Chronic Gastrointestinal Nematode Infection Mutes Immune Responses to Mycobacterial Infection Distal to the Gut

Abstract

Helminth infections have been suggested to impair the development and outcome of Th1 responses to vaccines and intracellular microorganisms. However, there are limited data regarding the ability of intestinal nematodes to modulate Th1 responses at sites distal to the gut. In this study, we have investigated the effect of the intestinal nematode Heligmosomoides polygyrus bakeri on Th1 responses to Mycobacterium bovis bacillus Calmette–Guérin (BCG). We found that H. polygyrus infection localized to the gut can mute BCG-specific CD4+ T cell priming in both the spleen and skin-draining lymph nodes. Furthermore, H. polygyrus infection reduced the magnitude of delayed-type hypersensitivity (DTH) to PPD in the skin. Consequently, H. polygyrus–infected mice challenged with BCG had a higher mycobacterial load in the liver compared with worm-free mice. The excretory–secretory product from H. polygyrus (HES) was found to dampen IFN-γ production by mycobacteria-specific CD4+ T cells. This inhibition was dependent on the TGF-βR signaling activity of HES, suggesting that TGF-β signaling plays a role in the impaired Th1 responses observed coinfection with worms. Similar to results with mycobacteria, H. polygyrus–infected mice displayed an increase in skin parasite load upon secondary infection with Leishmania major as well as a reduction in DTH responses to Leishmania Ag. We show that a nematode confined to the gut can mute T cell responses to mycobacteria and impair control of secondary infections distal to the gut. The ability of intestinal helminths to reduce DTH responses may have clinical implications for the use of skin test–based diagnosis of microbial infections.

A CFSE-based Assay to Study the Migration of Murine Skin Dendritic Cells into Draining Lymph Nodes During Infection with <em>Mycobacterium bovis</em> Bacille Calmette-Gu&#233;rin

“…Although not described in the protocol, LNs from this setup can also be prepared for analysis by confocal microscopy, to study migration processes such as the positioning of migratory cells in the LN 3 . Furthermore, similar results on BCG-triggered skin DC migration have been obtained using both BCG Pasteur 1173P2 3 and BCG SSI 1331 14 .…”

“…Indeed, both neutrophils and γ:δ T cells have been shown to relocate from skin to DLN in response to BCG 17,18 . In fact, the assay was recently used in a co-infection setting to show that a gut-localized nematode infection could mute BCG-triggered skin DC migration to DLN 14 . DC migration is often assessed between 24 to 72 hr in FITC skin painting since FITC-labeled DCs are difficult to detect 4 to 5 days after painting 19 .…”

Helminth-Tuberculosis Co-infection: An Immunologic Perspective

“…Similarly, mice infected with either Nippostrogylus brasiliensis [82] or Strongyloides venezuelensis [83] also demonstrated impaired bacterial control and higher bacterial burdens in the lungs. And a recent study has also demonstrated that mice co-infected with Heligmosomoides polygyrus bakeri and M. bovis BCG resulted in higher mycobacterial loads [84]. Despite these findings, there have been other studies in which there was little to no effect of pre-existing helminth infection on TB.…”

“…These macrophages then mediate through an IL-4R dependent process impairment of immune responses and bacterial control. Another mechanism by which helminthes modulate the immune response to TB is by the production of TGFβ, that can mediate the suppression of Th1 responses in mice resulting in higher bacterial burdens and decreased delayed type hypersensitivity responses [84]. The third mechanism at play is a direct effect on T cells with decreased Th17 responses and increased expression of CTLA-4 [83].…”

Intestinal nematode infection exacerbates experimental visceral leishmaniasis

“…Elevated type 2 and regulatory responses can be detected in blood of worm‐infected individuals . Both type 2 and regulatory responses are known to inhibit type 1 immunity and can thus be envisaged to affect immunity to infections controlled by type 1 responses, such as mycobacteria, Leishmania and other intracellular pathogens of macrophages . It has been shown that control and susceptibility of murine Leishmania donovani infection correlate well with generation of type 1 responses or lack thereof, respectively .…”