NK cell recruitment limits tissue damage during an enteric helminth infection

Abstract

Parasitic helminths cause significant damage as they migrate through host tissues to complete their life cycle. While chronic helminth infections are characterized by a well-described Type 2 immune response, the early, tissue-invasive stages are not well understood. Here we investigate the immune pathways activated during the early stages of Heligmosomoides polygyrus bakeri (Hpb), a natural parasitic roundworm of mice. In contrast to the Type 2 immune response present at later stages of infection, a robust Type 1 immune signature including IFNg production was dominant at the time of parasite invasion and granuloma formation. This early response was associated with an accumulation of activated Natural Killer (NK) cells, with no increase of other innate lymphoid cell populations. Parabiosis and confocal microscopy studies indicated that NK cells were recruited from circulation to the small intestine, where they surrounded parasitic larvae. NK cell recruitment required IFNγ receptor signaling, but was independent of CXCR3 expression. The depletion of tissue-infiltrating NK cells altered neither worm burden nor parasite fitness, but increased vascular injury, suggesting a role for NK cells in mediating tissue protection. Together, these data identify an unexpected role for NK cells in promoting disease tolerance during the invasive stage of an enteric helminth infection.

Cytokine elevation in the mouse small intestine at the early stage of infection with the gastrointestinal parasite <i>Heligmosomoides polygyrus</i>

“…1 ). A recent study also reported increased IFNγ gene expression in the early stage of Hp infection, which is consistent with our results [ 3 ]. It has been previously demonstrated that IFNγ is a key factor in the regulation of ILC2 [ 12 ].…”

“…As mentioned above, Th2 differentiation relies on ILC2s, and ILC2s require CD4+ T cells to survive. Cells that produce IFNγ, which is believed to be important for switching the role from ILC2 to CD4, are still unidentified, but NK cells accumulate before ILC2 in the early stages of infection, and IFNγ is involved [ 3 ]. We could not analyze which cell population produces IFNγ; therefore, further study is needed.…”

The gut microbiota limits Th2 immunity toHeligmosomoides polygyrus bakeriinfection

“…At the infection site, we observed a significant decrease in small intestinal length among Hpb HA107 à GF ( Figure 4E). Furthermore, these mice displayed a uniform inability to resolve tissue granulomas ( Figure 4F) -formations that typically arise during the tissue invasive stage of the parasite and normally resolve within 7-10 days post-infection 8,15 . Indeed, at 14 days post-infection, all Hpb HA107 à GF subjects exhibited persistent granulomas that were not present in any other groups.…”

“…Based on our results, we speculate that persistent granulomas result from a dysregulated tissue repair process facilitated by an excessive Th2 response. We and others have recently described an early type 1 immune response, characterized by IFNg-producing natural killer cells, in proximity to the Hpb granuloma that promotes disease tolerance and tissue regeneration during infection 15,23 . Although it remains to be determined whether the microbiota is required for IFNg induction in this context, this may be one mechanism by which the host exploits the microbiota to counter the type 2 immune response and promote granuloma resolution.…”

Transcriptomic Analysis of Ovine Hepatic Lymph Node Following Fasciola hepatica Infection – Inhibition of NK Cell and IgE-Mediated Signaling

“…During an infection trial with Cooperia oncophora in calves, NK cell proliferation increased (along with proliferation of T and B cells) after in vitro re-stimulation of mononuclear cells from mesenteric lymph nodes (68). More recent work on Heligmosomoides polygyrus bakeri, a natural parasitic roundworm of mice, has shown that recruitment of cytotoxic NK cells to the intestine early in infection increases host tolerance by mediating vascular integrity and endothelial cell survival (69). Very little published information regarding the role of NK cells during fasciolosis is available.…”