Bai Li

Chikungunya virus (CHIKV) pathogenesis research has long been constrained by the lack of suitable immunocompetent rodent models. Through serial passaging in A129 and C57BL/6 mice, we obtained an adapted strain (CHIKV-Adapt) harboring an E2-K200R substitution along with non-structural protein mutations. Phenotypic analysis in C57BL/6 mice, BALB/c mice, and hamster models demonstrated that compared to the wild-type virus CHIKV-Adapt induced significantly higher and more prolonged viremia, broader tissue tropism, and more severe internal joint inflammation, without exacerbating external swelling. Notably, the K200R mutation did not alter the viral replication kinetics in vitro and was predicted not to affect its binding pattern to the MXRA8 receptor. Furthermore, mice challenged 160 days after primary infection exhibited nearly complete protective immunity. These findings indicate that E2-K200R is a critical adaptive mutation that, together with accompanying non-structural mutations, significantly enhances CHIKV replication capacity and pathogenicity in immunocompetent rodents without changing its in vitro replication ability or predicted receptor-binding mode. The acquisition of this adapted strain provides a new tool for CHIKV pathogenesis research and vaccine evaluation.

Clinical evidence has associated H1N1 influenza with liver impairment, yet the underlying mechanisms remain poorly understood. Here, we investigated H1N1-induced liver damage and its potential mechanisms using a BALB/c mouse infection model. Pathological examination and serum aspartate transaminase (AST) and alanine transaminase (ALT) were assessed. Messenger ribonucleic acid-sequence was used to analyze the transcriptomic changes in tissues. Multiple inflammatory cytokines in tissues and inflammatory cells in the blood were detected on the fifth day post-infection. Our results showed that H1N1 infection caused significant liver pathology and elevated serum AST/ALT levels. Transcriptomic analysis revealed significant alterations in liver gene expression profiles following H1N1 infection, particularly in genes associated with inflammatory responses, including those involved in monocyte adhesion/activation and neutrophil/macrophage infiltration. Marked increases in inflammatory mediators were observed in lungs, serum, and liver, accompanied by systemic changes in circulating inflammatory cells, indicating H1N1 triggered a robust systemic inflammatory response. These findings suggest that H1N1-induced liver damage may be associated with the systemic inflammatory response induced by H1N1 and changes in liver gene regulation.

Soluble host factors in the upper respiratory tract can serve as the first line of defense against SARS-CoV-2 infection. In this study, we described the identification and function of a human airway trypsin–like protease (HAT), capable of reducing the infectivity of ancestral SARS-CoV-2. Further, in mouse models, HAT analogue expression was upregulated by SARS-CoV-2 infection. The antiviral activity of HAT functioned through the cleavage of the SARS-CoV-2 spike glycoprotein at R682. This cleavage resulted in inhibition of the attachment of ancestral spike proteins to host cells, which inhibited the cell-cell membrane fusion process. Importantly, exogenous addition of HAT notably reduced the infectivity of ancestral SARS-CoV-2 in vivo. However, HAT was ineffective against the Delta variant and most circulating Omicron variants, including the BQ.1.1 and XBB.1.5 subvariants. We demonstrate that the P681R mutation in Delta and P681H mutation in the Omicron variants, adjacent to the R682 cleavage site, contributed to HAT resistance. Our study reports what we believe to be a novel soluble defense factor against SARS-CoV-2 and resistance of its actions in the Delta and Omicron variants.