Abstract
Mast cells have been shown to affect the control of infections with the protozoan parasite Giardia intestinalis. Recently, we demonstrated that Giardia excretory-secretory proteins inhibited the activity of the connective tissue mast cell-specific protease chymase. To study the potential role of the chymase mouse mast cell protease (mMCP)-4 during infections with Giardia, mMCP-4+/+ and mMCP-4−/− littermate mice were gavage-infected with G. intestinalis trophozoites of the human assemblage B isolate GS. No significant changes in weight gain was observed in infected young (≈10 weeks old) mMCP-4−/− and mMCP-4+/+ littermate mice. In contrast, infections of mature adult mice (>18 weeks old) caused significant weight loss as compared to uninfected control mice. We detected a more rapid weight loss in mMCP-4−/− mice as compared to littermate mMCP-4+/+ mice. Submucosal mast cell and granulocyte counts in jejunum increased in the infected adult mMCP-4−/− and mMCP-4+/+ mice. This increase was correlated with an augmented intestinal trypsin-like and chymotrypsin-like activity, but the myeloperoxidase activity was constant. Infected mice showed a significantly lower intestinal neutrophil elastase (NE) activity, and in vitro, soluble Giardia proteins inhibited human recombinant NE. Serum levels of IL-6 were significantly increased eight and 13 days post infection (dpi), while intestinal IL-6 levels showed a trend to significant increase 8 dpi. Strikingly, the lack of mMCP-4 resulted in significantly less intestinal transcriptional upregulation of IL-6, TNF-α, IL-25, CXCL2, IL-2, IL-4, IL-5, and IL-10 in the Giardia-infected mature adult mice, suggesting that chymase may play a regulatory role in intestinal cytokine responses.
Highlights
Giardia intestinalis is a non-invasive protozoan intestinal parasite found worldwide that mainly causes a self-limiting diarrheal-disease, i.e., giardiasis in humans and other mammals [1]
The lack of mouse mast cell protease (mMCP)-4 resulted in significantly less intestinal transcriptional upregulation of IL-6, TNF-α, IL-25, CXCL2, IL-2, IL-4, IL-5, and IL-10 in the Giardia-infected mature adult mice, suggesting that chymase may play a regulatory role in intestinal cytokine responses
To address if the mast cell-specific protease chymase mouse mast cell protease-4 (mMCP-4) would have an impact on the protection of the host during infection with G. intestinalis, we infected seven to 13 weeks old and 18 to 36 weeks old congenic mMCP-4+/+, mMCP-4+/− and chymase-deficient mMCP-4−/− littermate mice in a series of completely blinded experiments (Table 1)
Summary
Giardia intestinalis ( named G. lamblia or G. duodenalis) is a non-invasive protozoan intestinal parasite found worldwide that mainly causes a self-limiting diarrheal-disease, i.e., giardiasis in humans and other mammals [1]. Giardia-infections are often asymptomatic but can result in acute or chronic diarrhea, malabsorption and weight loss [2]. The parasite has been estimated to contribute to 200 million symptomatic infections per year [3] and since 1954, at least 132 water-borne outbreaks of giardiasis have been reported worldwide [4]. The G. intestinalis group is genetically diverse with eight described genotypes or assemblages, but only parasites from assemblage A and B infect humans [1]. Malnutrition due to Giardia-infections has been replicated in mouse models [7,8]. The elderly is a group that is more affected by intestinal
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