Highly pathogenic avian influenza H5N1 clade 2.3.4.4b genotype B3.13 is highly virulent for mice, rapidly causing acute pulmonary and neurologic disease.

The highly pathogenic avian influenza (HPAI) A(H5N1) clade 2.3.4.4b viruses, responsible for the current outbreak in dairy cows in the United States, pose a significant animal and public health threat. In this study, we compare disease progression and pathology of three recent clade 2.3.4.4b isolates derived from a cow, a mountain lion, and a mink to a human HPAI A(H5N1) isolate from Vietnam in mice. Inoculating C57BL/6J and BALB/c mice with all four HPAI A(H5N1) isolates results in comparable levels of virus replication in the lung inducing significant local pro-inflammatory cytokine responses and severe respiratory disease. Infecting C57BL/6J mice with the bovine isolate yields high viral titers in the brain, a significant pro-inflammatory cytokine response and neurologic disease. Our findings suggest the recent bovine isolate possesses enhanced neuroinvasive/neurovirulent disease causing fatal respiratory and neurologic disease in C57BL/6J mice.