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Impact of endogenous IL-27 on innate and adaptive responses during acute and chronic toxoplasmosis

ABSTRACT: In mice infected with the parasite Toxoplasma gondii the cytokine IL-27 limits the development of T cell mediated pathology but it is unclear if IL-27 acts early to constrain the expansion of pathological T cells or acts late to limits their activities. Analysis of infected mice revealed the production of IL-27p28 by a subset of inflammatory monocytes and sustained IL-27p28 production at sites of acute and chronic infection. Administration of anti-IL-27p28 prior to infection resulted in the development of immune pathology associated with increased levels of macrophage and granulocyte activation and enhanced effector T cell responses. However, IL-27 blockade that started on 4 dpi still resulted in enhanced numbers of parasite specific effector T cells but did not result in adverse systemic pathology. Neutralization of IL-27p28 during the chronic phase of infection did not alter peripheral T cell responses but manifested as enhanced T cell responses in the brain. Thus, IL-27 has distinct suppressive effects that impact innate and adaptive immunity during acute and chronic phases of infection.

ORGANISM(S): Mus musculus

PROVIDER: GSE184350 | GEO | 2024/03/20

REPOSITORIES: GEO

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Project description:The liver fluke Fasciola hepatica is an economically important pathogen of livestock. Fasciolosis in humans is an important re-emerging zoonosis, with 180 million people at risk. Development of novel control strategies requires an understanding of parasite virulence and tissue invasion, and of how the parasite evades and modulates the immune response during early infection. A combination of immunological and proteomic analyses was employed to investigate the peritoneal fluid of sheep infected with F. hepatica to characterise early tissue invasion and liver pathogenesis. At 18 days post-infection (dpi), histopathology of sheep liver showed white necrotic foci/tracts indicative of F. hepatica migration. Within the peritoneal fluid of infected animals, specific F. hepatica antigen FhCL1 antibodies coincided with an intense innate and adaptive cellular immune response, with increasing numbers of total leukocytes and a marked eosinophilia (49%). Cytokine qPCR analysis revealed IL-10, IL-12, IL-13, IL-23 and TGFβ were elevated but not statistically significant at 18 dpi compared to uninfected sheep indicating that whilst the immune response is developing it has not polarised to the Th2 type associated with chronic fasciolosis. Proteomic analysis of the peritoneal fluid identified 178 proteins, with 25 proteins more highly expressed in the infected animals, based on fold changes in protein concentration compared to the uninfected animals. Components of the liver extracellular matrix, including collagen, periostin and the adhesion protein, VCAM-1, exhibited increased expression associated with early fasciolosis, which may be important in signalling host immune responses to tissue damage. In early F. hepatica infection cellular infiltration with marked eosinophilia, adaptive immune responses and products of liver pathology are evident in the peritoneum. Although cytokine responses are developing they are mixed and not yet polarised to a Th2-type. We have characterised biomarkers of parasite-induced liver damage which could be exploited for diagnosis, and vaccine development aimed at reducing/preventing liver pathology.

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Impact of endogenous IL-27 on innate and adaptive responses during acute and chronic toxoplasmosis

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