I received my PhD and postdoctoral training in pulmonary and host-defenses research. I am directing a fungal immunology research lab at the VA Ann Arbor Hospital and remain funded by the VA since 2002
I teach/direct a PhD level class Experimental Immunology (IMM 850), which prepares PhD students for qualifying exams in our T32-funded graduate program. I have successfully trained multiple post docs, grad students undergraduate students and post-bacs towards medical/graduate schools with the ultimate goal of training medical scientist (both physicians and PhDs) with over 95% placement rate at the desired next-step for their careers.
Areas of Interest
The major focus of our research is on a leading invasive fungal infection, cryptococcosis. Cryptococcal infections continue to have an unacceptably high mortality rate due to the limited effectiveness and toxicity of antifungal drugs, rapidly increasing drug resistance, and the ever-increasing number of susceptible hosts.
The major group of studies focus on immunomodulation mechanisms during infection with Cryptococcus sp, targeting and dissecting both “poles” of immunomodulation:
a) Host’s factors, including their alterations induced by immunotherapeutic interventions; and
b) Immunomodulatory microbial factors that impact anti-cryptococcal host defenses.
Our recent studies fill the critical gaps in understanding cryptococcal host-pathogen interactions in the lungs, CNS and other organs affected during disseminated disease.
- The studies of Immunomodulation and the effects of immunotherapy in C. neoformans infection focused on the effects of TNFa and anti-TNFa antibody therapy. These studies demonstrate that TNFa signaling is fundamentally required for programing of dendritic cells (DC), which in turn leads to proper activation and polarization of the T-cell responses. Studies reveled that this DC programing includes epigenetic modification that allows them to maintain DCTh1 phenotype despite the subsequent changes in the cytokine microenvironment induced by the pathogen itself. Cryptococcus can interfere with host defenses to subvert DC activation, pushing them towards non-protective DCTh2 phenotype that programs detrimental responses/immunopathology. To this end, our studies showed that the pathogen can exploit the host’s own receptors and signaling pathways, such as the scavenger receptor MARCO or IL-10 or inducing immunopathology by activation of RIPK3/Fas-Associated Death Domain pathway. In contrast, signaling via NOTCH and CARD9 promote protective immunity.
- Immune subversion is triggered by a group of distinct virulence factors, which contribute to different aspects of C. neoformans pathogenesis. Apart from virulence genes (Ure1, Lac1, Pyk1, Rub1, Ena1, Vad1, and Ssa1) of which role we dissected in the past, we continue to examine effects of new individual virulence factors using deleted and complemented mutant strains, including Sho1, Msb2 and Flp1. We have also introduced bioinformatics approaches to broadly understand virulence factor network interactions and to predict new genes that may code for virulence factors.
- The most recent studies are on CNS-disseminated cryptococcosis and the role of inflammation in pathology of cerebral infection. The groundbreaking message of these studies is that cryptococcosis, traditionally viewed solely as a disease of weak immunity, can induce severe inflammatory damage responses within the CNS. Specifically, CXCR3+ T-cells and CCR2+ monocytes drive severe CNS damage in a much more powerful way than the fungus present in the infected brain. These studies in collaboration with the NIH/NIAID allowed us to obtain human data, to make important comparisons and validations, while testing in the mouse model interventions that could not be tested in humans. They also led to the successful renewal of the VA Merit grant and a group of large-caliber publications
As an interdisciplinary immunology lab we use a broad variety of biomedical approaches working with whole animal systems, cell cultures, and molecular biology, and nanotechnology approaches to study molecular mechanisms, obtain detailed immunological profiling and of our specimens and/or to manipulate the immune system. We also work with human specimens to some extent. Examples of our techniques include animal immunization and microbial challenges, adoptive transfers, experimental immunotherapy, flow cytometry and flow sorting, SC-RNAseq, ChIPseq, NanoStrin Analysis, multi-color fluorescent and confocal microscopies, immune cell functional assays in vitro, targeted gene mutations and generation of transgenic microbes for immunology research. We increasingly use bioinformatics to analyze our increasingly complex datasets.
Research Opportunities for Rotating Students
Modulation of immune response in pathobiology of CNS infection
Modulation of pulmonary host defenses in chronic infections