An Intestinal Helminth Promotes Enteric Viral Infection Independent of Type 2 Immunity - Project Summary/Abstract Parasitic helminths infect ~25% of the global population, mostly colonizing the gastrointestinal tract. Emerging clinical evidence suggests that helminth infections, although typically non-pathogenic per se, may promote certain viral (e.g., HIV) and bacterial (e.g., M. tuberculosis) infections by dampening protective inflammatory immune responses. Recent studies in mice have recapitulated this phenomenon, as helminth infections were found to impair Th1 and CD8+ T cell responses against several enteric viruses, leading to dramatically increased viral replication in the intestine. Helminths induce a strong “type 2” immune response mediated by the characteristic cytokines IL-4 and/or IL-13. In prior work, helminth-mediated suppression of the host’s antiviral program required type 2 immunity, as co-infected IL4Ra-KO mice (which cannot respond to IL-4 and IL-13) mounted robust antiviral responses and efficiently controlled viral replication. Thus, the classic “type 1 vs. type 2” immune dichotomy paradigm has been implicated in helminth promotion of viral infection. Seeking to expand on these findings in a model of enteric adenoviral infection, we infected mice with Heligmosomoides polygyrus (“H.p.” - a model of human chronic hookworm infection), followed by oral gavage of mouse adenovirus 2 (“mAdV2”, which models acute adenoviral gastroenteritis). At early (day 3) and late (day 14-21) time points after viral infection, mice co-infected with H.p. + mAdV2 had dramatically increased viral titers in feces and small intestine tissue compared with mAdV2 infection alone. Tuft cells can sense helminth infections and initiate type 2 responses, but mice lacking tuft cells (Pou2f3-KO) showed similar viral enhancement upon H.p. co-infection as compared to WT mice. Surprisingly, all tested components of type 2 immunity were dispensable for viral enhancement, as mice deficient for IL-4Ra, IL-5, IL-25 and IL-33R all failed to control mAdV2 when colonized with H.p. Interestingly, infection with an unrelated helminth, Nippostrongylus brasiliensis, also enhanced mAdV2 infection. Thus, in contrast to other viral infections, intestinal helminths promote mAdV2 infection independent of type 2 immunity. This project aims to determine the mechanism of helminth-mediated mAdV2 enhancement by testing three non-mutually-exclusive hypotheses. In Aim 1, we will test the hypothesis that helminths blunt the anti-mAdV2 adaptive immune response, with a particular focus on IFNg-producing CD4s recruited to the intraepithelial compartment (as recently described) and helminth-mobilized Tregs. In Aim 2, we will assess whether helminths promote mAdV2 infection by impairing early interferon responses. In Aim 3, we seek to determine whether helminth secretory products, which modulate host immunity and epithelial cells independent of type 2 signals, are responsible for mAdV2 enhancement. If successful, this project will elucidate a novel mechanism of helminth-virus crosstalk with potential implications for human health.
