Immunity, Infection and Inflammation Research

Lena Al-Harthi, PhD

The lab of Lena Al-Harthi, PhD, is focused on understanding mechanism(s) driving HAND and HIV latency in the central nervous system.

Edward Barker, PhD

Research of Edward Barker, PhD, focuses on Interleukin-22 (IL-22), an essential cytokine contributing to homeostasis of mucosal epithelial cells. IL-22 is produced by lymphocytes and Il-22 receptor is found primarily on epithelial cells and fibroblasts. Loss of CD4+ T-helper lymphocytes during HIV infection may contribute to decreased IL-22 presence in the gut; however, a subpopulation of innate lymphoid cells (ILCs), mainly NKp44 activation receptor expressing ILC3, is capable of maintaining IL-22 levels even when T-cells are depleted in the gastrointestinal (GI) tract. Our data indicate that that there are higher frequencies of gut-derived ILCs (including those that express NKp44) that produce the inflammatory cytokine interferon-gamma (IFN-) when they were obtained from viremic HIV-infected individuals as compared to cells obtained from the GI tract of uninfected individuals. IFN- increases the transcytosis of bacteria across the epithelial layer and breaks down the epithelial barrier integrity.  We hypothesize that HIV creates an environment that alters the function of ILCs from cells that are important in maintaining homeostasis in the GI tract to cells that contribute to increased inflammation and barrier dysfunction in the gut of infected patients. We postulate that HIV both directly and indirectly induces inflammatory ILC by 1) stimulating intestinal myeloid dendritic cells (mDC) to secrete pro-inflammatory cytokines 2) modifying the gut Microbiome to increase pathobiont bacteria, which in turn trigger mDCs to secrete higher levels of pro- inflammatory cytokines 3) inducing the expression of ligands to NKp44 on T-cells which trigger homeostatic ILC (which normally secrete IL-22) to also begin to secrete IFN- and 4) inducing the expression of ligands on HIV-infected T-cells, which in turn, trigger pro-inflammatory ILCs to secrete IFN-. To address these hypotheses, we propose the following: Specific Aim 1: To evaluate the relationship between gut homeostatic ILC cytokine profiles, expression of ILC activating receptor ligands, and epithelial barrier function in untreated HIV infection and to determine whether associations exist between gut NK/ILC cell inflammatory cytokine production and clinical correlates of HIV pathogenesis in HIV-infected subjects on suppressive combination anti-retroviral therapy. Specific Aim 2: To determine the mechanism in which HIV and HIV-altered mucosal bacteria (HAMB) contribute to the induction of colonic inflammatory homeostatic Aim 3: To determine the mechanism in which HIV and HIV-altered mucosal bacteria (HAMB) contribute to increased frequencies of pro-inflammatory ILC1s.

Animesh Barua, PhD

Animesh Barua, PhD, focuses on development of immunotherapies against OVCA: Cancer Chemotherapeuitcs are toxic to normal tissues and affects the quality of life specially in postmenopausal women with OVCA. Immunotherapies are safe and offer effective alternatives to chemotherapeutics. In this project, we are testing herbal products to enhance tumoricidal functions of NK cells.

Seema Desai, MS, PhD

Seema Desai, MS, PhD, is an assistant orofessor in the Department of Immunology/Microbiology and Medicine at Rush University. Desai’s HIV research experience spans from pediatric to geriatric HIV. Desai came to Rush in 2007 after completing a postdoctoral fellowship at the University of Miami, Miller’s School of Medicine.  Her research focus is on aging with HIV disease and substance abuse (alcohol) and is NIH funded. The laboratory evaluates immune perturbations- innate and adaptive in aging HIV infected subjects. The Desai lab conducts experiments using multi-parametric flow cytometry for analyzing T cell phenotype and function and uses multiplex platform for cytokine studies. Her laboratory performs innovative Telomere studies.

Christopher B. Forsyth, PhD

Christopher B. Forsyth, PhD, works with Ali Keshavarzian, MD, to study the critical role of environmental factors in promoting gut-derived inflammation and disease for the last three decades.  The rationale for our approach is that: (1) Most chronic systemic (and intestinal) diseases are a consequence of interactions between genetic susceptibility and deleterious environmental factors.  Identifying the environmental factors could provide opportunities to stratify individuals based on risk factors as well as identify therapeutic targets to prevent and/or treat these disorders. (2) Chronic diseases are primarily inflammatory disorders and gut-derived inflammation is a plausible source/trigger for inflammatory cascades. Gut-derived inflammation could be a consequence of changes in intestinal barrier integrity (i.e., intestinal hyperpermeability) and/or changes in intestinal microbiota composition/function (i.e., dysbiosis) both of which would lead to exposure of the immune system to pro-inflammatory bacterial factors like endotoxins.  (3) Chronic diseases are more common in Western societies (and societies that adopt the Western life style) thus environmental factors associated with the Western life style are promising factors to study. Examples of Western life style-associated risk factors we study include: alcohol consumption, dietary factors including fiber and fat content, stress, as well as circadian rhythm disruption.  Our group has studied the impact of these factors on numerous pathological and disease states including: intestinal barrier function and microbiota composition, obesity/metabolic syndrome, HIV/AIDS, Parkinson’s disease, multiple system atrophy (MSA), post traumatic stress disorder (PTSD), epilepsy, alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), food allergy, inflammatory bowel disease (ulcerative colitis, Crohn’s disease), irritable bowel syndrome (IBS), colon and breast cancer, neonatal development, and osteoarthritis. Our laboratory combines data from clinical studies with data from mouse models, and in vitro molecular methods including genomics, transcriptomics, and metabolomics, as well as tissue protein measurements and staining. 

Tibor T. Glant, MD, PhD

The ongoing research projects of Tibor T. Glant, MD, PhD, professor, Section of Molecular Medicine in the Department of Orthopedic Surgery, focus on the genetics and autoimmunity of inflammatory joint diseases; more specifically the pathogenesis of rheumatoid arthritis and ankylosing spondylitis. These studies include (i) the screening, identification and localization of “disease susceptible” gene(s) that control autoimmune processes and inflammatory cell migration into rheumatoid synovium, (ii) the autoimmune mechanisms of ankylosing spondylitis including the screening, identification and localization of “disease susceptible” gene(s) in a corresponding animal model, (iii) the immunology/immunopathology and genetics of extracellular matrix components (specifically cartilage macromolecules), (iv) the mechanisms of antigen presentation in normal and pathological (autoimmune) conditions, and tolerization of autoimmune-prone individuals against the disease, (v) potential gene- and immunotherapeutic interventions in autoimmune/inflammatory diseases. (vi) Recently, we have identified a gene, and partially characterized its disease-associated function, which gene (if defected by mutation or inherited by parents) is responsible for at least two rare skin diseases such as pyoderma gangrenosum and a sever myeloproliferative disease leading to Sweet’s syndrome. All these studies were initiated by animal models and then supported and/or confirmed by information of patients with the corresponding human disease. A ‘hold on” project is the cellular and molecular (signaling) mechanisms of pathological bone resorption in failed joint replacements. All these major directions involve studies employing state-of-the-art strategies and techniques in basic molecular biology, biochemistry, genetics, cell biology and immunology.

Vineet Gupta, PhD

Vineet Gupta, PhD, studies cell adhesion receptors, called integrins, and how they regulate a variety of biological processes.

Ali Keshavarzian, MD

Ali Keshavarzian, MD, studies the involvement of the intestinal tract in human diseases. The lab emphasizes translational research utilizing human clinical research, animal models of disease (primarily mice), as well as ex vivo and in vitro studies to investigate disease mechanisms. Major areas of research include mechanisms related to inflammation, cancer, circadian rhythms disruption promotion of disease, alcohol-related diseases, and intestinal microbiota (diet)-host interactions. The role of intestinal barrier integrity (i.e., leaky gut) promoting disease is also a major theme of the lab. Current areas of research that are funded include studies of: (1) inflammatory bowel disease (IBD), (2) alcoholic liver disease, (3) colon cancer, and (4) Parkinson’s disease. Other active projects are exploring the role of the intestinal tract in (5) HIV pathogenesis, (6) mind body medicine impacting the brain-gut axis, (7) food allergy, (8) irritable bowel syndrome (IBS), (9) pancreatic cancer, (10) metabolic syndrome-obesity, (11) epilepsy, (12) osteoarthritis, and (13) the role of socioeconomic status in disease processes (especially focused on the microbiota). The GI Lab has many projects focused on immunology research. In all of the diseases mentioned the focus of our research is to mechanistically understand the role of inflammation and specific immune cells, especially T cell subsets, innate lymphoid cells, and cytokines on disease progression. This includes active investigations of the role of these immune cell subsets in alcoholic liver disease, IBD, colon cancer and Parkinson’s disease. In addition, the lab is interested mechanistically in understanding how changes in the intestinal microbiota are influencing immune function especially during circadian rhythm disruption, alcohol consumption, and leaky gut. Other key personnel include Faraz Bishehsari, MD/PhD, Garth Swanson, MD, Robin M. Voigt-Zuwala, PhD and Christopher B. Forsyth, PhD.

Alan Landay, PhD

The laboratory of Alan Landay, PhD, has multiple ongoing research projects focused on understanding both the cause and the consequences of  immune pathogenesis and inflammation in HIV and chronic diseases of aging.

Amanda Marzo, PhD

The overall goal of the lab of Amanda Marzo, PhD, is to understand the mechanisms underlying the induction and maintenance of memory CD8 T cells, the factors responsible for sustaining effector function and the mechanisms for their persistence. Mucosal barriers of the gastrointestinal and female reproductive tract are major sites of pathogen exposure and disease transmission. For the most part, efficacious vaccines that rely on T cells directed against mucosa-acquired infections have been ineffective. This shortcoming may result from insufficient numbers of functional memory CD8 T cells being generated and/or maintained at the site of initial transmission. Recently, mTOR has been implicated in regulating the intrinsic transcriptional programs that determine the fates of effector and memory CD8 T cells. My lab is interested in understanding how mTOR controls the generation of effector and memory CD8 T cells and influences trafficking of mucosal memory CD8 T cells.

Katalin Mikecz, MD, PhD

Katalin Mikecz, MD, PhD, is a professor in the Department of Orthopedic Surgery. She studies autoimmune responses to cartilage components in arthritis-susceptible mice and in rheumatoid arthritis (RA) patients. RA is an autoimmune disease affecting nearly 1% of the human population and causing painful inflammatory destruction of the joints. Immune recognition of self antigens, particularly those in the joint is a hallmark of RA. One of the major components of joint (articular) cartilage is a large molecule called proteoglycan (PG) or aggrecan. With age, some amino acids in the protein backbone of the PG molecule undergo chemical modifications. One of the most common post-translational modifications is the enzymatic conversion of the amino acid arginine to citrulline. While this modification (citrullination) apparently does not cause any problem in healthy individuals, in RA patients the cells of the adaptive immune system mistakenly recognize citrullinated proteins as foreign molecules and mount an inflammatory attack to eliminate them from the body. During this process, B cells produce antibodies that can bind to molecules containing citrulline, thereby targeting these citrullinated proteins for engulfment and destruction by other immune cells. Most patients with RA produce anti-citrullinated protein antibodies (ACPA). We have recently found that ACPA bind to human cartilage PG, a macromolecule that induces both arthritis and ACPA production when injected into mice. With regard to RA, citrullinated self PG can be either an inducer or a target of ACPA. In this project we characterize citrullinated PG-specific T- and B-cell responses in RA patients and identify ACPA bound to cartilage in their joints. We will also investigate the mechanisms that connect citrullinated PG-specific immune responses to the development of joint inflammation in ACPA-producing mice with citrullinated PG-induced autoimmune arthritis. We believe that these studies, by providing insights into the role of citrullinated PG in provoking immune attacks against the joints in both RA and a mouse model of the human disease, will facilitate the development of new treatments for RA.

Tibor A. Rauch, PhD

Tibor A. Rauch, PhD, Department of Orthopedic Surgery, focuses on how epigenetic factors form bridges between the environment and the genetic information-harboring DNA by interpreting external stimuli and regulating gene expression. Alterations in epigenetic mechanisms influence immune system activity and contribute to the pathogenesis of various inflammatory diseases including rheumatoid arthritis (RA). RA is a degenerative autoimmune disease and it is well established that both genetic risk factors (mutations) and epigenetic alterations (epimutations) can be implicated in the etiology of RA. Our research is mainly focused on (i) exploring epigenetic factors involved in RA, (ii) understanding their contribution to the initiation and the progression of the disease and (iii) testing new drugs that target differentially expressed epigenome modifiers. We employ genome-wide DNA methylation profiling techniques, gene expression microarrays, and a wide variety of recombinant DNA technologies for achieving the above-delineated goals. We investigate arthritis-associated epigenetic events in cell cultures and a mouse model of RA.

Getting involved in one of these projects can allow you to (i) contribute to the better understanding of pathomechanisms of RA and (ii) delineate new therapeutic options for arthritis.

Sasha Shafikhani, PhD

The primary focus of the lab of Sasha Shafikhani, PhD, is (i) to determine the virulence mechanisms in the bacterial pathogen, particularly Pseudomonas aeruginosa; (ii) to determine the eukaryotic host responses that are intended to control bacterial pathogen infections; and (iii) to employ bacterial toxins as molecular tools to dissect important mammalian cellular processes such as cytokinesis, apoptotic program cell death, and apoptotic compensatory proliferation signalling.