Host susceptibility factors to pediatric encephalitis in South East Asia – SEAe-HostFactors

Infectious encephalitis is of public health concern worldwide, given its high mortality and neurological sequelae rates. Reported incidences range between 3.5 and 7.4 cases per 100,000 patient years, with higher incidences in children than adults, and in Asia than other parts of the world. Southeast Asia (SEA) is a particularly significant biodiversity hotspot that is at high risk for the emergence of novel pathogens and an area of choice for the characterization of endemic pathogens that have the potential to disseminate globally. We have conducted a large prospective study on acute encephalitis (SEA encephalitis project), which included 695 children with encephalitis from four countries in SEA (Cambodia, Laos, Vietnam and Myanmar). Preliminary results highlight that Japanese encephalitis virus (JEV) and Enterovirus 71 (EV71) are among the most frequent aetiologies. JEV and EV71 encephalitis outcomes are severe with more than 10% case fatality rate and 40% of neurological sequelae, and it is therefore critical to better understand the pathogenesis of these deadly infections. The high seroprevalence of JEV in SEA contrasts with the relative rarity of JEV-associated encephalitis which almost exclusively occur in children, and emphasises the hypothesis that host factors contribute to JEV-encephalitis. EV71 has emerged as a major encephalitis aetiology that is often fatal and typically affects young children in endemic regions. Yet, only a small fraction of EV71-infected children develops encephalitis.
Members of our consortium have recently discovered that Herpes simplex virus 1 (HSV-1) encephalitis results from single-gene inborn errors of TLR3 immunity in some children. Furthermore, environmental factors and malnutrition have been identified as predisposing factors for severe outcomes associated with EV71, and microbiome composition has been reported to play a critical role in immune system maturation at the intestinal and systemic levels, and also to contribute to viral invasion.

Our first objective is to identify host genetics factors predisposing to JEV- and EV71-associated encephalitis by a strategy combining next generation sequencing (NGS) and in-depth functional studies. Our second objective is to analyse the microbiome composition of patients with JEV- and EV71-associated encephalitis and identify specific microbiome signatures that may correlate with the onset of encephalitis. We will finally analyse these host factors together, to identify potential interactions between microbiome and host genetic susceptibility factors that may synergistically increase susceptibility to JEV- and EV71-associated encephalitis.

Partner 1 is the co-PI of the SEAe project, an expert on host pathogen interactions, and has the expertise to lead microbiome analysis studies. Partner 2 is widely recognized for its pioneering work on the dissection of host genetic susceptibility to viral encephalitis. Partner 3 is based in Cambodia, is a critical contributor to the SEAe project, and will help select and process the biological human samples needed to complete the project.

This project is innovative and multidisciplinary, as it brings together clinicians and basic scientists, and addresses original and key medical and biological questions in the fields of infection biology, virology, neuroscience and immunology. These questions are central to the understanding of the pathogenesis of viral encephalitis, and can now be properly addressed with the technological advances of NGS, the progresses in human genetics and microbiome studies, and the availability of a unique cohort of children with encephalitis from South East Asia. The partners involved in this study are perfectly complementary, and the results obtained by the end of this project will move forward the state of the art, with expected major scientific and medical outputs.