Adaptive immunity alters distinct host feeding pathways during nematode induced inflammation, a novel mechanism in parasite expulsion.
Gastrointestinal infection is often associated with hypophagia and weight loss; however, the precise mechanisms governing these responses remain poorly defined. Furthermore, the possibility that alterations in feeding during infection may be beneficial to the host requires further study. We used the nematode Trichinella spiralis, which transiently inhabits the small intestine before migrating to skeletal muscle, as a biphasic model of infection to determine the cellular and molecular pathways controlling feeding during enteric and peripheral inflammation. Through the infection of genetically modified mice lacking cholecystokinin, Tumor necrosis factor α receptors and T and B-cells, we observed a biphasic hypophagic response to infection resulting from two separate immune-driven mechanisms. The enteroendocrine I-cell derived hormone cholecystokinin is an essential mediator of initial hypophagia and is induced by CD4+ T-cells during enteritis. In contrast, the second hypophagic response is extra-intestinal and due to the anorectic effects of TNFα during peripheral infection of the muscle. Moreover, via maintaining naive levels of the adipose secreted hormone leptin throughout infection we demonstrate a novel feedback loop in the immunoendocrine axis. Immune driven I-cell hyperplasia and resultant weight loss leads to a reduction in the inflammatory adipokine leptin, which in turn heightens protective immunity during infection. These results characterize specific immune mediated mechanisms which reduce feeding during intestinal or peripheral inflammation. Importantly, the molecular mediators of each phase are entirely separate. The data also introduce the first evidence that I-cell hyperplasia is an adaptively driven immune response that directly impinges on the outcome to infection.
Manchester Immunology Group, Faculty of Life Sciences, University of Manchester, Manchester, UK. john.worthington@manchester.ac.uk
John J
JJ
Worthington
Linda C
LC
Samuelson
Richard K
RK
Grencis
John T
JT
McLaughlin
D056704:Adaptive Immunity / Q000502:physiology*; D000818:Animals; D004751:Enteritis / Q000276:immunology / Q000469:parasitology*; D005247:Feeding Behavior; D001068:Feeding and Eating Disorders / Q000469:parasitology*; D058507:Host Specificity; D006790:Host-Parasite Interactions; D007411:Intestinal Diseases, Parasitic / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D017160:Trichinella spiralis / Q000276:immunology*; D014235:Trichinellosis / Q000276:immunology*; D015431:Weight Loss