The 2023 BSI Congress saw the return of our hugely popular 'Bright Sparks in Immunology’ sessions, which recognise exceptional work from PhD students and postdocs. Here, Dr Matthew Sinton tells us more about his work on the role of adipose tissue in the immune response to sleeping sickness infection, which won him the award in the postdoc category.
What is the role of adipose tissue in infection?
When we think of getting an infection, the fat in our body isn’t likely to be the first thing on our mind, but there’s growing evidence that adipose tissue is an important player in the immune response to infectious diseases. We know that numerous infections lead to weight loss, and it has long been thought that this is because when we get sick, we often don’t want to eat, and so begin to use up our lipid stores. However, there is a growing body of evidence showing that the adipose tissue changes its structure and function during infection, and that these changes actively contribute to the immune response. We still don’t know a lot about the interactions between adipose tissue and the immune system, and we also don’t know a great deal about the impact on our immune system of drawing upon these internal nutrient stores instead of getting our nutrients from our diet.
Adipose tissue was once thought of as an inert energy depot, but we now know that it is an incredibly active tissue, exerting strong endocrine functions on various tissues throughout the body, while also maintaining communication with organs like the liver and brain. We also know that the fat cells within the adipose tissue, called adipocytes, secrete a range of immune factors – including cytokines like TNF-α and IL-6 – and hormones like adiponectin and leptin, which have also been shown to have immune functions. These have been studied in the context of obesity, which causes systemic inflammation, but obesity is a relatively modern phenomenon. So what happens in this tissue when we have an infection, and how might it contribute to the local immune response?
Studying sleeping sickness
During my time in Professor Annette MacLeod’s Lab (University of Glasgow), we started to explore this question using the pathogen Trypanosoma brucei, which is an extracellular parasite that infects humans and animals in countries of Sub-Saharan Africa, leading to a disease called sleeping sickness. The parasite is transmitted through the bite of an infected tsetse fly, and once it enters the bloodstream, it starts to colonise tissues throughout the body, starting with peripheral tissues such as the skin and adipose tissue, and eventually making its way to the brain borders and even the brain parenchyma. Throughout the course of this infection, people develop severe pathologies, including narcolepsy-like symptoms, and excessive weight loss and adipose tissue wasting. Ultimately, if left untreated, the disease is fatal and even if treated it can still leave people with severe disabilities.
Our starting point was to look at what happens in the skin during infection, as the skin is an important reservoir for T. brucei transmission, and the parasites must survive the local immune response while they wait to be taken up by the bite of a tsetse fly. Additionally, there is a layer of subcutaneous adipocytes throughout the skin, making it an ideal tissue for exploring the role of adipocytes in the response to infection.
An intriguing discovery
We started off with a broad characterisation of skin from mice, using a combination of single cell and spatial transcriptomics, which was a team effort with Juan Quintana (a Research Fellow in the lab), and Praveena Chandrasegaran and Agatha Nabilla Lestari (both MSc students in the lab). Using this approach, we were able to determine not only which cell populations were changing during infection, but also where these cells were located and what they might be interacting with. One of the most striking initial outcomes of this analysis was the expansion and migration of gd T cells in the skin during infection. We identified a population of IL-17A+ Vg6 cells in the dermis and epidermis under homeostasis, which then migrated to the subcutaneous adipose tissue layer during infection, which was fascinating to us. We were really intrigued because a number of studies have demonstrated that IL-17 is important for controlling adipocyte function. For example, Kohlgruber et al. (2018)1identified that IL-17A+ gd T cells control adipose tissue thermogenesis, and shortly after, Teijeiro et al. (2021)2found that IL-17A is an important driver of adipose tissue expansion during obesity.
These studies made us wonder if these Vg6 cells might be having some effect on the subcutaneous adipocytes during T. brucei infection. Using a Vg4/6 knockout model, we observed that during infection, control animals lost significant adipose tissue mass as expected, but that the knockouts started out with less of this tissue and did not lose any during infection. This was a really exciting finding, but we wanted to know if the Vg6 cells were the only ones upregulating IL-17A during infection and, as we expected, they were not. We also found that TH17 expanded in the adipose tissue during infection. We were fortunate enough to have received serum from patients infected with T. brucei through the TrypanoGEN+ network, and when we measured cytokines in these samples, we found that IL-17A was elevated in samples from infected patients.
A dual approach
To try and figure out how IL-17A might be interacting with adipocytes during infection, and given that we now knew multiple cell types were upregulating this cytokine, we took two approaches. One was to delete IL-17A itself (using an Il17af−/− mouse model) and the other was to delete IL-17 receptor A (IL-17RA) from the adipocytes themselves (using an AdipoqCre × Il17rafl/fl mouse model). We found both of these models to be protected from weight loss and adipose tissue wasting (as they were in the Vg4/6 model that we used), strongly supporting the idea that IL-17A drives these phenotypes during T. brucei infection. However, there was an additional really exciting finding that arose from using the IL-17RA deletion model, which was that the parasite burden in the adipose tissue was higher than that in littermate controls. In fact, there were around double the number of parasites in the tissue when the adipocytes could no longer sense IL-17 signalling through IL-17RA, which was completely unexpected.
There are a number of possible causes for this. One is that IL-17 signalling through IL-17RA may induce the expression of antimicrobial peptides that can directly kill the parasites. Alternatively, the adipocytes may be releasing specific factors that are able to coordinate the local immune response. When we performed cell–cell communication predictions, we found that during infection, adipocytes upregulate numerous genes, including those encoding P-selecting and CCL12. So, it is plausible that recruitment of various immune cells is impaired when adipocytes can no longer sense IL-17. Moreover, we found that adipocyte precursor cells (preadipocytes) are heavily involved in the production of cytokines/chemokines during infection (e.g. Il6, Il15, Il18bp, Cxcl9 and Cxcl10) and presentation of antigens (e.g. H2-DMa and H2-M3). Together, this gives the impression that adipocytes and their precursors are switching their focus to supporting and/or coordinating the local immune response during T. brucei infection.
Final thoughts
We were really excited to share our findings with the field, as they highlight the important role of adipocytes in the immune response to infection. Hopefully this is something that will be tested in other infectious disease models. The prevalence of obesity and metabolic disorders is rapidly increasing globally, and it is vitally important that we study adipose (and other) tissues from new angles, so that we can understand both how they contribute to immunity, and how this contribution is impaired if the tissue becomes dysfunctional.
Dr Matthew Sinton, University of Manchester