Journal Article

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

Bartelt, Luther A., Swann, Jonathan R., Zaenker, Edna I., Guerrant, Richard L., Donowitz, Jeffery, Bolick, David T., Papin, Jason, Medlock, Gregory L., Mayneris-Perxachs, Jordi, Carroll, Ian M., Singer, Steven M., Kolling, Glynis L., Thomas-Beckett, Rose Viguna, Rogala, Allison

2017

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Activation energy / Adaptation / Adaptations / Animals / Bioinformatics / Biology / Biology and Life Sciences / Biomedical engineering / Cell activation / Child / Child malnutrition / Children / Coinfection - immunology / Coinfection - microbiology / Coinfection - parasitology / Colonization / Concurrent infection / Cytokines - immunology / Diet / Disease Models, Animal / E coli / Energy expenditure / Escherichia coli - physiology / Escherichia coli infections / Escherichia coli Infections - immunology / Escherichia coli Infections - microbiology / Funding / Giardia / Giardia lamblia - physiology / Giardiasis / Giardiasis - immunology / Giardiasis - parasitology / Health aspects / Humans / Impairment / Infections / Infectious diseases / Inflammation / Interleukin 1 / Intestinal microflora / Intestinal Mucosa - immunology / Intestinal Mucosa - microbiology / Intestinal Mucosa - parasitology / Intestine / Male / Malnutrition / Malnutrition - immunology / Malnutrition - microbiology / Malnutrition - parasitology / Markers / Medicine / Medicine and Health Sciences / Metabolism / Metabolites / Mice / Mice, Inbred C57BL / Microorganisms / Myeloid Cells - immunology / Nicotinamide / Pathogenesis / Pathogens / Pathways / Pediatrics / Protein deficiency / Proteins / Proteolysis / Recruitment / Rodents