Pei Zhou

Recent reports have highlighted the increasing frequency of influenza A virus (IAV) spillover events from other species to dogs and cats. IAV, particularly the H3 subtype, exhibits a broad host range and a propensity for interspecies transmission, as exemplified by the sustained circulation of H3N2 and H3N8 canine influenza viruses in dog populations. This raises concerns about the potential role of companion animals as intermediate hosts in influenza virus transmission. To evaluate the susceptibility of dogs and cats to the prevalent H3 subtype influenza viruses, we experimentally inoculated groups of both species with three prevalent influenza viruses: H3N2 avian influenza virus (AIV), H3N8 avian influenza virus, and H3N2 swine influenza virus (SIV). Results showed that while all inoculated dogs exhibited seroconversion to all three viruses at 7, 14, and 21 days post-inoculation (dpi), they displayed no clinical signs, viral shedding, or evidence of viral replication in their organ tissues. In contrast, despite the cats did not exhibit apparent clinical signs, all inoculated cats exhibited seroconversion to all viruses at 7, 14 and 21 dpi, sustained nasal viral shedding for approximately one week, and demonstrated viral replication in their lungs, trachea, and nasal turbinate. Our findings underscore the higher susceptibility of cats compared to dogs to H3 subtype influenza viruses. These results emphasize the critical need for enhanced surveillance of cats within the influenza virus transmission network.

As companion animals, dogs are susceptible to various subtypes of influenza A virus (IAV), with the H3N2 and H3N8 subtypes of canine influenza virus (CIV) stably circulating among canines. Compared to the H3N8 CIV, the H3N2 CIV is more widely prevalent in canine populations and demonstrates increased adaptability to mammals, potentially facilitating cross-species transmission. Therefore, a comprehensive elucidation of the mechanisms underlying H3N2 CIV adaptation to mammals is imperative. In this study, we serially passaged the GD14-WT strain in murine lungs, successfully establishing a lethal H3N2 CIV infection model. From this model, we isolated the lethal strain GD14-MA and identified the key lethal mutations PA(S184N) and PB2(E627K). Moreover, the GD14-ma[PA(S184N)+PB2(E627K)] strain exhibited markedly enhanced pathogenicity in dogs. Viral titers in lung tissues from infected dogs and mice showed that GD14-ma[PA(S184N)+PB2(E627K)] does not increase its pathogenicity to mice and dogs by upregulating viral titers compared to the GD14-WT strain. Notably, sequence alignments across all H3N2 IAVs showed an increasing prevalence of the PA (S184N) and PB2 (E627K) mutations from avian to human hosts. Finally, single-cell RNA sequencing of infected mouse lung tissues showed that GD14-ma[PA(S184N)+PB2(E627K)] effectively evaded host antiviral responses, inducing a robust inflammatory reaction. Considering the recognized role of the PB2 (E627K) mutation in the mammalian adaptation of IAVs, our findings underscore the importance of ongoing surveillance for the PA (S184N) mutation in H3N2 IAVs. IMPORTANCE: Since the 21st century, zoonotic viruses have frequently crossed species barriers, posing significant global public health challenges. Dogs are susceptible to various influenza A viruses (IAVs), particularly the H3N2 canine influenza virus (CIV), which has stably circulated and evolved to enhance its adaptability to mammals, including an increased affinity for the human-like SAα2,6-Gal receptor, posing a potential public health threat. Here, we simulated H3N2 CIV adaptation in mice, revealed that the synergistic PA(S184N) and PB2(E627K) mutations augment H3N2 CIV pathogenicity in dogs and mice, and elucidated the underlying mechanisms at the single-cell level. Our study provides molecular evidence for adapting the H3N2 CIV to mammals and underscores the importance of vigilant monitoring of genetic variations in H3N2 CIV.

Canine parvovirus type 2 (CPV-2) is a member of the Parvoviridae family, characterized by its small, non-enveloped virions containing a linear single-stranded DNA genome of approximately 5 kb. Parvoviruses entirely reliant on the host cell’s division machinery for replication. In this study, we demonstrate that CPV-2 infection triggers the host translation shutoff, a process in which the nonstructural protein 1 (NS1) plays a pivotal role. Our findings indicate that the CPV-2 NS1-induced host translation shutoff is not associated with transcription, protein degradation pathways, or eIFα phosphorylation, but rather involves the reduction of phosphorylation of the mammalian target of rapamycin (mTOR). In conclusion, this research reveals that CPV-2 NS1 induces a host translation shutoff by reducing mTOR phosphorylation, a mechanism that could potentially inform the development of more efficacious control and therapeutic strategies for CPV-2 and other parvoviral infections. IMPORTANCE: Autonomous parvoviruses, which possess compact genomes, are obligate intracellular parasites that necessitate host cell division for their replication cycle. Consequently, the modulation of host translation and usurpation of cellular machinery are hypothesized to facilitate immune evasion, enhance viral transmission, and perpetuate long-term infection. Despite the biological significance, the precise mechanisms by which autonomous parvoviruses regulate host translation remain understudied. Our study elucidates that CPV-2 infection induces a shutoff of host translation through the attenuation of mTOR phosphorylation. This mechanism may enable the virus to subvert the host immune response and engender pathogenic effects.