Ascaris Suum Infection Downregulates Inflammatory Pathways in the Pig Intestine In Vivo and in Human Dendritic Cells In Vitro

Abstract

Ascaris suum is a helminth parasite of pigs closely related to its human counterpart, A. lumbricoides, which infects almost 1 billion people. Ascaris is thought to modulate host immune and inflammatory responses, which may drive immune hyporesponsiveness during chronic infections. Using transcriptomic analysis, we show here that pigs with a chronic A. suum infection have a substantial suppression of inflammatory pathways in the intestinal mucosa, with a broad downregulation of genes encoding cytokines and antigen-processing and costimulatory molecules. A. suum body fluid (ABF) suppressed similar transcriptional pathways in human dendritic cells (DCs) in vitro. DCs exposed to ABF secreted minimal amounts of cytokines and had impaired production of cyclooxygengase-2, altered glucose metabolism, and reduced capacity to induce interferon-gamma production in T cells. Our in vivo and in vitro data provide an insight into mucosal immune modulation during Ascaris infection, and show that A. suum profoundly suppresses immune and inflammatory pathways.

Body fluid from the parasitic worm Ascaris suum inhibits broad‐acting pro‐inflammatory programs in dendritic cells

“…58,59 Our analysis of the early transcriptional profile of helminth PCF-treated LPS + IFN-c-matured moDCs supports these previous findings and suggests that helminth PCF may interfere with TLR4 signaling to exert its immunosuppressive effects, as indicated by identification of decreased expression of molecules downstream of TLR4 activation. 58,59 Our analysis of the early transcriptional profile of helminth PCF-treated LPS + IFN-c-matured moDCs supports these previous findings and suggests that helminth PCF may interfere with TLR4 signaling to exert its immunosuppressive effects, as indicated by identification of decreased expression of molecules downstream of TLR4 activation.…”

“…14,17,18,20 In soluble egg antigen, one of the multiple compounds that can induce DC-mediated Th2 immune responses is omega-1; a glycosylated T2 RNase that can inhibit pro-inflammatory protein synthesis, induce strong surface expression of OX40L on DCs and increase the IL-4/IFN-c ratio in DCs and allogenic naive CD4 + T-cell co-culturing experiments. 20 The observations in our study, and the study by Midttun et al 58 that helminth PCF down-regulated PTGS2 transcripts as well as COX-2 protein levels indicate that helminth PCF-treated moDCs might not be able to induce prostaglandin E 2 -dependent DC-mediated Th2 responses. 58 Moreover, a recent study showed that soluble egg antigen treatment of DCs induced prostaglandin E 2 synthesis, resulting in autocrine induced OX40L, which further primed DCs to initiate Th2 responses.…”

“…63 Understanding DC-mediated Th2 induction has been a long-standing focus in immunology and is mainly based on studies wherein soluble egg antigen (SEA) from Schistosoma mansoni and T. suis soluble products were employed to initiate DC-mediated Th2 immune response. 58 Moreover, a recent study showed that soluble egg antigen treatment of DCs induced prostaglandin E 2 synthesis, resulting in autocrine induced OX40L, which further primed DCs to initiate Th2 responses. 18,19 T2 RNase homologs have been suggested to be present in the A. suum genome, 18 implying that helminth PCF might hold similar Th2-inducing properties, but this notion was previously refuted based on findings that PCF treatment did not alter IL-4 levels in allogenic naive CD4 + T cells co-cultured with DCs.…”

Modulation of human dendritic cell activity by Giardia and helminth antigens

“…Similarly, helminth parasites are known to have strong immunomodulatory properties, affecting responses to third party antigens, including dampening host responses to cholera and mycoplasma vaccinations . These modulatory effects may be closely linked to DC function as products from the porcine whipworm Trichuris suis supress production of TLR‐4‐associated cytokines in human DCs in vitro, whilst body fluid derived from the roundworms Ascaris lumbricoides or A. suum can interfere with LPS‐induced maturation and/or function of human and murine DCs …”

The tropics, helminth infections and hygiene hypotheses

“…This has also been investigated in pigs using transcriptomic analysis, showing that chronic A. suum infection induces suppression of inflammatory pathways in the intestinal mucosa, downregulating genes encoding cytokines and antigen-processing and co-stimulatory molecules. This effect was reproduced by A. suum body fluid in human dendritic cells (DCs) in vitro [26]. However, few of the immunomodulatory molecules found in excretory/ secretory products of these species have been characterized, among them PAS-1 has been extensively studied [27].…”