Preexisting helminth infection induces inhibition of innate pulmonary anti-tuberculosis defense by engaging the IL-4 receptor pathway

Potian, Julius A.; Rafi, Wasiulla; Bhatt, Kamlesh; McBride, Amanda; Gause, William C.; Salgame, Padmini

doi:10.1084/jem.20091473

Cited by 174 publications

(194 citation statements)

References 58 publications

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“…Evidence suggests that a skewed Th2 response caused due to S. mansoni infection compromises protection conferred by M. bovis BCG vaccination in humans (7-9) and in mice systemically infected with Mtb (12). Similarly, other models of helminth coinfections such as Nippostrongylus brasiliensis, a rodent intestinal helminth that migrates to the lung, also drives Th2 responses and generation of alternatively activated macrophages in the lung, resulting in impaired resistance to Mtb (27). Interestingly, while helminth coinfections increase M. bovis BCG (11) and Mtb (27) lung burden, the increase in mycobacterial burden is often transient (27) and moderate (about 1 log higher in coinfected hosts) (11,27), suggesting that the effect of helminth coinfections on Mtb control is not profound enough to fully explain the increased severity of TB in helminth-coinfected individuals observed in TB endemic regions.…”

Section: Discussionmentioning

confidence: 99%

Helminth-induced arginase-1 exacerbates lung inflammation and disease severity in tuberculosis

Monin¹,

Griffiths²,

Lam³

et al. 2015

Journal of Clinical Investigation

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Section: Discussionmentioning

confidence: 99%

Helminth-induced arginase-1 exacerbates lung inflammation and disease severity in tuberculosis

Monin¹,

Griffiths²,

Lam³

et al. 2015

Journal of Clinical Investigation

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“…Worms, through the immune responses they evoke, have been suggested as one factor that can impair BCG vaccine efficacy and increase susceptibility to mycobacterial infection (6,35). In support of this, there is ample evidence that worms and worm products can counteract Th1 immunity and downmodulate inflammatory responses to secondary Ags (36).…”

Section: Discussionmentioning

confidence: 99%

“…Both of these responses can counteract Th1 development. Accordingly, worm infection is proposed to impair immune responses that control mycobacteria (4)(5)(6). Infection with worms has also been associated with a reduced ability to respond to BCG vaccination (7,8).…”

mentioning

confidence: 99%

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

Obieglo

Feng

Bollampalli

et al. 2016

The Journal of Immunology

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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.

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“…Thus, an impaired CD8 T cell effector response to vaccinia virus has been observed in a Schistosoma mansoni-infected host (47). More recently, it has been shown that IL-4 produced during a parasitic infection with Nippostrongylus brasiliensis impairs the innate immune response to a bystander infection with Mycobacterium tuberculosis (48). The IL-4-induced decreased antimicrobial peptide secretion by keratinocytes would be one of the potential mechanisms responsible for this increased susceptibility (49).…”

Section: Discussionmentioning

confidence: 99%

Negative Regulation of NKG2D Expression by IL-4 in Memory CD8 T Cells

Ventre

Brinza

Schicklin

et al. 2012

The Journal of Immunology

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IL-4 is one of the main cytokines produced during Th2-inducing pathologies. This cytokine has been shown to affect a number of immune processes such as Th differentiation and innate immune responses. However, the impact of IL-4 on CD8 T cell responses remains unclear. In this study, we analyzed the effects of IL-4 on global gene expression profiles of Ag-induced memory CD8 T cells in the mouse. Gene ontology analysis of this signature revealed that IL-4 regulated most importantly genes associated with immune responses. Moreover, this IL-4 signature overlapped with the set of genes preferentially expressed by memory CD8 T cells over naive CD8 T cells. In particular, IL-4 downregulated in vitro and in vivo in a STAT6-dependent manner the memory-specific expression of NKG2D, thereby increasing the activation threshold of memory CD8 T cells. Furthermore, IL-4 impaired activation of memory cells as well as their differentiation into effector cells. This phenomenon could have an important clinical relevance as patients affected by Th2 pathologies such as parasitic infections or atopic dermatitis often suffer from viral-induced complications possibly linked to inefficient CD8 T cell responses.

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Preexisting helminth infection induces inhibition of innate pulmonary anti-tuberculosis defense by engaging the IL-4 receptor pathway

Abstract: Preexisting helminth infection impairs immunity against subsequent M. tuberculosis infection, in part by inducing alternatively activated macrophages.

Cited by 174 publications

References 58 publications

Helminth-induced arginase-1 exacerbates lung inflammation and disease severity in tuberculosis

Helminth-induced arginase-1 exacerbates lung inflammation and disease severity in tuberculosis

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

Negative Regulation of NKG2D Expression by IL-4 in Memory CD8 T Cells

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