The complement system is a critical part of innate immune responses that most animal viruses encounter
during natural infections. Complement is an important factor in neutralization of many RNA viruses, but the
role it plays in pathogenesis and dissemination during paramyxovirus infections is largely unknown. Here,
we seek to fill gaps in our understanding of interactions of complement with the highly pathogenic
paramyxovirus Nipah virus (NiV).
This project emerged from our recent published finding that NiV virions recruit complement Factor I
as a novel mechanism to prevent neutralization, and that Factor I binds the NiV F protein on cell surfaces.
These important findings raise the questions of: 1) what role NiV recruitment of this host cell inhibitor plays
in blocking complement pathways at the cell surface and in preventing complement-mediated cell lysis, and
2) the role of complement in NiV infections of animals. Here, we will define mechanisms and functional
consequences for NiV recruitment of Factor I to the cell surface (Aim 1) and the role of complement in
either enhancing or restricting NiV tissue tropism and pathogenesis (Aim 2).
Our preliminary data have shown that Complement Factor I binds to the surface of cells expressing
the NiV F protein but not the G protein. In Aim 1, we will use biochemical approaches and cell culture
experiments to determine the requirements for F-mediated recruitment of Factor I. Functional assays will
determine the effect of F protein-Factor I interactions on which complement pathways are activated at the
cell surface and the extent of antibody-dependent and -independent cell lysis.
We hypothesize that complement pathways could act to inhibit NiV dissemination. Alternatively,
complement could promote NiV dissemination and disease, especially given the importance of complement
factors in lymphocyte recruitment and integrity of the blood brain barrier. In Aim 2, we will use a recently
developed ferret model under BSL4 conditions to compare the course of NiV infection in the presence and
absence of intact complement pathways. Time-course experiments will define the tissue-specific viral load
(e.g., lung vs brain), changes in tissue pathological lesions and overall clinical outcomes.
There is intense interest in defining mechanisms that modulate the interplay between host innate
immune systems, such as complement, and emerging paramyxoviruses with the potential for bioterrorism.
By establishing the above key feasibility issues with this R21
Exploratory/Developmental grant mechanism,
we will be in an excellent position
for more advanced mechanistic studies using animal models.