Distinct respiratory and neurological disease phenotypes in lethal Nipah virus Malaysia versus Bangladesh infection in IFNAR knockout mice

Nipah virus (NiV) strains Malaysia (NiV-M) and Bangladesh (NiV-B) cause severe respiratory and neurological disease in humans, yet no FDA-approved medical countermeasures currently exist. Since 2000, NiV-B has been responsible for most human outbreaks, underscoring the need for relevant animal models of this strain to support public health preparedness. While mice offer a scalable platform for high-throughput in vivo screening, susceptibility to NiV disease requires immunosuppression, and detailed clinical characterization, particularly for NiV-B, remains limited. Here, we comprehensively assessed NiV-M and NiV-B infection in mice lacking type I interferon receptor function (IFNAR KO) after intranasal (IN) or intraperitoneal (IP) inoculation. Our results reveal distinct, strain-specific patterns of disease, viral tropism, and early inflammatory responses. Following IP inoculation, lethal NiV-M disease was characterized by high levels of viral replication in the lung and other peripheral tissues, significantly higher circulating inflammatory mediator levels compared to NiV-B infection (4 and 6 days post-infection), and predominantly respiratory signs. In contrast, lethal NiV-B disease was associated with lower levels of viral replication in the lung and other peripheral tissues, minimal to absent circulating inflammatory mediators, and predominantly neurological signs, independent of inoculation route. Together, these data refine and strengthen the utility of IFNAR-deficient mouse models of NiV-M and NiV-B for studies of NiV pathogenesis and for preclinical evaluation of therapeutic candidates.