Dataset Information

The Microbiota Contributes to CD8+ T Cell Activation and Nutrient Malabsorption following Intestinal Infection with Giardia duodenalis.

ABSTRACT: Giardia duodenalis is a noninvasive luminal pathogen that impairs digestive function in its host in part by reducing intestinal disaccharidase activity. This enzyme deficiency has been shown in mice to require CD8(+) T cells. We recently showed that both host immune responses and parasite strain affected disaccharidase levels during murine giardiasis. However, high doses of antibiotics were used to facilitate infections in that study, and we therefore decided to systematically examine the effects of antibiotic use on pathogenesis and immune responses in the mouse model of giardiasis. We found that antibiotic treatment did not overtly increase the parasite burden but significantly limited the disaccharidase deficiency observed in infected mice. Moreover, while infected mice had more activated CD8(+) ?? T cells in the small intestinal lamina propria, this increase was absent in antibiotic-treated mice. Infection also led to increased numbers of CD4(+) ?? T cells in the lamina propria and activation of T cell receptor ??-expressing intraepithelial lymphocytes (IEL), but these changes were not affected by antibiotics. Finally, we show that activated CD8(+) T cells express gamma interferon (IFN-?) and granzymes but that granzymes are not required for sucrase deficiency. We conclude that CD8(+) T cells become activated in giardiasis through an antibiotic-sensitive process and contribute to reduced sucrase activity. These are the first data directly demonstrating activation of CD8(+) T cells and ?? T cells during Giardia infections. These data also demonstrate that disruption of the intestinal microbiota by antibiotic treatment prevents pathological CD8(+) T cell activation in giardiasis.

SUBMITTER: Keselman A

PROVIDER: S-EPMC5038064 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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The Microbiota Contributes to CD8+ T Cell Activation and Nutrient Malabsorption following Intestinal Infection with Giardia duodenalis.

Keselman Aleksander A Li Erqiu E Maloney Jenny J Singer Steven M SM

Infection and immunity 20160919 10

Giardia duodenalis is a noninvasive luminal pathogen that impairs digestive function in its host in part by reducing intestinal disaccharidase activity. This enzyme deficiency has been shown in mice to require CD8(+) T cells. We recently showed that both host immune responses and parasite strain affected disaccharidase levels during murine giardiasis. However, high doses of antibiotics were used to facilitate infections in that study, and we therefore decided to systematically examine the effect ...[more]

PMID: 27456829

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Project description:Giardia duodenalis, an important flagellated noninvasive protozoan parasite, infects the upper small intestine and causes a disease termed giardiasis globally. Few members of the heat shock protein (HSP) family have been shown to function as potential defenders against microbial pathogens, while such information is lacking for Giardia. Here we initially screened and indicated that in vitro Giardia challenge induced a marked early upregulation of HSP70 in intestinal epithelial cells (IECs). As noted previously, apoptotic resistance, nitric oxide (NO)-dependent cytostatic effect and parasite clearance, and epithelial barrier integrity represent effective anti-Giardia host defense mechanisms. We then explored the function of HSP70 in modulating apoptosis, NO release, and tight junction (TJ) protein levels in Giardia-IEC interactions. HSP70 inhibition by quercetin promoted Giardia-induced IEC apoptosis, viability decrease, NO release reduction, and ZO-1 and occludin downregulation, while the agonist celastrol could reverse these Giardia-evoked effects. The results demonstrated that HSP70 played a previously unrecognized and important role in regulating anti-Giardia host defense via attenuating apoptosis, promoting cell survival, and maintaining NO and TJ levels. Owing to the significance of apoptotic resistance among those defense-related factors mentioned earlier, we then elucidated the anti-apoptotic mechanism of HSP70. It was evident that HSP70 could negatively regulate apoptosis in an intrinsic way via direct inhibition of Apaf-1 or ROS-Bax/Bcl-2-Apaf-1 axis, and in an extrinsic way via cIAP2-mediated inhibition of RIP1 activity. Most importantly, it was confirmed that HSP70 exerted its host defense function by downregulating apoptosis via Toll-like receptor 4 (TLR4) activation, upregulating NO release via TLR4/TLR2 activation, and upregulating TJ protein expression via TLR2 activation. HSP70 represented a checkpoint regulator providing the crucial link between specific TLR activation and anti-Giardia host defense responses. Strikingly, independent of the checkpoint role of HSP70, TLR4 activation was proven to downregulate TJ protein expression, and TLR2 activation to accelerate apoptosis. Altogether, this study identified HSP70 as a potentially vital defender against Giardia, and revealed its correlation with specific TLR activation. The clinical importance of HSP70 has been extensively demonstrated, while its role as an effective therapeutic target in human giardiasis remains elusive and thus needs to be further clarified.

Project description:Giardia duodenalis, originally regarded as a commensal organism, is the etiologic agent of giardiasis, a gastrointestinal disease of humans and animals. Giardiasis causes major public and veterinary health concerns worldwide. Transmission is either direct, through the faecal-oral route, or indirect, through ingestion of contaminated water or food. Genetic characterization of G. duodenalis isolates has revealed the existence of seven groups (assemblages A to G) which differ in their host distribution. Assemblages A and B are found in humans and in many other mammals, but the role of animals in the epidemiology of human infection is still unclear, despite the fact that the zoonotic potential of Giardia was recognised by the WHO some 30 years ago. Here, we performed an extensive genetic characterization of 978 human and 1440 animal isolates, which together comprise 3886 sequences from 4 genetic loci. The data were assembled into a molecular epidemiological database developed by a European network of public and veterinary health Institutions. Genotyping was performed at different levels of resolution (single and multiple loci on the same dataset). The zoonotic potential of both assemblages A and B is evident when studied at the level of assemblages, sub-assemblages, and even at each single locus. However, when genotypes are defined using a multi-locus sequence typing scheme, only 2 multi-locus genotypes (MLG) of assemblage A and none of assemblage B appear to have a zoonotic potential. Surprisingly, mixtures of genotypes in individual isolates were repeatedly observed. Possible explanations are the uptake of genetically different Giardia cysts by a host, or subsequent infection of an already infected host, likely without overt symptoms, with a different Giardia species, which may cause disease. Other explanations for mixed genotypes, particularly for assemblage B, are substantial allelic sequence heterogeneity and/or genetic recombination. Although the zoonotic potential of G. duodenalis is evident, evidence on the contribution and frequency is (still) lacking. This newly developed molecular database has the potential to tackle intricate epidemiological questions concerning protozoan diseases.

Dataset Information

The Microbiota Contributes to CD8+ T Cell Activation and Nutrient Malabsorption following Intestinal Infection with Giardia duodenalis.

Publications

The Microbiota Contributes to CD8+ T Cell Activation and Nutrient Malabsorption following Intestinal Infection with Giardia duodenalis.

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