Victoria Baxter, DVM, PhD,
Assistant Professor
Host-Pathogen Interactions, Southwest National Primate Research Center, Texas Biomedical Research Institute | Project A: The push to “clean up” laboratory mice and rid them of natural pathogens has resulted in the immune systems of specific pathogen free (SPF) mice to be equivalent to that of neonatal humans. As a result, a “dirty mouse” movement has emerged, with the goal of maturing the immune system of SPF mice through the reintroduction of endogenous infections so that the mice better translate the immune responses seen in adult humans. Our lab’s sequential infection model of prior infection exposure (PIE) involves sub-clinically infecting SPF mice with four viral and parasitic pathogens, the first of which is murine gammaherpesvirus 68 (MHV-68), an oncogenic herpesvirus similar to Epstein-Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV). PIE mice demonstrate a more mature and differentiated T cell response at baseline and show altered immune responses to vaccination and experimental infection with a mouse-adapted SARS-CoV-2 strain. However, the relative contribution of each of the four PIE pathogens to this altered immune response and the effect of PIE on the development of cancer are currently unknown. For this project, the student will evaluate the role PIE plays in the development of cancer by determining 1) how each of the four PIE pathogens affects immune maturation individually and in combination, focusing on the immune cell subsets and pathways stimulated by MHV-68 infection, and 2) whether PIE influences the incidence and severity of cancer using spontaneous and syngeneic mouse tumor models. |
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Diako Ebrahimi, PhD,
Assistant Professor
Host-Pathogen Interactions, Texas Biomedical Research Institute | Project B: Human DNA encodes a family of DNA and RNA editing enzymes known as APOBEC. These proteins primarily function to defend against both endogenous and exogenous viruses by inducing lethal mutations in viral genomes. However, research indicates that dysregulation of these enzymes can result in mutations within the host DNA, contributing to tumor formation and evolution. Indeed, APOBEC-induced mutations are among the most prevalent in many cancer patients. In our lab, we employ quantitative biology approaches alongside various experimental techniques, including single-cell and spatial transcriptomics, to investigate the dysregulation of these enzymes and the role of viral infections. Our projects offer an exceptional cross-disciplinary training opportunity, encompassing the acquisition of diverse data analysis techniques, next-generation sequencing technologies, and a wide array of experimental methods spanning infectious diseases and cancer research. |
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Vitaly Ganusov, PhD,
Assistant Professor
Host-Pathogen Interactions, Texas Biomedical Research Institute | Project C: Treatment of several cancers has been revolutionized by using power of the immune system. One approach is to use antibodies that block suppressive signals to T cells resulting in these T cells proliferating, attacking, and killing cancer cells. Another approach is to isolate T cells from patients and grow them in culture to generate large quantities of cancer-specific T cells. These T cells can then be transferred back to the patient in hope that they find and eliminate the cancerous cells. The latter approach has generated remission in some cancer patients in part because transferred T cells can be maintained for very long times. However, in many patients transferred T cells are unable to eliminate the cancer. The reasons for such failure are incompletely understood but may involve failure of T cells to survive the transfer, failure to migrate to cancerous sites, and failure to kill the cancer cells. My work focuses on building mathematical models of T cell dynamics following adoptive transfer into mice and non-human primates (NHPs), with the goal of understanding how such T cells migrate in the body, how they localize to the site of cancer replication, and how they may be able to eliminate the cancer. Mathematical models will be parameterized using data from different experiments. One experiment involves migration of intravenously introduced activated T cells tracked with whole body imaging techniques such as SPECT/CT in NHPs. Another experiment involves migration of radioactively-labeled, cancer specific CD8 T cells in various tissues of mice, including the cancer site. Finally, the third experiment involves measurements of how cancer-specific CD8 T cells eliminate tumors in collagen-fibrin gels. By analyzing data from these experiments, we will build and parameterize mathematical models of T cell-based cancer therapies. |
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Larry Schlesinger, MD,
Professor, President/CEO
Host-Pathogen Interactions, Texas Biomedical Research Institute | Project D: The Schlesinger lab explores human monocyte and macrophage biology and the pathogenesis of tuberculosis (TB) and diseases due to other intracellular pathogens that subvert lung immune mechanisms. Our recent studies provide evidence that M. tuberculosis (M.tb) manipulates cellular responses to limit macrophage apoptosis and promote M.tb intracellular growth. Inhibition of apoptosis, a type of programmed cell death, is implicated in numerous cancers. As such, inducing apoptosis has been a focus for boosting cancer treatment (form of immunotherapy). More recently, our studies have indicated that inducing apoptosis limits intracellular M.tuberculosis (M.tb) growth, including drug-resistant strains – identifying key overlaps in pathways implicated in both cancer and infectious diseases.
Nuclear receptor (NRs) are a family of structurally conserved, ligand-activated transcription factors that regulate development, homeostasis, metabolism, & the immune system. Drugs targeting NRs represented 16% of small-molecule drugs in 2017 and generated $27 billion in 2009 demonstrating that pharmacological targeting of NRs is feasible & effective. We have demonstrated that M.tb enhances expression of peroxisome proliferator-activated receptor gamma (PPARg), a NR that is vital to M.tb growth in macrophages and mice (Rajaram et al 2010; Guirado et al 2018).We identified MCL-1, an anti-apoptotic BCL-2 family member, as a novel PPARg effector that is critical for M.tb growth (Arnett et al 2018). Our recent data show that combination of preclinical MCL-1 and BCL-2 inhibitors induces apoptosis and robustly inhibits drug-sensitive and -resistant M.tb growth in human macrophages (primary niche for M.tb) and granulomas (where long term control is maintained, yet M.tb remains viable & recalcitrant to antibiotics). We considered repurposing cancer chemotherapies and thereby used an FDA-approved BCL-2 inhibitor that was awarded breakthrough designation by the FDA in 2017, in combination with MCL-1 inhibitors that are in phase I/II clinical trials for cancer therapy. This exciting work uncovered targeting the intrinsic apoptosis pathway as a promising approach for not only cancer, but also infectious disease treatment (Arnett et al 2023). Building on this success, we have identified an emerging NR family (NR4A1,2&3) whose expression, similar to PPARg, is induced during M.tb infection; and is implicated in various inflammatory diseases, including diabetes, aging, and cancer. In contrast to PPARg, our preliminary data indicate that the NR4As induce apoptosis and limit M.tb growth in macrophages, and so may oppose PPARgactivity. Previous studies show that the NR4As can interact with BCL-2 in mitochondria to initiate apoptosis. Our recent RNA-seq analysis has indicated that the NR4As can also transcriptionally regulate key genes involved in apoptosis. We are interested in developing novel NR4A agonists and interrogating how the NR4As induce apoptosis, both as transcription factors in the nucleus and through non-nuclear functions like regulation of BCL-2 localization. This work is expected to advance our understanding regarding the role of NR4As in apoptosis regulation, to identify potential targets for both TB and cancer treatment. |
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