Research Project: Natural History Studies of Henipaviruses and Emerging Bat Borne Viruses

Location: Zoonotic and Emerging Disease Research

Project Number: 3022-32000-027-002-S
Project Type: Non-Assistance Cooperative Agreement

Start Date: Aug 22, 2022
End Date: Apr 30, 2027

Objective:
NiV, Hendra virus (HeV) and Cedar virus within the Henipavirus genus of the paramyxovirus virus family. NiV causes febrile encephalitis and severe respiratory disease in humans with a case-fatality rate (CFR) as high as 100% in some outbreaks. Pteropid fruit bats are understood to serve as natural reservoirs for both NiV and HeV, and horses and pigs (livestock) as both susceptible and amplifying hosts. NiV and HeV are biosafety level-4 pathogens due to high mortality rates from infection, lack of effective medical countermeasures, and ease of transmission. Considered a high consequence pathogen, NiV is classified as a Category C priority pathogen and transboundary select agent by several US government agencies including USDA. The characteristics of NiV enhancing its global pandemic potential include: animals and humans are susceptible; NiV is capable of promiscuous transmission between and among humans and animals; it is an RNA virus with potential to mutate; and if a human-adapted strain were to infect communities in South Asia, high human and agricultural population densities and global interconnectedness would rapidly spread the infection. Its ability to impact livestock populations cannot be understated given the impact of infection control practices during early outbreaks where large scale livestock culls were mandated infection control practices. There are numerous other mammalian species that are susceptible to NiV and HeV infection. Hamsters and Ferrets have been helpful in understanding features of transmission and pathogenesis but each have some drawbacks related to infection kinetics and access to reagents for study of host responses. We and others have developed NHP models for NiVM, NiVB, CedV, and HeV which appear to reflect disease in humans and potentially swine from the limited systematic characterization of infection processes have been reported. The studies in this initiative will use hamster and NHP models to systematically dissect the events leading to death, transmission, and survival of this critically important family of viruses. The data will be compared with studies in swine when these data are generated. This work will establish critical partnerships leading the field in high consequence pathogen research and leverage existing expertise in next-generation genomics and diagnostics (Harvard-Broad), cutting edge immuno-pathology (UTMB and Stanford) and disease ecology (UTMB). Natural history studies performed at UTMB’s BSL4 will serve to help establish critical biosample banks to be used for diagnostics validations as well as develop methods to characterize disease progression in animal models where host specific reagents are not as readily available (ie hamsters and swine). This work will also provide a sounding board for development of facility specific standardized procedures and protocols to enhance future NBAF containment operations. It will leverage existing global partnerships in West Africa, India and Southeast Asia for access to contemporary field samples and virus isolates related to bat related paramyxovirus outbreaks and/or disease surveillance when possible.

Approach:
Hamsters have been used as infection models of NiV and HeV to study disease and transmission as a more accessible model for studying pathogenesis as well as evaluation of medical countermeasures such as vaccines or therapeutics. While their small size and susceptibility to infection are appreciated, details leading to death or survival in this model are less established. This is in part due to lack of hamster specific reagents to evaluate host responses. The following studies will evaluate henipavirus pathogenesis, transmission, and protective immunity using the following approaches. 1. Natural History: This proposal will carry out a series of natural history studies using different isolates of Henipaviruses. These studies naturally will inform timing for subsequent, scheduled euthanasia studies to provide sufficient samples for detailed histopatholgical analysis and longitudinal single cell transcriptomics studies in collaboration with the Broad. 2. Transmission: We will also examine aerosol or direct contact mediated transmission capacity of different isolates. 3. Immunity: We will conduct a series of studies to evaluate natural immunity including protection from back challenge in survivors, passive transfer protection, and immune cell ablation studies. NHPs are considered the gold standard for modeling human henipaviral infection as they recapitulate many of the most salient feature of disease where African Green monkeys (AGM) are among the best characterized. Detailed natural history studies of henipaviruses are needed to better understand the events leading to death, disease, and possibly survival. This proposal will conduct a series of natural history studies using AGM to evaluate different henipaviral diseases. 1. NiV Host Response: We will conduct a scheduled euthanasia study with a uniformly lethal doses of NiV Bangladesh and terminally sampled at several timepoints. Tissues, blood, and serum samples will be taken for histological and immunological characterization as well as detailed single cell transcriptomics in collaboration with the Broad. 2. NiV: Indian Isolate Natural History in AGM: Leveraging a new collaboration with partners at the National Institute of Virology in Pune, India; we will assess the virulence and lethality of an isolate derived from recent outbreaks in Kerala, India known to have key substitutions that may impact severity and communicability of disease. 3. Emerging Bat Borne Paramyxovirus Pilot study in AGM: Recently emerged bat-borne paramyxoviruses including Sosuga, Ghana-Bat, and Angavokely viruses will be evaluated in pilot studies to determine pathogenic potential of these emerging viruses. FIELD STUDIES 1. We will leverage existing partnerships in Senegal, Sierra Leone, and Nigeria to perform serosurveillance studies collections of bat, human, and agricultural sera. 2. We will establish new partnerships in Ghana and Madagascar to better define the disease ecology of previously reported henipaviruses.