# An Intestinal Helminth Promotes Enteric Viral Infection Independent of Type 2 Immunity

> **NIH NIH R21** · UNIVERSITY OF WASHINGTON · 2024 · $264,750

## Abstract

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 cro...

## Key facts

- **NIH application ID:** 10866799
- **Project number:** 1R21AI182722-01
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Jakob H. von Moltke
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $264,750
- **Award type:** 1
- **Project period:** 2024-05-21 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10866799

## Citation

> US National Institutes of Health, RePORTER application 10866799, An Intestinal Helminth Promotes Enteric Viral Infection Independent of Type 2 Immunity (1R21AI182722-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10866799. Licensed CC0.

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