Coinfection with the Intestinal NematodeHeligmosomoides polygyrusMarkedly Reduces Hepatic Egg-Induced Immunopathology and Proinflammatory Cytokines in Mouse Models of Severe Schistosomiasis

Abstract

Infection with the trematode helminth Schistosoma mansoni results in a parasite egg-induced, CD4 T-cellmediated, hepatointestinal granulomatous and fibrosing inflammation that varies greatly in severity, with a higher frequency of milder forms typically occurring in regions where the disease is endemic. One possible explanation for this is that in these regions the degree of inflammation is lessened by widespread concurrent infection with gastrointestinal nematodes. We tested this hypothesis by establishing a murine coinfection model in which mice were infected with the intestinal nematode parasite Heligmosomoides polygyrus prior to infection with S. mansoni. In CBA mice that naturally display a severe form of schistosomiasis, preinfection with H. polygyrus resulted in a marked reduction in schistosome egg-induced hepatic immunopathology, which was associated with significant decreases in the levels of interleukin-17 (IL-17), gamma interferon, tumor necrosis factor alpha, IL-23, IL-6, and IL-1␤ and with increases in the levels of IL-4, IL-5, IL-10, and transforming growth factor ␤ in mesenteric lymph node cells, purified CD4 T cells, and isolated liver granuloma cells. There also were increases in liver Ym1 and forkhead box P3 transcription factor expression. In another model of high-pathology schistosomiasis induced in C57BL/6 mice by immunization with schistosome egg antigens in complete Freund's adjuvant, coinfection with the nematodes also resulted in a marked inhibition of hepatic immunopathology accompanied by similar shifts in cytokine production. These findings demonstrate that intestinal nematodes prevent Th1-and Th17-cell-mediated inflammation by promoting a strong Th2-polarized environment associated with increases in the levels of alternatively activated macrophages and T regulatory cells, which result in significant amelioration of schistosome-induced immunopathology.

Major Secretory Antigens of the Helminth Fasciola hepatica Activate a Suppressive Dendritic Cell Phenotype That Attenuates Th17 Cells but Fails To Activate Th2 Immune Responses

“…Therefore, regulation of IL-17 is critical to the control of inflammatory pathology associated with helminth infection. It has been suggested previously that the strong polarized Th2 environment promoted by helminths prevents the development of Th1/Th17 immune responses (5). However, our data indicate that Fasciola secreted molecules actually suppress the differentiation of Th17 cells, independently of Th2 cells, by altering the function of DCs.…”

Hookworm virulence factors: making the most of the host

“…The mechanisms of immune regulation seem to be multifactorial and might include increased threshold for effective immune activation of T cells; defective intracellular signaling; a decrease in the number of co-stimulatory molecules; an increase in the number of T regs; an increase in the amount of intracellular negative regulator of T cell activation in T cells; dysregulation of cytokine secretion such as IL-10 and TGF-b; and a T cell imbalance [84,87,88]. Alternatively activated macrophages (AAMs) have also been implicated and are thought to be activated by the parasite in order to suppress the immune system through a contactdependent mechanism and the production of IFN-g and nitric oxide (NO) in response to parasite glycoconjugates [83,84,88].…”

Induction and regulation of pathogenic Th17 cell responses in schistosomiasis

“…In particular, IL-4-dependent AAM are indispensable for the development of a Th2 response and for averting severe disease and death [49]. We have observed the expression of AAM markers, including the chitinase-related molecule Ym1, Relmá, and arginase, and the Treg lineage-specific transcription factor Foxp3 to inversely correlate with hepatic egg-induced immunopathology and IL-17 levels [112]. Similarly, these cell markers were decreased in infected SEA/CFA immunized T-bet−/− mice displaying exacerbated immunopathology and high levels of IL-17 [89].…”

“…Given the many mechanistic similarities between the immunopathology of T cell-mediated autoimmune diseases and schistosomiasis, we assessed the impact of a coinfection with the murine gastrointestinal parasitic nematode helminth Heligmosomoides polygyrus on the severe schistosome-induced pathology characteristic of CBA mice and SEA/CFA-immunized BL/6 mice. In both instances, there was significantly reduced immunopathology in the co-infected mice, which was accompanied by decreased MLNC and granuloma cell production of IL-17, IFN-ã and TNF-á and increased production of IL-4, IL-5, IL-10, and TGF-â [112]. How H. polygyrus manages to switch schistosome-infected mice from a Th17/Th1-polarized response with severe pathology to a predominantly Th2 response with mild pathology still remains to be fully understood, but may depend on its ability to stimulate Foxp3 expression and regulatory capabilities in naïve CD4 T cells by way of excretory/secretory products [126] or to induce AAM differentiation [49].…”

“…How H. polygyrus manages to switch schistosome-infected mice from a Th17/Th1-polarized response with severe pathology to a predominantly Th2 response with mild pathology still remains to be fully understood, but may depend on its ability to stimulate Foxp3 expression and regulatory capabilities in naïve CD4 T cells by way of excretory/secretory products [126] or to induce AAM differentiation [49]. In support of the latter possibility, expression of the AAM markers Ym1 and Relma was significantly increased in the livers of H. polygyrus and S. mansoni co-infected mice compared to mice infected with S. mansoni alone [112]. Yet another significant way that intestinal nematodes such as H. polygyrus could influence the immunopathology of schistosomiasis is by virtue of their ability to alter the composition of the gut microbiota [127].…”