SARS-CoV-2 intra-host viral diversity associated with host innate and vaccine-induced immunity in an obese mouse model.

BACKGROUND

Obesity associated immune dysfunction is attributed to severe outcome of infectious diseases including Coronavirus Disease 2019 (COVID-19) and suboptimal vaccine responses.

METHODS

Utilizing diet-induced obese (DIO) mice vaccinated with COVID-19 mRNA vaccine, we investigated SARS-CoV-2 Omicron BA.1 variant intra-host mutation under the influence of different host immune states with or without vaccination. SARS-CoV-2 Omicron BA.1 infected mouse lung transcriptome and virus genome were acquired by RNA-sequencing.

RESULTS

Consistent with previous report that COVID-19 mRNA vaccine failed to induced serum neutralizing antibody but boosted host innate immunity upon virus challenge. At 2 days after virus challenging, the interferon and antiviral related genes were upregulated in the lungs of lean mice (regular weight controls) and vaccinated DIO mice, but not in unvaccinated DIO mice suggesting host innate immune responses to infection was not elicited in DIO mice, which was then restored by vaccination. Analysis of viral genomes in the different lung samples showed that SARS-CoV-2 was predominately under neutral or slightly negative selection in mouse lungs irrespective of immune status. However, increased intra-host viral genomic diversity was found at later infection time and vaccination-boosted host innate antiviral status in DIO mice. In total, 59 iSNVs (intra-host single nucleotide variant) were detected from 22 viral-positive-samples, 1 to 8 iSNV sites in each sample. Among which, most of the iSNVs were detected from the lungs of COVID-19 mRNA vaccine immunized DIO mice. Correlation analysis of viral mutation and host transcriptome signatures showed that the appearance of iSNV in ORF1ab, Nucleocapsid (N) and Membrane (M) genes was associated with host innate immunity. Remarkably, the Leu176His mutation in M gene was identified in all the vaccinated obese mouse lungs whereas only in one lung at 4dpi in unvaccinated DIO, which may imply the interplay between viral mutation and host antiviral immunity in the context of obesity.

CONCLUSIONS

This study advances our comprehension of SARS-CoV-2 mutation and evolution in obese related insufficient vaccine response, highlighting the impact of immune compromised host on viral evolution.