title: Metabolic, immune, and gut microbial signals mount a systems response to Leishmania major infection.
abstract: Parasitic infections such as leishmaniasis induce a cascade of host physiological responses, including metabolic and immunological changes. Infection with Leishmania major parasites causes cutaneous leishmaniasis in humans, a neglected tropical disease that is difficult to manage. To understand the determinants of pathology, we studied L. major infection in two mouse models: the self-healing C57BL/6 strain and the nonhealing BALB/c strain. Metabolic profiling of urine, plasma, and feces via proton NMR spectroscopy was performed to discover parasite-specific imprints on global host metabolism. Plasma cytokine status and fecal microbiome were also characterized as additional metrics of the host response to infection. Results demonstrated differences in glucose and lipid metabolism, distinctive immunological phenotypes, and shifts in microbial composition between the two models. We present a novel approach to integrate such metrics using correlation network analyses, whereby self-healing mice demonstrated an orchestrated interaction between the biological measures shortly after infection. In contrast, the response observed in nonhealing mice was delayed and fragmented. Our study suggests that trans-system communication across host metabolism, the innate immune system, and gut microbiome is key for a successful host response to L. major and provides a new concept, potentially translatable to other diseases.
authors.affiliation: Division of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London , Exhibition Road, London SW7 2AZ, United Kingdom.
authors.forename: Sabrina D
authors.initials: SD
authors.lastname: Lamour
authors.forename: Kirill A
authors.initials: KA
authors.lastname: Veselkov
authors.forename: Joram M
authors.initials: JM
authors.lastname: Posma
authors.forename: Emilie
authors.initials: E
authors.lastname: Giraud
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Rogers
authors.forename: Simon
authors.initials: S
authors.lastname: Croft
authors.forename: Julian R
authors.initials: JR
authors.lastname: Marchesi
authors.forename: Elaine
authors.initials: E
authors.lastname: Holmes
authors.forename: Karin
authors.initials: K
authors.lastname: Seifert
authors.forename: Jasmina
authors.initials: J
authors.lastname: Saric
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000378:metabolism* / Q000652:urine; D000069196:Gastrointestinal Microbiome / Q000276:immunology*; D054884:Host-Pathogen Interactions; D018320:Leishmania major / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D013045:Species Specificity
chemical_list: D015415:Biomarkers
keywords: Leishmania; correlation; cytokine; host; infection; metabolic; microbiota; multivariate; profiling; response