Previous work has demonstrated that Trypanosoma brucei occupy several adipose tissue depots, including the subcutaneous adipose tissue in mice and humans, and due to its proximity to the skin, it is proposed to be an important for transmission. Here, we demonstrate that parasites in the inguinal white adipose tissue (iWAT) niche induce sexually dimorphic responses. During infection, male mice experience reduced adipose tissue mass, altered tissue function, and changes in feeding behaviour, whereas females do not. This tissue impairment correlates with an accumulation of TH17 T cells in the iWAT. Genetic ablation of IL-17A/F abolishes infection-associated weight loss and alters feeding behaviour, limiting tissue wasting in male mice. Importantly, we detected a significant elevation in serum IL-17A in sleeping sickness patients, indicating that IL-17A/F signalling is also conserved in humans. We propose a model whereby IL-17A/F acts locally in adipocytes via engagement with its cognate receptor leading to lipolysis and tissue wasting, and/or systemically, via signalling in the hypothalamus to modulate feeding behaviour. Together, our findings suggest key sex-dependent roles for IL-17A/F in regulating adipose tissue and energy balance, as well as a coordinator of brain-adipose tissue communication during sleeping sickness, opening new directions to understand energy balance during infection.

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Background Infectious diseases are a major driving force of natural selection. One human gene associated with strong evolutionary selection isAPOL1. TwoAPOL1variants, G1 and G2, emerged in sub-Saharan Africa in the last 10,000 years, possibly due to protection from the fatal African sleeping sickness, analogous toPlasmodium-driven selection of the sickle-cell trait. As homozygosity for the HbS allele causes sickle cell anaemia, homozygosity for theAPOL1G1 and G2 variants has also been associated with chronic kidney disease (CKD) and other kidney-related conditions. What is not known is the extend of non-kidney-related disorders and if there are clusters of diseases associated with individualAPOL1genotypes. Methods Using principal component analysis, we identified a cohort of 10,179 UK Biobank participants with recent African ancestry. We conducted a phenome-wide association test between all combinations ofAPOL1G1 and G2 genotypes and conditions identified with International Classification of Disease phenotypes using Firth's bias-reduced logistic regression and a false discovery rate to correct for multiple testing. We further examined associations with chronic kidney disease indicators: estimated glomerular filtration rate (eGFR) and urinary albumin:creatinine (uACR). Results The phenome-wide screen revealed 74 (mostly deleterious) potential associations with hospitalisation for a range of conditions. G1/G2 compound heterozygotes were specifically associated with hospitalisation in 64 (86.5%) of these conditions, with an over-representation of infectious diseases (including COVID-19) and endocrine, nutritional, and metabolic diseases. The analysis also revealed complexities in the relationship betweenAPOL1and CKD that are not evident when the risk variants are grouped together: high uACR was associated specifically with G1 homozygosity; low eGFR with G2 homozygosity and G1/G2 compound heterozygosity; progression to end stage kidney disease was associated with G1/G2 compound heterozygosity. Conclusions Among 9,594 participants, stratifying individualAPOL1risk variant genotypes had a differential effect on associations with both kidney and non-kidney phenotypes. The compound heterozygous G1/G2 genotype was distinguished as uniquely deleterious in its association with a range of ICD-10 phenotypes. The epistatic nature of the G1/G2 interaction means that such associations may go undetected in a standard genome-wide association study. These observations have the potential to significantly impact the way that health risks are understood, particularly in populations whereAPOL1G1 and G2 are common such as in sub-Saharan Africa and its diaspora.

The meningeal space is an important structure in the brain borders, which provides immunosurveillance for the central nervous system, but the impact of infections on the meningeal immune landscape is far from being fully understood. The extracellular protozoan parasite Trypanosoma brucei, which causes Human African Trypanosomiasis (HAT) or sleeping sickness, accumulate in the meningeal spaces, ultimately inducing severe meningitis and resulting in death if left untreated. Thus, sleeping sickness represents an attractive model to study immunological dynamics in the meninges during infection. Here, combining single cell transcriptomics and mass cytometry by time of flight (CyTOF), coupled with in vivo interventions, we found that chronic T. brucei infection triggers the development of ectopic lymphoid aggregates (ELAs) in the murine meninges during chronic infection. These infection-induced ectopic structures are defined by the presence of ER-TR7+ fibroblastic reticular cells (FRCs) and follicular dendritic cells (FDCs) that initiate a signalling cascade driving local T cell activation towards a T follicular helper (TFH)-like phenotype, as well as B cell class switching. Furthermore, the GC-like B cells found in the infected meninges produce high-affinity autoantibodies able to recognise mouse brain antigens. We found that systemic lymphotoxin β (LTβ) signalling blockade led to a significant depletion of meningeal FDC-like cells and autoreactive B cells, indicating that LTβ signalling is critical to induce and maintain local responses in the meninges. In humans, we identified the presence of autoreactive IgG antibodies able to recognise human brain lysates in the cerebrospinal fluid of second stage HAT patients compared to first stage HAT patients, consistent with our findings in experimental infections. Taken together, our data provide evidence that the meningeal immune response results in the acquisition of lymphoid tissue-like properties during chronic T. brucei infection, broadening our understanding of meningeal immunity in the context of chronic infections. These findings have wider implications for understanding the mechanisms underlying the formation ELAs during chronic inflammation resulting in autoimmunity in mice and humans, as observed in other autoimmune neurodegenerative disorders such as neuropsychiatric lupus and multiple sclerosis.