Understanding mechanisms of disease tolerance during intestinal helminth infection

Abstract

Abstract Intestinal helminths infect over two billion people worldwide and can cause significant morbidity. In many cases, however, individuals fail to develop resistance to these tissue-invasive pathogens, indicating that mammalian hosts have evolved unknown strategies to tolerate infection. To investigate the mechanisms underlying host tolerance to helminth infection, we examined the initial tissue invasive stage of Heligmosomoides polygyrus bakeri (Hpb), a natural parasitic roundworm infection of mice. Unexpectedly, we observed a rapid and robust Type 1 inflammatory response that preceded the expected Type 2 immune response. This early Type 1 response was associated with a gut-specific expansion of IFNγ-producing Eomesodermin+ Natural Killer (NK) cells with no increase in other innate lymphoid cell populations. Parabiosis and confocal microscopy studies indicated that Eomes+ NK cells are recruited from circulation and surround the larvae in association with the intestinal vasculature. The recruitment of NK cells to the small intestinal lamina propria is dependent on IFNγ-induced expression of CXCL9 and CXCL10, and the presence of αβ+ T cells. NK cell depletion did not alter worm burden or fitness, but resulted in increased incidence of intestinal bleeding, suggesting a role for NK cells in promoting intestinal vascular integrity. In summary, our work provides new insight into the cellular dynamics required for protection during intestinal helminth infection and will help inform strategies to maximize host fitness in the context of tissue injury and repair.