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PLoS Pathog. 2017 Jul 27;13(7):e1006471. doi: 10.1371/journal.ppat.1006471. eCollection 2017 Jul.

Cross-modulation of pathogen-specific pathways enhances malnutrition during enteric co-infection with Giardia lamblia and enteroaggregative Escherichia coli.

Author information

1
Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
2
Center for Gastrointestinal Biology and Disease, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
3
Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia, Charlottesville, Virginia, United States of America.
4
Division of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London, United Kingdom.
5
Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, United States of America.
6
Division of Pediatric Infectious Diseases, Children's Hospital of Richmond at Virginia Commonwealth University, Richmond, Virginia, United States of America.
7
Department of Biology, Georgetown University, Washington, DC, United States of America.

Abstract

Diverse enteropathogen exposures associate with childhood malnutrition. To elucidate mechanistic pathways whereby enteric microbes interact during malnutrition, we used protein deficiency in mice to develop a new model of co-enteropathogen enteropathy. Focusing on common enteropathogens in malnourished children, Giardia lamblia and enteroaggregative Escherichia coli (EAEC), we provide new insights into intersecting pathogen-specific mechanisms that enhance malnutrition. We show for the first time that during protein malnutrition, the intestinal microbiota permits persistent Giardia colonization and simultaneously contributes to growth impairment. Despite signals of intestinal injury, such as IL1α, Giardia-infected mice lack pro-inflammatory intestinal responses, similar to endemic pediatric Giardia infections. Rather, Giardia perturbs microbial host co-metabolites of proteolysis during growth impairment, whereas host nicotinamide utilization adaptations that correspond with growth recovery increase. EAEC promotes intestinal inflammation and markers of myeloid cell activation. During co-infection, intestinal inflammatory signaling and cellular recruitment responses to EAEC are preserved together with a Giardia-mediated diminishment in myeloid cell activation. Conversely, EAEC extinguishes markers of host energy expenditure regulatory responses to Giardia, as host metabolic adaptations appear exhausted. Integrating immunologic and metabolic profiles during co-pathogen infection and malnutrition, we develop a working mechanistic model of how cumulative diet-induced and pathogen-triggered microbial perturbations result in an increasingly wasted host.

PMID:
28750066
PMCID:
PMC5549954
DOI:
10.1371/journal.ppat.1006471
[Indexed for MEDLINE]
Free PMC Article

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