Dr. Alexei Tumanov's research focuses on the regulation of mucosal immunity, cancer and host response to pathogens. We investigate how the immune system regulates the delicate balance between protective immunity and immunopathology at mucosal surfaces, in particular in the gut and lung. Our main research is centered on understanding the biology of lymphotoxin (LT), member of tumor necrosis factor superfamily of cytokines. Although LT and its receptor, LTbR are known as key regulators of lymphoid organ development and maintenance, recent studies revealed the critical role of LT in protection against several mucosal pathogens and regulation of intestinal inflammation. To understand the role of LT signaling in disease, we generated various mouse strains with genetically modified components of LT pathway. Specific ongoing projects include:
1) Understanding the role of LT in inflammatory bowel disease and colorectal cancer.
Our recent studies reveal the critical role of LT in the regulation of innate lymphoid cells (ILCs) in the gut. ILCs are heterogeneous cell population which play key roles in the regulation of inflammation and immunity at mucosal surfaces, particularly in gastrointestinal tract. Despite recent advances in dissecting the roles of different ILC populations in intestinal homeostasis, the cellular and molecular mechanisms of protective versus pathogenic responses mediated by distinct populations of ILCs in inflammatory bowel disease (IBD) remain poorly understood, which limits the development of novel therapies. The goal of this project is to elucidate how LTbR signaling regulates intestinal inflammation in IBD and colitis-associated cancer, the major fatal complication for patients with IBD.
2) Defining the role of innate lymphoid cells in Campylobacter-induced colitis.
Campylobacter jejuni is a common human enteric pathogen that causes acute enterocolitis and increases the risk of developing long-term intestinal dysfunction. Our data suggest that innate immune mechanisms contribute to intestinal pathology in C. jejuni-induced colitis. We investigate how distinct populations of ILCs regulate intestinal inflammation in C. jejuni-induced colitis.
3) Regulation of influenza-induced lung pathology.
Lung pathology is a significant cause of the morbidity and mortality associated with acute respiratory virus infection. Respiratory viruses, such as influenza virus not only cause damage to the epithelium, but activate immune defense mechanisms. Although these immune mechanisms are employed to destroy and remove infected cells in an attempt to clear the virus, they can also promote lung pathology. However, the key cellular and molecular mechanisms that regulate the balance between protection and tissue damage during acute viral infection remain are not well understood. The overall goal of this project is to elucidate how LTbR regulates influenza-associated lung damage.
4) Tumor immunotherapy.
Novel immunotherapies for cancer are having major clinical impact. However, accompanying immune-mediated adverse reactions, such as liver toxicity, remain the major obstacle of these therapies. The goal of this project is to improve effectiveness of cancer therapy by targeting LTbR pathway in the liver.
Complete list of publications in PubMed: https://www.ncbi.nlm.nih.gov/pubmed?term=Tumanov+AV%5Bauthor%5D&cmd=detailssearch
Gubernatorova E.O., Liu X, Othman A., Muraoka W.T, Koroleva E.P., Andreescu S., Tumanov A.V. Europium-doped cerium oxide nanoparticles limit reactive oxygen species formation and ameliorate intestinal ischemia-reperfusion injury. Adv Healthc Mater, May 8. doi: 10.1002/adhm.201700176, 2017.
Koroleva E.P., Fu Y.X., Tumanov A.V. Lymphotoxin in physiology of lymphoid tissues - Implication for antiviral defense. Cytokine. Sep 9. pii: S1043-4666(16)30472-0, 2016.
Gubernatorova E.O., Koroleva E.P., Halperin S., Perez-Chanona E., Jobin C., Tumanov A.V.
Gubernatorova E.O., Koroleva E.P., Halperin S., Perez-Chanona E., Jobin C., Tumanov A.V. Murine model of intestinal ischemia-reperfusion injury. J Vis Exp, e53881, doi:10.3791/53881, 2016.
Macho-Fernandez E., Koroleva E.P., Spencer C.M., Tighe M., Torrado E., Cooper A.M, Fu Y-X, Tumanov A.V. Lymphotoxin beta receptor signaling limits mucosal damage through driving IL-23 production by epithelial cells. Mucosal Immunol, 2015 Mar;8(2):403-13.
Koroleva E.P., Halperin S., Gubernatorova E.O., Spencer C.M, Tumanov A.V. Citrobacter rodentium- induced colitis: a robust model to study mucosal immune responses in the gut. J Immunol Methods, 2015, 421:61-72.
Kruglov A.A., Grivennikov S.I., Kuprash D.V., Winsauer C., Prepens S., Seleznik G. M., Heikenwalder M., Eberl G., Littman D.R., Tumanov A.V., Nedospasov S.A. Non-redundant function of soluble LTα3 produced by innate lymphoid cells in intestinal homeostasis. Science, 342(6163):1243-6, 2013.
Tumanov AV, Koroleva EP, Guo X, Wang Y, Kruglov A, Nedospasov S, Fu YX. Lymphotoxin controls the IL-22 protection pathway in gut innate lymphoid cells during mucosal pathogen challenge. Cell Host Microbe, 10(1):44-53, 2011.
Wang Y., Koroleva E.P., Kruglov A.A., Kuprash D.V., Nedospasov S.A., Fu Y-X, Tumanov A.V. Lymphotoxin beta receptor signaling in intestinal epithelial cells orchestrates innate immune responses against mucosal bacterial infection. Immunity, 32(3): 403-13, 2010.
Tumanov A.V., Koroleva E.P., Christiansen P.A., Khan M.A., Ruddy M.J., Burnette B., Papa S., Franzoso G., Nedospasov S., Fu Y-X., Anders R.A. T cell derived lymphotoxin regulates liver regeneration. Gastroenterology, 136(2):694-704, 2009.
Lo J.C., Wang Y., Tumanov A.V., Bamji M., Yao Z., Reardon C.A., Getz G.S., Fu Y-X. Lymphotoxin beta receptor-dependent control of lipid homeostasis. Science, 316(5822):285-8, 2007.
Grivennikov, S.I., Tumanov, A.V., Liepinsh, D. J., Kruglov, A.A., Marakusha, B.I., Shakhov, A.N., Murakami, T., Drutskaya, L.N., Förster, I., Clausen, B.E., Tessarollo, L., Ryffel, Bernhard, Kuprash, D.V., Nedospasov, S.A.: Distinct and non-redundant in vivo functions of TNF produced by T cells and macrophages/neutrophils: protective and deleterious effects. Immunity, 22 (1): 93-104, 2005.
Tumanov, A. V., Kuprash, D. V., Grivennikov, S. I., Lagarkova, M. A., Abe, K., Shakhov, A. N., Drutskaya, L. N., Stewart, C. L., Chervonsky, A. V., and Nedospasov, S. A.: Distinct role of surface lymphotoxin expressed by B cells in the organization of secondary lymphoid tissues. Immunity. 17: 239-250, 2002.