# Large-particle aerosol exposure to the Bangladesh or Malaysia strain of Nipah virus results in markedly divergent disease presentation in African Green Monkeys

## TL;DR

This study shows that two strains of Nipah virus cause very different diseases in monkeys, with one being more deadly and causing stronger immune responses.

## Contribution

The study reveals distinct pathogenesis and immune responses between two Nipah virus strains in a nonhuman primate model.

## Key findings

- NiV-B caused rapid respiratory failure and high fatality with weak antibody responses, while NiV-M had a slower course and some survivors.
- NiV-B triggered early, intense inflammation, whereas NiV-M evaded the immune system longer before causing damage.
- The African green monkey model demonstrated clear differences in immune response, disease progression, and organ damage between the two strains.

## Abstract

Nipah virus (NiV), a highly pathogenic zoonotic paramyxovirus, causes severe respiratory and neurological disease in humans, with a case-fatality rate around 60%. Descriptions of cases in the clinical setting suggest that the two primary lineages of NiV cause disease with different presentations and outcomes. To define strain-specific differences in disease progression and host responses, African green monkeys were exposed to either the Malaysia (NiV-M) or Bangladesh (NiV-B) strain using a large-particle aerosol exposure. NiV-M infection resulted in a fatality rate of 27%, while NiV-B infection led to a 75% fatality rate characterized by rapid respiratory decline and systemic viral dissemination. Among survivors, NiV-M–infected animals mounted robust immunoglobulin M, immunoglobulin G, and neutralizing antibody responses, whereas NiV-B survivors exhibited weaker and delayed humoral responses. Non-survivors of both strains showed elevated pro-inflammatory cytokines, thrombocytopenia, and multi-organ dysfunction. Imaging showed that NiV-M infection was associated with neuroinflammation and systemic vasculitis, while NiV-B infection caused progressive pulmonary pathology. Histopathological analysis confirmed widespread vasculitis and encephalitis in animals with NiV-M infection and diffuse pulmonary hemorrhage and fibrin thrombi, consistent with vascular injury and coagulopathy, in animals with NiV-B infection. Cytokine profiling and flow cytometry showed a more intense and dysregulated immune response to NiV-B infection. Fatal outcomes in both groups were associated with thrombocytopenia, elevated pro-inflammatory cytokines, and multi-organ dysfunction. This study highlights fundamental differences in virulence, immune evasion, and pathogenesis between NiV strains and underscores the value of the African green monkey aerosol model for evaluating medical countermeasures under conditions that closely mimic natural human exposure.

Nipah virus (NiV) is a highly lethal zoonotic pathogen that causes respiratory and neurological disease in humans. There are no approved treatments or vaccines and understanding how different strains of NiV cause disease is critical for developing effective medical countermeasures. In this study, we used African green monkeys, a well-established nonhuman primate model, to compare the progression of disease caused by two NiV strains: Malaysia (NiV-M) and Bangladesh (NiV-B). We used a large-particle aerosol exposure method to mimic natural infection, which occurs via inhalation of droplets. NiV-B caused rapid respiratory failure, minimal antibody responses, and high fatality. In contrast, NiV-M led to a slower disease course, and some animals survived with strong antibody responses and signs of neurological involvement. Blood tests, imaging, and tissue analyses revealed clear differences in the immune response to each strain: NiV-B triggered an early, intense inflammatory response, while NiV-M evaded the immune system longer before causing damage. These findings provide insight and highlight differences in disease severity, immune response, and clinical outcomes of the two NiV strains. Our results reinforce the value of the African green monkey model for testing future NiV vaccines and treatments for infection.