German Gornalusse, PhD, MSc (Obstetrics & Gynecology)
Our research focuses on the mechanisms of HIV latency and reactivation in the human gut. We are currently using in vitro models to test the hypothesis that microfold cells, highly specialized enterocytes, drive T cell proliferation and HIV reactivation via their increase activity of type I/III interferon pathways. The differentiation programs that lead to the generation of M cells are largely unknown. Their isolation and ex vivo culture is challenging, and there are no available immortalized M-cell lines. There are, however, protocols to generate M cell-like cells in vitro. Our co-Investigator Dr. Jason Smith has established in his lab a culture system using duodenal and ileal enteroids to generate M cells; these enteroids arise from stem cells found in intestinal crypts. Therefore, we are currently employing these stem-cell derived enteroid models to investigate whether secreted products from M cells (e.g. soluble ISG15 and other cytokines) reactivate HIV and/or induce proliferation in latently infected CD4+ T cells from people living with HIV and other cellular models. If we find that certain factors derived from M cell cultures drive CD4+ T cell proliferation in vitro, we will go back to ex vivo duodenal and ileal tissues and further define which molecular networks are involved. In summary, we are employing stem-cell derived cellular systems to model in vitro the dynamics of the HIV reservoir. This project, along with an ongoing clinical study, will provide key information about the intestinal microarchitecture of the HIV reservoir that is necessary for the development of novel latency reversal agents or strategies to target latently infected cells via M cells.
Jakob von Moltke, PhD (Immunology)
Our lab studies immune responses to parasitic worms (helminths) and allergens. Remarkably, despite being enormously diverse, helminths and allergens all give rise to a “type 2” immune response that is characterized by profound changes in tissue physiology such as increased mucus production (runny nose) and hypercontractility of smooth muscle (coughing/sneezing). Although these clinical manifestations of type 2 immunity are well known, some of the most fundamental questions about how type 2 immunity is first activated remain unanswered. Indeed, we do not even know how the immune system first senses the presence of helminths and allergens. Therefore, our recent discovery that specialized cells in the intestinal lining called tuft cells are required for initiation of type 2 immunity provided an exciting advance. Notably, the number of tuft cells in the intestine increases enormously during helminth infection and we have shown that this requires reprogramming of stem cells to bias them towards production of tuft cells.
Although they were discovered more than 50 years ago, the function of tuft cells remained unknown. We believe tuft cells are ideally positioned to both sense worms and transmit signals to the immune system and we are using genetic mouse models combined with microscopy, single cell analysis, and specialized tissue culture to study the underlying mechanisms. We are also particularly interested in how signals from the immune system shape the fate decisions of non-immune stem cells. Although helminths provide a useful model for scientific inquiry, we believe our findings will provide insight into the immune pathways underlying allergic disease and could suggest novel therapeutic targets for treating both helminth infection and allergies.
Jenny Robinson, PhD (Orthopaedics & Sports Medicine and Mechanical Engineering)
Our primary goal is to understand what cues are needed to promote connective tissue (ligament, cartilage, fibrocartilage) regeneration after knee injuries and reduce the onset of osteoarthritis. We have a particular interest on how these cues may differ in male and female athletes. We engineer biomaterial-based environments that mimic native tissue biochemical and mechanical properties to pinpoint specific cues that are required for regeneration of the connective tissues in the knee. We aim to use this knowledge to inform the treatment options for patients with knee injuries to ensure they can get back to performance with reduced or minimal chance for the development of osteoarthritis.
Elia Tait Wojno, PhD (Immunology)
Dr. Elia Tait Wojno and her team work on dissecting how immune and epithelial responses at mucosal barriers are regulated during helminth parasite infection and allergy, with a special emphasis on how cytokines and prostaglandins influence stem cell function to promote inflammation. Currently, we do not fully understand how immune and epithelial stem cells in the lung and intestine control altered tissue function and inflammation. We use in vitro and in vivo studies of immune, epithelial, and stem cell biology in mice and humans to identify basic mechanisms that underlie mucosal barrier inflammation and host protection against infection. These studies will reveal the importance of stem cell-mediated effects on promoting inflammation in tissues and have the potential to inform the development and use of new, stem cell-directed therapies to manage inflammatory conditions in the lung and gut.