Public Health Research Institute Center
New Jersey Medical School - Rutgers, The State University of New Jersey
225 Warren Street
Newark, New Jersey 07103
Phone: (973) 854-3470
Fax: (973) 854-3101
The focus of my current research is the opportunistic human pathogenic yeast, Candida albicans. It is the leading cause of invasive fungal disease in premature infants, surgical patients and cancer patients receiving immunosuppressive chemotherapy. Almost 80% of all AIDS patients suffer from Candidiasis. While candidiasis occurs in the compromised host, on the other hand, vulvovaginal candidiasis (VVC) is more often seen in healthy women, at least for the first episode of the disease. One of the most intriguing aspects of C. albicans is the jump from commensalism to pathogenicity. My research is directed to elucidate the complex signaling pathways that contribute to the virulence & pathogenesis of this organism. Our approaches include molecular, biochemical and immunological techniques to study these events. This involves isolation of encoding genes, construction of knock-out strains to study gene function, DNA Microarrays, and GFP localization etc. Two component signaling proteins (histidine kinases and response regulators) and downstream MAP kinases are the main focus of research. Current effort is focused on:
1. Mechanism of resistance / sensitivity to triazole antifungal drugs:
Two component signal transduction proteins have been reported in bacteria, lower eukaryotes but to date two-component proteins have not yet been identified in animals and are absent in human genome. Previous studies have confirmed the role of two-component proteins in the pathogenesis of C. albicans in a mouse model of hematogenously disseminated candidiasis, survival in human PMNs in vitro, adherence to human esophageal tissue and adaptation to oxidants. These features of two-component proteins make them very attractive target for antifungal drug discovery. We have recently reported that mutants of C. albicans lacking Ssk1p and Chk1p are hypersensitive to triazoles, fluconazole and voriconazole. Importantly, the ssk1 mutant retains the wild type levels of sensitivity to other antifungals such as miconazole, ketoconazole (imidazole), amphotericin B, caspofungin, 5-FC, and a variety of other inhibitors such as Congo red, calcofluor white, and nikkomycin Z. So the hypersensitivity of the ssk1 mutant to triazoles appears to be very specific. The ssk1 mutant has elevated accumulation of fluconazole that may explain its hypersensitivity. Of interest, compared to wild type, both mutants are more readily killed by fluconazole and voriconazole which are normally fungistatic towards this pathogen. Therefore, these mutations result in a fungicidal rather than fungistatic effect with triazoles. An undesirable trait of triazole therapy in general is that resistance can develop, especially in the case of non-albicans Candida species. We hypothesize therefore, that compounds which target Ssk1p or Chk1p may be useful in co-therapy with triazoles to potentiate the activity of the latter compounds. Equally important, my studies will provide new observations on the uptake of triazoles, of which there is very little information in the literature. I also hypothesize that therapy which includes a triazole and a drug which targets Ssk1p or proteins it regulates may enable triazoles to be fungicidal rather than fungistatic. Collectively, our results identify the Ssk1 protein as a promising target for therapeutic strategies. This research is supported by a grant from NIH-NIAID.
2. Host-Pathogen Interactions: Candida adherence and penetration of vascular endothelium / oral epithelium and identification of signal transduction pathway(s) that contribute to Candida albicans invasion.
The incidence of bloodstream infections caused by Candida species has increased dramatically; these organisms now account for 8% of all bloodstream isolates. The mortality associated with candidemia is approx. 40%. Because of this unacceptably high mortality, new strategies to treat and prevent this infection are necessary. Our hypothesis is that the ability of C. albicans to invade and damage host cells is critical for the organism to establish and maintain a deep-seated infection. This hypothesis is based on our finding that C. albicans two-component response regulator ssk1 mutant with decreased virulence in the mouse model of invasive candidiasis and also have reduced adherence to human esophageal tissue and endothelial cells in vitro. We therefore, hypothesize that information relevant to the in vitro interaction of C. albicans and endothelial cells will serve as a model for studying host-Candida interactions. In addition to providing information on adherence, invasion and damage to the vascular endothelium, we also will establish fungal signaling events and protein cross-talk information during pathogenesis. Our hypothesis is that each of these events is crucial to disease development in the vasculature. We are currently using proteomics and DNA microarrays to identify the genes regulated by SSK1 upon interaction with endothelial cells, and the proteins with which it interacts. From the microarray experiments candidate genes will be chosen for construction of knock out stains; mutants will be evaluated phenotypically both in vivo (virulence) and in vitro (with the endothelial cells). The results of these studies will provide the foundation for the future development of novel therapeutic approaches to block candidal adherence and enhance host defense. This research is supported by a grant from American Heart Association (AHA).
Khandelwal NK, Chauhan N, Sarkar P, Esquivel BD, Coccetti P, Singh A, Coste AT, Gupta M, Sanglard D, White TC, Chauvel M, d'Enfert C, Chattopadhyay A, Gaur NA, Mondal AK, Prasad R (2018) Azole resistance in a Candida albicans mutant lacking the ABC transporter CDR6/ROA1 depends on TOR signaling. J Biol Chem 293: 412-432. PMI: 29158264
Jenull S, Tscherner M, Gulati M, Nobile CJ, Chauhan N, Kuchler K (2017) The Candida albicans HIR histone chaperone regulates the yeast-to-hyphae transition by controlling the sensitivity to morphogenesis signals. Sci Rep 7: 8308. PMI: 28814742
Kuchler K, Jenull S, Shivarathri R, Chauhan N (2016) Fungal KATs/KDACs: A New Highway to Better Antifungal Drugs? PLoS Pathog 12: e1005938. PMI: 27832212
Tscherner M, Zwolanek F, Jenull S, Sedlazeck FJ, Petryshyn A, Frohner IE, Mavrianos J, Chauhan N, von Haeseler A, Kuchler K (2015) The Candida albicans Histone Acetyltransferase Hat1 Regulates Stress Resistance and Virulence via Distinct Chromatin Assembly Pathways. PLoS Pathog 11: e1005218. PMI: 26473952
Shor E, Chauhan N (2015) A case for two-component signaling systems as antifungal drug targets. PLoS Pathog 11: e1004632. PMI: 25723524
Mavrianos J, Desai C, Chauhan N (2014) Two-component histidine phosphotransfer protein Ypd1 is not essential for viability in Candida albicans. Eukaryot Cell. PMI: 24489039
Ph.D (Molecular Biology), 2000, Jawaharlal Nehru University (JNU), New Delhi, India
M.Phil. (Biotechnology), 1994, University of Delhi, India
M.Sc. (Microbiology), 1990, AMU, Aligarh, UP, India
B.Sc. (Chemistry), 1987, Bareilly College, Rohilkhand University, Bareilly, UP, India