Enhanced encephalitic tropism of bovine H5N1 compared to the Vietnam H5N1 isolate in mice

In recent years, the landscape of highly pathogenic avian influenza (HPAI) virus infections has shifted, as evidenced by an increase in infections among mammals. This includes the recent circulation of H5N1 in dairy cattle herds in the USA and a rise in associated human cases. In this study, we investigated differences in tissue tropism of two HPAI H5N1 strains, the isolate A/Vietnam/1203/2004 (VN1203) isolated from a fatal human case in 2004 and the bovine isolate A/Bovine/Ohio/B24osu-342/2024 (Bov342) isolated in 2024, in C57BL/6J mice. Infection with either HPAI H5N1 isolate was uniformly lethal in mice. However, tissue tropism differed significantly: while VN1203 replication was largely restricted to the respiratory tract, Bov342 successfully replicated in the respiratory tract as well as various regions of the brain. Bov342-challenged animals exhibited clinical signs consistent with central nervous system (CNS) infection, and infectious virus was detected in brain tissue. Correspondingly, cytokine profiles in the brain differed significantly between the isolates. Notably, in addition to abundant evidence of CNS infection in Bov342-challenged mice via immunohistochemistry, sporadic intranuclear and intracytoplasmic immunoreactivity was observed in other tissues in the head, including the choroid plexus, retina, and inner ear. This study demonstrates that while both HPAI H5N1 isolates are uniformly lethal in C57BL/6J mice upon aerosol exposure, significant differences exist in tissue tropism, with Bov342 resulting in respiratory disease as well as increased neurotropism and inflammation in the brain and nasal turbinates compared to VN1203, which predominantly induces respiratory disease. Significance statement The rise in HPAI H5N1 infections among mammals, including humans in the USA, highlights an emerging One Health concern. Understanding the phenotypic changes of HPAI H5N1 and associated increase in infection of mammalian hosts is critical. In this study, we investigated the tissue tropism in mice of a bovine HPAI H5N1 strain isolated in 2024 and compared it to a strain isolated from a human patient in 2004. Our findings reveal that the bovine isolate exhibits enhanced neurotropism, unlike the respiratory-restricted replication observed with the HPAI H5N1 isolate from 2004. This difference in tissue tropism, accompanied by distinct cytokine responses in the brain, underscores the potential for altered disease outcomes in other mammalian hosts.