Project description:The H5N1 avian influenza virus clade 2.3.4.4b outbreak represents a major pandemic threat for humans, with some reported cases of severe and fatal respiratory illness. A key unanswered question is the pathogenesis of severe H5N1 disease following respiratory infection. In this study, we explored mechanisms of pathogenesis of severe H5N1 disease in cynomolgus and rhesus macaques following infection with the H5N1 isolate A/Texas/37/2024 (huTX37-H5N1). Cynomolgus macaques developed severe pneumonia that was lethal in 100% of macaques by 7 days post-infection. By contrast, rhesus macaques demonstrated dose-dependent mortality, and surviving animals showed protective immunity against high-dose re-challenge. A multi-omics analysis demonstrated that H5N1 infection was characterized by robust induction of proinflammatory cytokines, innate immune cells, complement, coagulation, apoptosis, and immune exhaustion pathways. Taken together, our data indicate inflammation and immune dysregulation as key mechanisms of H5N1 pathogenesis in nonhuman primates.
Project description:The 2024 outbreak of highly pathogenic avian influenza virus (HPAIV) H5N1 in U.S. dairy cattle presented an unprecedented scenario where the virus infected bovine mammary glands and was detected in milk, raising serious concerns for public health and the dairy industry. Unlike previously described subclinical influenza A virus (IAV) infections in cattle, H5N1 infection induced severe clinical symptoms, including respiratory distress, mastitis, and abnormal milk production. To understand the host immune responses and changes particularly in the mammary gland, we performed scRNA-seq analysis on bovine milk somatic cells (bMSC) in-vitro infected with H5N1 isolate from dairy farm. We identified ten distinct cell clusters and observed a shift toward type-2 immune responses, characterized by T-cells expressing IL13 and GATA3, and three different subtypes of epithelial cells based on expression of genes associated with milk production. Our study revealed temporal dynamics in cytokine expression, with a rapid decline in luminal epithelial cells and an increase in macrophages and dendritic cells, suggesting a role in increased antigen presentation. These findings indicate that bovine H5N1 infection triggers complex immune responses involving both pro-inflammatory and regulatory pathways. This research fills a critical gap in understanding the immune responses of bovine mammary glands to H5N1 infection and highlights the need for further investigation into therapeutic strategies for managing such outbreaks.
Project description:Experimental spillover of H5N1 clade 2.3.4.4b high pathogenicity avian influenza virus from gulls to minks reveals mammalian adaptation without spillback potential
Project description:The 2022 North American outbreak of 2.3.4.4b H5N1 avian influenza virus revealed significant mammalian adaptation and pathogenicity, yet mechanisms remain unclear. To address this knowledge gap, we investigated the North American H5N1 strain (GA/W22-145E/22), which demonstrated unique immune cell-mediated systemic dissemination, neuroinvasion, and 100% mortality in ferrets, unlike the non-lethal Eurasian strain (KR/W811/21). Genomic and reverse genetics studies identified PB2478I and NP450N mutations as key determinants of enhanced polymerase activity, immune cell tropism, and pathogenicity. Mutant GA/W22-145E/22 virus carrying PB2478V/NP450S showed complete survival without systemic dissemination. Furthermore, GA/W22-145E/22 demonstrated robust replication in human PBMCs and bovine mammary gland organoids, raising concerns about zoonotic spillover. These findings underscore PB2478I and NP450N as pivotal markers of pathogenicity, emphasizing the urgent need for enhanced surveillance and targeted interventions
2025-08-25 | GSE302017 | GEO
Project description:Highly Pathogenic Avian Influenza A virus subtype H5N1 (clade 2.3.4.4b) Isolated from a natural protected area in Peru