Abstract
Microsporidia are a group of intracellular pathogens causing self-limited and severe diseases in immunocompetent and immunocompromised individuals, respectively. A cellular type 1 adaptive response, mediated by IL-12, IFNγ, CD4+, and CD8+ T cells has been shown to be essential for host resistance, and dendritic cells (DC) play a key role at eliciting anti-microsporidial immunity. We investigated the in vitro response of DC and DC precursors/progenitors to infection with Encephalitozoon intestinalis (Ei), a common agent of human microsporidosis. Ei-exposed DC cultures up-regulated the surface expression of MHC class II and the costimulatory molecules CD86 and CD40, only when high loads of spores were used. A vigorous secretion of IL-6 but not of IL-1β or IL-12p70 was also observed in these cultures. Ei-exposed DC cultures consisted of immature infected and mature bystander DC, as assessed by MHC class II and costimulatory molecules expression, suggesting that intracellular Ei spores deliver inhibitory signals in DC. Moreover, Ei selectively inhibited the secretion of IL-12p70 in LPS-stimulated DC. Whereas Ei-exposed DC promoted allogeneic naïve T cell proliferation and IL-2 and IFNγ secretion in DC-CD4+ T cell co-cultures, separated co-cultures with bystander or infected DCs showed stimulation or inhibition of IFNγ secretion, respectively. When DC precursors/progenitors were exposed to Ei spores, a significant inhibition of DC differentiation was observed without shifting the development toward cells phenotypically or functionally compatible with myeloid-derived suppressor cells. Neutralization experiments demonstrated that this inhibitory effect is IL-6-dependent. Altogether this investigation reveals a novel potential mechanism of immune escape of microsporidian parasites through the modulation of DC differentiation and maturation.
Highlights
The phylum Microsporidia comprises a numerous group of obligate intracellular fungal parasites that infect a wide range of invertebrate and vertebrate animals
When we measured the percentage of infected cells and the number of spores per Dendritic cells (DC), we found that both proportionally increased with the multiplicity of infection (MOI; Figure 1B)
DCs were healthy and responsive, as they expressed high levels of all maturation markers and cytokines after stimulation with LPS (Figures 1C,D). These results show that Encephalitozoon intestinalis (Ei) spores are able to infect DC in a relatively silent manner, at low and moderate MOIs, and that only the exposure to high dose of infection (30:1 parasite to cell ratio) could promote a relatively weak but significant level of maturation characterized by increased expression of CD40, CD86, MHC class II and IL-6 but nondetected/low levels of IL-1β and IL-12p70
Summary
The phylum Microsporidia comprises a numerous group of obligate intracellular fungal parasites that infect a wide range of invertebrate and vertebrate animals. Current understanding of the immune mechanisms characterizing and mediating the effective response to microsporidial infection has derived mostly from studies using the experimental infection of immune-deficient and immunocompetent mice with Encehalitozoon cuniculi (Ec) This model has indicated that (1) It is the cellular rather than humoral the important type of adaptive response that mediates protective immunity to Microsporidia; (2) IFNγ and IL-12, two cytokines known to mediate the development of the type 1 cellular response, are essential for protection; (3) an immune pathway mediated by CD8+ T cells via perforin-dependent cytotoxicity and IFNγ production appears to be the primary, and most important mechanism of protection, with the intestinal intraepithelial lymphocyte (IEL) CD8+ T cell compartment playing a key effector role; (4) in the absence of CD8+ T cells, a protective cellular response can be generated that is presumably mediated by IFNγ-producing CD4+ T cells (Ghosh and Weiss, 2012; Moretto et al, 2012). Some mice studies with the more common human pathogen Encephalitozoon intestinalis (Ei) have revealed the importance of both CD4+ and CD8+ T cell populations as well as IFNγ and IL-12 production for host resistance (Salát et al, 2002, 2004)
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