Professor of Pathology

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Education

M.S., (Biochemistry), Suma cum Laude (Dean's list), Department of Biochemistry, School of Natural Sciences, Charles University, Prague, Czech Republic
Ph.D. (Experimental Medicine), Suma cum Laude, Center for the Study of Host Resistance, Research Institute of Montreal General Hospital, McGill University, Montreal, Canada
Postdoctoral Fellow, Laboratory of Animal Models and Retroviral Vaccines, National Cancer Institute, NIH, Bethesda, MD, USA

Research Interests

Innate immune regulatory activity and neutrophil dysregulation as a driving mechanism of pathogenesis in HIV-1-infection. Recent evidence demonstrates that neutrophils, the most abundant nucleated immune cell population in the body, play an important role in the regulation of adaptive and innate immune systems. We have shown that neutrophils from HIV-1-infected individuals display an activated phenotype, specific transcriptional profile, and increased rate of degranulation. We propose that HIV-1 infection is associated with altered myeloid cell homeostasis resulting in changes in the population frequency and functional activity of diverse granulocytic populations. Dysregulation of granulocytic recruitment, function, and clearance contributes to the pathogenesis of cardiovascular and liver diseases associated with HIV-1 infection. Specifically, neutrophils in the blood of HIV-1-infected individuals express high levels of PD-L1 that is induced by HIV-1 virions and products of microbial translocation including lipopolysaccharide (LPS). Neutrophil PD-L1 levels correlate with the expression of PD-1 on CD4+ and CD8+ T cells, elevated levels of neutrophil degranulation markers in plasma, and increased frequency of low density neutrophils expressing the phenotype of granulocytic myeloid-derived suppressor cells (G-MDSCs). Neutrophils purified from the blood of HIV-1-infected patients suppress T cell function via several mechanisms including PD-L1/PD-1 interaction and production of reactive oxygen species (ROS). The accumulated data suggest that chronic HIV-1 infection results in an induction of immunosuppressive activity of neutrophils characterized by high expression of PD-L1 and an inhibitory effect on T cell function. This newly identified mechanism of immune suppression mediated by neutrophils may alter our understanding of HIV-1 pathogenesis. Furthermore, we have shown that neutrophils from HIV-1-infected individuals display high capacity to undergo NETosis. Production of neutrophil extracellular traps (NETs) likely contributes to increased risk of cardiovascular and liver diseases in HIV-1-infected individuals.

Neutrophils and cancer. Our research focuses on neutrophils and granulocytic myeloid-derived suppressor cells (G-MDSCs), cell populations that have been recently identified to play a critical role in the regulation of adaptive and innate immune responses in cancer and chronic inflammatory conditions. Production of neutrophil extracellular traps (NETs) by neutrophils contributes to increased risk of cardiovascular and liver disease in cancer patients.

The impact of hormonal contraceptives on HIV-1 acquisition and transmission. Safe and effective methods of contraception represent a critical component of preventive health care reducing maternal and infant mortality, especially in women living in resource-limited settings. Depot medroxyprogesterone acetate (DMPA; Depo-Provera) is a highly effective progestin-based contraceptive and one of the most commonly used contraceptives in sub-Saharan Africa. Several epidemiological studies indicate an association between the use of DMPA and an increased risk of HIV-1 infection. Modelling studies indicate that the use of injectable contraceptives may be responsible for hundreds of thousands of new HIV-1 transmissions annually. It is therefore critically important to identify safe forms of contraception without a significant deleterious effect on systemic and mucosal immune environment. We demonstrated that medroxyprogesterone acetate (MPA) suppresses antigen- immune function of T cells and dendritic cells via direct and indirect mechanisms and increases the rate of HIV-1 proliferation. In a clinical study performed at UAB, we analyzed vaginal biopsies and various immune parameters in the blood of women using various forms of hormonal contraceptives. We showed that the use of MPA is associated with thinning of vaginal epithelial wall and decreased production of IFN-α by plasmacytoid dendritic cells. We have shown that MPA reduces defense mechanisms of genital epithelium by suppression of factors critical for the barrier function and structural integrity of the vaginal and cervical epithelium. Decreased production of these factors reduces the resistance of genital epithelial tissue to microabrasions and increases the probability of HIV-1 transcytosis and transmigration leading to an exposure of target cells in the parabasal epithelium and lamina propria. Furthermore, DMPA and NuvaRing (etonogestrel) significantly suppress the cervicovaginal levels of principal anti-HIV-1 inhibitory factors human β-defensin 2 and 3 and secretory leukocyte protease inhibitor (SLPI). In a recent randomized clinical study in Lusaka, Zambia, we showed that administration of MPA decreases the production of several factors in the cervicovaginal fluid of HIV-1-infected women that may contribute to higher shedding of the virus and potentially to increased rates of viral transmission. In search for safe contraceptives, we have demonstrated that norethisterone (NET) and levonorgestrel (LNG) do not inhibit the function of dendritic cells and T cells and therefore represent safe potential alternative to DMPA.