IL-17 signalling is critical for controlling subcutaneous adipose tissue wasting and parasite burden during chronic Trypanosoma brucei infection
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE233314 | GEO | 2023/05/27
REPOSITORIES: GEO
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Project description:In the skin, Trypanosoma brucei colonises the subcutaneous white adipose tissue (WAT) and harbours a pool of parasites competent for forward transmission. The interaction between parasites, adipose tissue, and the local immune system is likely to drive adipose tissue wasting and weight loss observed in cattle and humans infected with T. brucei. However, mechanistically, this process is not fully understood. Here, using several complementary approaches including mass cytometry by time of flight, bulk and single cell transcriptomics, we found that T. brucei infection drives a local expansion of several IL-17A-producing cells in the murine WAT, including TH17 and V6+ T cells. We also found that global IL-17 deficiency, or mice lacking IL-17 receptor expression specifically on adipocytes, were protected from infection-induced WAT wasting and weight loss. Unexpectedly, we found that abrogation of IL-17 signalling on adipocytes results in higher burden of extravascular parasites in the WAT. Taken together, our study highlights the central role of IL-17 signalling on adipocytes in controlling WAT responses to infection, suggesting that adipocytes are a critical coordinator of the tissue immune response to T. brucei infection.
2023-05-27 | GSE233311 | GEO
Project description:In the skin, Trypanosoma brucei colonises the subcutaneous white adipose tissue (WAT) and harbours a pool of parasites competent for forward transmission. The interaction between parasites, adipose tissue, and the local immune system is likely to drive adipose tissue wasting and weight loss observed in cattle and humans infected with T. brucei. However, mechanistically, this process is not fully understood. Here, using several complementary approaches including mass cytometry by time of flight, bulk and single cell transcriptomics, we found that T. brucei infection drives a local expansion of several IL-17A-producing cells in the murine WAT, including TH17 and V6+ T cells. We also found that global IL-17 deficiency, or mice lacking IL-17 receptor expression specifically on adipocytes, were protected from infection-induced WAT wasting and weight loss. Unexpectedly, we found that abrogation of IL-17 signalling on adipocytes results in higher burden of extravascular parasites in the WAT. Taken together, our study highlights the central role of IL-17 signalling on adipocytes in controlling WAT responses to infection, suggesting that adipocytes are a critical coordinator of the tissue immune response to T. brucei infection.
2023-05-27 | GSE233312 | GEO
Project description:IL-17 signalling is critical for controlling subcutaneous adipose tissue wasting and parasite burden during chronic Trypanosoma brucei infection
| PRJNA975847 | ENA
Project description:IL-17 signalling is critical for controlling subcutaneous adipose tissue wasting and parasite burden during chronic Trypanosoma brucei infection [bulk RNA-seq]
| PRJNA975857 | ENA
Project description:IL-17 signalling is critical for controlling subcutaneous adipose tissue wasting and parasite burden during chronic Trypanosoma brucei infection [single-cell RNA-seq]
| PRJNA975862 | ENA
Project description:African trypanosomes have been recently shown to colonise the skin in a process critical for parasite transmission. However, the tissue responses to infection, especially in the lead to parasite transition from the host skin to the vector remain unresolved. Here, using a combination of spatial and single cell transcriptomics, coupled with imaging mass cytometry and genetic models, we investigated the local immune response of the skin in both a murine model of infection and in human samples from the Democratic Republic of Congo (DRC). Our results provide several novel key findings previously unappreciated in the context of parasitic infections in the skin. Firstly, we identified that the skin stromal cells, in particular interstitial preadipocytes located in the subcutis, upregulate several genes involved in inflammatory signalling and antigen presentation, including several molecules involved in T cell activation and survival. Secondly, we detected a significant expansion of a population of IL-17 producing Vg6 gdT cells in the infected murine skin compared to naïve controls, that occur mainly in the subcutis, that we further validated at the protein level by flow cytometry. In silico cell-cell communication analyses between adipocytes and T cells suggests that adipocytes trigger T cell activation locally via Il6, Il10, and Tnfsf18 signalling, amongst others. Thirdly, mice deficient of Vg6 gdT cells show extensive inflammation, increased IFNg-producing CD4+ T cells, and tissue parasite burden compared to naïve controls, indicating that Vg6 gdT cells are important to limit skin inflammation and parasite replication. Based on these observations, we proposed a model whereby interstitial preadipocytes (and potentially adipocytes) as well as Vg6 gdT cells act concertedly in the subcutis to limit tissue damage and parasite load, thus imposing an immunological barrier for transmission. These studies shed light into the mechanisms of gdT cells-mediated immunity in the skin in the context of African trypanosomes infection, as well as a potential role of immature and mature adipocytes as homeostatic regulators on the skin during chronic infection.
2023-08-08 | GSE226113 | GEO
Project description:African trypanosomes colonise the skin to ensure parasite transmission. However, how the skin responds to trypanosome infection remains unresolved. Here, we investigate the local immune response of the skin in a murine model of infection using spatial and single cell transcriptomics. We detect expansion of dermal IL-17A-producing Vγ6+ cells during infection, which occurs in the subcutaneous adipose tissue. In silico cell-cell communication analysis suggests that subcutaneous interstitial preadipocytes trigger T cell activation via Cd40 and Tnfsf18 signalling, amongst others. In vivo, we observe that female mice deficient for IL-17A-producing Vγ6+ cells show extensive inflammation and limit subcutaneous adipose tissue wasting, independently of parasite burden. Based on these observations, we propose that subcutaneous adipocytes and Vγ6+ cells act in concert to limit skin inflammation and adipose tissue wasting. These studies provide new insights into the role of γδ T cell and subcutaneous adipocytes as homeostatic regulators of skin immunity during chronic infection.
| S-EPMC10465518 | biostudies-literature
Project description:Trypanosoma brucei, the protozoan parasite responsible for sleeping sickness, evades the immune response of mammalian hosts and digestion in the gut of the insect vector by means of its coat proteins tethered to the cell surface via glycosylphosphatidylinositol (GPI) anchors. To evaluate the importance of GPI for parasite survival, we cloned and disrupted a trypanosomal gene, TbGPI10, involved in biosynthesis of GPI. TbGPI10 encodes a protein of 558 amino acids having 25% and 23% sequence identity to human PIG-B and Saccharomyces cerevisiae Gpi10p, respectively. TbGPI10 restored biosynthesis of GPI in a mouse mutant cell line defective in mouse Pig-b gene. TbGPI10 also rescued the inviability of GPI10-disrupted S. cerevisiae, indicating that TbGPI10 is the orthologue of PIG-B/GPI10 that is involved in the transfer of the third mannose to GPI. The bloodstream form of T. brucei could not lose TbGPI10; therefore, GPI synthesis is essential for growth of mammalian stage parasites. Procyclic form cells (insect stage parasites) lacking the surface coat proteins because of disruption of TbGPI10 are viable and grow slower than normal, provided that they are cultured in nonadherent flasks. In regular flasks, they adhered to the plastic surface and died. Infectivity to tsetse flies is partially impaired, particularly in the early stage. Therefore, parasitespecific inhibition of GPI biosynthesis should be an effective chemotherapy target against African trypanosomiasis.
| S-EPMC27025 | biostudies-literature
Project description:In trypanosomes, in contrast to most eukaryotes, the large subunit (LSU) ribosomal RNA is fragmented into two large and four small ribosomal RNAs (srRNAs) pieces, and this additional processing likely requires trypanosome-specific factors. Here, we examined the role of 10 abundant small nucleolar RNAs (snoRNAs) involved in rRNA processing. We show that each snoRNA involved in LSU processing associates with factors engaged in either early or late biogenesis steps. Five of these snoRNAs interact with the intervening sequences of rRNA precursor, whereas the others only guide rRNA modifications. The function of the snoRNAs was explored by silencing snoRNAs. The data suggest that the LSU rRNA processing events do not correspond to the order of rRNA transcription, and that srRNAs 2, 4 and 6 which are part of LSU are processed before srRNA1. Interestingly, the 6 snoRNAs that affect srRNA1 processing guide modifications on rRNA positions that span locations from the protein exit tunnel to the srRNA1, suggesting that these modifications may serve as check-points preceding the liberation of srRNA1. This study identifies the highest number of snoRNAs so far described that are involved in rRNA processing and/or rRNA folding and highlights their function in the unique trypanosome rRNA maturation events.
| S-EPMC6411936 | biostudies-literature
Project description:Trypanosoma brucei, the infective agent for African trypanosomiasis, possesses a homologue of the translocase of the mitochondrial inner membrane 50 (TbTim50). It has a pair of characteristic phosphatase signature motifs, DXDX(T/V). Here, we demonstrated that, besides its protein phosphatase activity, the recombinant TbTim50 binds and hydrolyzes phosphatidic acid in a concentration-dependent manner. Mutations of D242 and D244, but not of D345and D347, to alanine abolished these activities. In silico structural homology models identified the putative binding interfaces that may accommodate different phosphosubstrates. Interestingly, TbTim50 depletion in the bloodstream form (BF) of T. brucei reduced cardiolipin (CL) levels and decreased mitochondrial membrane potential (ΔΨ). TbTim50 knockdown (KD) also reduced the population of G2/M phase and increased that of G1 phase cells; inhibited segregation and caused overreplication of kinetoplast DNA (kDNA), and reduced BF cell growth. Depletion of TbTim50 increased the levels of AMPK phosphorylation, and parasite morphology was changed with upregulation of expression of a few stumpy marker genes. Importantly, we observed that TbTim50-depleted parasites were unable to establish infection in mice. Proteomics analysis showed reductions in levels of the translation factors, flagellar transport proteins, and many proteasomal subunits, including those of the mitochondrial heat shock locus ATPase (HslVU), which is known to play a role in regulation of kinetoplast DNA (kDNA) replication. Reduction of the level of HslV in TbTim50 KD cells was further validated by immunoblot analysis. Together, our results showed that TbTim50 is essential for mitochondrial function, regulation of kDNA replication, and the cell cycle in the BF. Therefore, TbTim50 is an important target for structure-based drug design to combat African trypanosomiasis. IMPORTANCE African trypanosomiasis is a neglected tropical disease caused by the parasitic protozoan Trypanosoma brucei. During its digenetic life cycle, T. brucei undergoes multiple developmental changes to adapt in different environments. T. brucei BF parasites, dwelling in mammalian blood, produce ATP from glycolysis and hydrolyze ATP in mitochondria for generation of inner membrane potential. We found that TbTim50, a haloacid dehalogenase (HAD) family phosphatase, is critical for T. brucei BF survival in vitro and in vivo. Depletion of TbTim50 in BF reduced levels of CL and mitochondrial ΔΨ and caused a detrimental effect on many cellular functions. Cells accumulated in the G1 phase, and the kinetoplast was overreplicated, likely due to depletion of mitochondrial proteasome (mitochondrial heat shock locus ATPase [HslVU]), a master regulator of kDNA replication. Cell growth inhibition was accompanied by changes in morphology, AMPK phosphorylation, and upregulation of expression of a few stumpy-specific genes. TbTim50 is essential for T. brucei survival and is an important therapeutic target for African trypanosomiasis.
| S-EPMC8546626 | biostudies-literature