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NIH grant 1R21AI202464-01: Differential Ephrin-A Receptor Usage Determines Tissue Tropism of Novel Bat Henipaviruses
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Benhur Lee. Award: $252000.
Start: 2026-08-21T00:00:00.
PROJECT SUMMARY
Henipaviruses such as Nipah virus (NiV) are WHO priority pathogens that cause severe respiratory and
neurological disease with case fatality rates up to 100%. While canonical henipaviruses utilize ephrin-B2/B3
receptors for entry, we discovered that the recently identified bat-derived Yunnan henipaviruses 1 and 2
(YBaHNV1/2) have evolved to use ephrin-A (EFNA) ligands instead—representing a fundamental shift in
receptor biology within the Henipavirus genus. Our preliminary data demonstrate that YBaHNV1 exhibits
promiscuous EFNA usage (EFNA1-5) while YBaHNV2 shows restricted specificity (EFNA1/4 only), and these
distinct receptor repertoires predict fundamentally different tissue tropism patterns based on EFNA expression:
EFNA5 enrichment in CNS neurons, EFNA1 in respiratory epithelia, and EFNA4 broadly expressed. This natural
variation provides an unprecedented opportunity to understand how receptor specificity governs henipavirus
tissue tropism and pathogenic potential.
The objective of this R21 is to characterize the cellular tropism and molecular basis of differential EFNA receptor
usage by YBaHNV1 and YBaHNV2, establishing the relationship between receptor specificity and tissue tropism
while assessing spillover risk. Our central hypothesis is that differential EFNA usage dictates distinct patterns of
cellular tropism, with YBaHNV1's ability to use EFNA5 conferring enhanced neurotropic potential absent in
YBaHNV2.
In Aim 1, we will define cellular tropism using primary human cells and organoids, correlate infection with
endogenous EFNA expression, and perform soluble receptor binding protein (sRBP) cross-competition studies
to determine differential receptor usage patterns on specific cell types. In Aim 2, we will determine binding
affinities for functional EFNA ligands and test cross-species orthologs from humans, bats, pigs, and mice to
identify molecular determinants of species barriers. We will use biologically-contained NiV-ΔF replicons (BSL-2
approved) that can be pseudotyped with YBaHNV F/RBP proteins for authentic single-cycle infection studies.
This work will establish the first functional characterization of EFNA-mediated henipavirus entry, reveal how
changes in receptor repertoire alter tissue tropism, and provide critical data for pandemic preparedness by
identifying which cell types and species are at risk from these emerging viruses.document fetched 2026-08-30 02:46