Lethal Disease Following H5N1 Avian Influenza Virus Clade 2.3.4.4b Infection in Macaques
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PROVIDER: PRJNA1214282 | ENA |
REPOSITORIES: ENA
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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.
2025-08-01 | GSE287709 | GEO
Project description:Background Clade 2.3.4.4b highly pathogenic avian influenza (HPAI) H5N1 viruses are widely circulating in North America with unprecedented transmission into novel host species. A high incidence of neurologic disease is observed in carnivores infected with clade 2.3.4.4b HPAI H5N1 viruses and historical outbreaks of HPAI H5N1 in humans are also associated with neurologic complications, raising concerns about neurotropism and neurovirulence of clade 2.3.4.4b HPAI H5N1 viruses. Methods We analyzed virus replication kinetics, cellular tropism, and host responses to infection in human cerebral organoids (hCOs) inoculated with clade 2.3.4.4b HPAI H5N1 viruses compared to a historical clade 1 HPAI H5N1 virus and a seasonal influenza A virus. Results HPAI H5N1 viruses replicated to high titers in hCOs, but replication of the seasonal influenza A virus was not detected. Viral antigen and RNA were detected primarily in neuron- and astrocyte-like cells. Interferon responses to infection with HPAI H5N1 viruses were observed in a small population of bystander cells. Higher levels of cell death and proinflammatory cytokines and chemokines were observed in organoids inoculated with the historical HPAI H5N1 isolate. Conclusions Clade 2.3.4.4b HPAI H5N1 viruses exhibit similar neurotropism compared to a historical clade 1 HPAI H5N1 virus. Lower levels of cell death and inflammatory cytokine production induced by clade 2.3.4.4b viruses may indicate reduced neuropathogenic potential of these viruses in humans.
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Project description:The unexpected circulation of clade 2.3.4.4b H5N1 influenza viruses in dairy cattle and the transmission to diverse mammalian species poses a pandemic risk. We sought to explore cattle and human respiratory susceptibility to the 2.3.4.4b H5N1 virus. We establish long-term expandable cattle airway and mammary organoids. The 2.3.4.4b H5N1 virus exhibits high replicative fitness in cattle mammary organoids, recapitulating its remarkable mammary tropism. The virus also replicates robustly in cattle airway organoids, suggesting an underrecognized respiratory component in ongoing outbreaks. Interestingly, human airway and nasal organoids are highly susceptible to the 2.3.4.4b H5N1 virus. Yet, a novel organoid-based neutralization assay reveals that N1 antibodies in human sera had cross-neutralizing activity against the 2.3.4.4b H5N1 and ancestral H5N1-VN1194 viruses. The cross-neutralization, exclusively manifested in the organoid-based assay, is enhanced after seasonal influenza vaccination and diminished after depleting N1-specific antibodies. Therefore, cross-neutralizing N1 antibodies are likely limiting zoonotic infection by H5N1 viruses in humans.
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Project description:Highly pathogenic avian influenza A(H5N1) viruses of clade 2.3.4.4b are currently spreading widely among poultry, cattle, and other mammals in the United States, raising concern for zoonotic transmission and pandemic potential. To investigate the pathogenicity and host response of the newly emerged A/Cattle/Texas/063224-24-1/2024 (H5N1b/2024) strain in comparison to reference viruses, we performed bulk RNA sequencing of primary human respiratory models, including ex vivo alveolar lung tissue (aHuLu), organoid-derived bronchial epithelium (brEp), and 3D nasal air-liquid interface epithelium (nALI). Infections were carried out in parallel with H5N1/2004 (clade 1), H3N2/1999 (seasonal influenza A), and H5N8/2016 (low pathogenic avian influenza). Differential gene expression analysis was performed with DESeq2, including donor as a covariate. The dataset provides genome-wide transcriptional profiles at 24 h post-infection, enabling comparative analysis of viral replication, host immune activation, and tissue-specific responses across human respiratory compartments. These data support the use of physiologically relevant primary human models for assessing zoonotic risk of emerging influenza A viruses.
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