetic compartmentalization of virus between saliva and nasal swab sample sites in many individuals. Altogether, these data provide a high-resolution profile of within-host SARS-CoV-2 evolutionary dynamics.

Recent changes in the mutational dynamics of the SARS-CoV-2 main-protease substantiate the danger of emerging resistance to antiviral drugs.

“…For deepening the knowledge of the evolutionary process of in-host DAA evasion and the resulting impact on druggability, we further propose continuous time-resolved sequencing of SARS-CoV-2 samples collected from COVID-19 patients, who are treated with protease inhibitors, during their treatment phase. Similar studies, but with untreated patients, have recently been reported 71,72 . Finally, we propose the expression of the newly evolved M pro variants for inhibition experiments and subsequent determination of their experimental structural complexes.…”

Rapid transmission and tight bottlenecks constrain the evolution of highly transmissible SARS-CoV-2 variants

“…However, we found that all transmission pairs had equal bottlenecks even when we tested mutually exclusive transmission pairs. Second, virus populations may be spatially segregated within hosts, and the transmitted population may not have been well sampled by our analysis of nasal swabs [43][44][45][46][47] . However, given the low viral diversity identified in nearly all cases, even spatially segregated viral populations are likely to be genetically similar to each other.…”

Recent changes in the mutational dynamics of the SARS-CoV-2 main protease substantiate the danger of emerging resistance to antiviral drugs

“…These include a quantitative model of the in-host evolutionary dynamics of coronaviruses under the pressure of a targeted antiviral drug, accompanied by structural-bioinformatic studies of M pro variants in complex with its natural substrate and inhibitors. Evolutionary studies with remdesivir-treated ( 71 ) and untreated ( 72 , 73 ) patients have recently been reported. For deepening the knowledge of the evolutionary process of in-host DAA evasion and the resulting impact on druggability, we further propose continuous time-resolved sequencing of SARS-CoV-2 samples collected from COVID-19 patients, who are treated with protease inhibitors, during their treatment phase.…”