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Interleukin-17 drives sex-dependent weight loss and changes in feeding behaviour during Trypanosoma brucei infection

ABSTRACT: African trypanosomes, the causative agents of Human and Animal African trypanosomiasis or sleeping sickness, reside in tissue niches proposed to be important for disease outcome and transmission. Here, we demonstrate that parasites in the inguinal white adipose tissue (iWAT) niche induce sexually dimorphic physiological and immunological responses. Following chronic Trypanosoma brucei infection, male mice experience weight loss, reduced adipose tissue mass and altered tissue function, as well as changes in feeding behaviour, whereas females do not. We identified that interleukin-17 (IL-17), a cytokine that we show is elevated in sleeping sickness patients, orchestrates a sex-specific response to T. brucei infection in experimental infections. Deletion of murine IL-17a/f abolishes infection-associated weight loss, alters feeding behaviour, and limits adipose tissue wasting in male mice only. We propose that these effects might be triggered locally in adipocytes via engagement of IL-17 with its cognate receptor leading to lipolysis and tissue wasting, and/or systemically, via IL-17 signalling in the hypothalamus, potentially suggesting that IL-17 signalling coordinates brain-adipose tissue communication during sleeping sickness. Our findings also suggest a key sex-dependent role for the IL-17 isoforms IL-17A and IL-17F in regulating adipose tissue and energy balance during infection. Altogether, the results presented here open new directions to understand energy balance and brain-adipose tissue communication during chronic infection.

ORGANISM(S): Mus musculus

PROVIDER: GSE210600 | GEO | 2022/10/08

REPOSITORIES: GEO

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Project description:Approximately 20% of sleeping sickness patients exhibit respiratory complications which are commonly attributed to secondary bacterial infections, with an unknown role of the parasite. Using a Glossina morsitans tsetse fly initiated Trypansoma brucei infection in mice we found that parasites rapidly and permanently colonize the lungs, representing one of the major target organs next to the adipose tissue. Trypanosomes were found by immunofluorescence staining and scanning electron microscopy to occupy the extravascular spaces surrounding the blood vessels of the alveoli and bronchi. Parasites were even found in the lung cartilage. Trypanosomes were often observed as nests of multiplying parasites exhibiting close interactions with collagen and highly active secretion of extracellular vesicles that are engaged in intercellular communication. The local immune response was analysed by flow cytometry after 10 and 21 days of infection and was characterized by a substantial increase of CD11b+ Ly6C+ monocytes, CD11b+ Ly6C+ F4/80+ macrophages and CD11b+ CD11c+ dendritic cells. CD11b+ Ly6G+ neutrophils only accumulated prominently at the late infection time point. Interestingly, parasite presence resulted in a significant reduction of B220+ IgM+ B cells, CD11b+ CD11clo/- SiglecF+ eosinophils and TcR-β- NK1.1+ natural killer cells. Digital transcriptomics revealed infection-induced upregulation of Il-10, IFN-ɣ- and IFN-α-responses, IL-2-, IL-6- and TNF-signalling, a Th1 pro-inflammatory signature, negative immune checkpoint regulators and a predominant M1 macrophage polarization. Il12a and genes associated with complement and the B cell receptor were downregulated. No infection-associated pulmonary dysfunction could be detected by in vivo lung function measurements, mirroring the limited pulmonary complications during sleeping sickness. However, the substantial reduction of eosinophils, B cells and NK cells may render individuals more susceptible to opportunistic infections. Collectively, these observations provide essential insights in the peculiar parasite biology, immunological reactions and physiological function of a largely overlooked target organ which may trigger new diagnostic approaches for sleeping sickness.

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Interleukin-17 drives sex-dependent weight loss and changes in feeding behaviour during Trypanosoma brucei infection

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