Public Health Research Institute Center
University of Medicine and Dentistry of New Jersey
225 Warren Street
Newark, New Jersey 07103

Phone: (973) 854-3470
Fax: (973) 854-3101
e-mail: chauhan1@umdnj.edu


Research Interests

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).




Recent Articles


Bambach A, Chauhan N, Kruppa A, Ghosh A, Alex D, Rolfes R and Calderone R. The Goa1p of Candida albicans localizes to mitochondria during oxidative and osmotic stress and is required for stress adaptation. [Submitted]

Chauhan N and Calderone R. (2008) Two-component signal transduction proteins as potential drug targets in medically important fungi. Infect. Immun. 76(11): 4795-4803.

Menon V, De Bernardis F, Calderone R and Chauhan N. (2008) Transcriptional profiling of the Candida albicans Ssk1p receiver domain point mutants and their virulence. FEMS Yeast Res. 8: 556-563.

Chauhan N, Kruppa M and Calderone R. (2007) The Ssk1p response regulator and Chk1p histidine kinase mutants of Candida albicans are hypersensitive to fluconazole and voriconazole. Antimicrob. Agents Chemother. 51(10): 3747-3751.

Chauhan, N and Calderone R. (2007). Virulence factors as drug targets: how and why. The 6th ISHAM Virtual Mycological Congress. Theme: “Antifungal Antibiotics”. Oct 16th –Oct 31st 2007.

Chauhan, N, Latge, JP and Calderone R. (2006) Signaling and oxidant adaptation in Candida albicans and Aspergillus fumigatus. Nature Microbiology Reviews. 4(6): 434-44.

Menon V, Li D, Chauhan N, Rajnarayanan R, Dubrovska A, West AH and Calderone R. (2006) Functional studies of the Ssk1p response regulator protein of Candida albicans as determined in receiver domain point mutants. Mol. Microbiol. 64(4): 997-1013.

Hana Sandovsky – Losica, Chauhan N, Calderone R and Esther Segal. (2006) Gene transcription studies of Candida albicans following infection of HEp2 epithelial cells. Med. Mycology. 44:329-334.

Chauhan N, Toni Ciudad, Ane Rodriguez Alejandre, German Larriba, Richard Calderone and Encarnacion Andaluz (2005) Virulence and karyotype analysis of the rad52 mutants of Candida albicans: regeneration of a truncated chromosome of a reintegrant strain (rad52/RAD52) in the host. Infect. Immun. 73(12):8069-78.

Chauhan N, Kumar R, Badhai J, Preet A and Yadava PK. (2005) Immunogenicity of cholera toxin B epitope inserted in Salmonella flagellin expressed on bacteria and administered as DNA vaccine. Mol. Cell. Biochem. 276:1-6.

Singh, P., Chauhan, N., Ghosh, A., Dixon, F and Calderone R. (2004) The SKN7 of Candida albicans: mutant construction and phenotypic analysis. Infect. Immun. 72(4):2390-4.

Kruppa M, Krom BP, Chauhan N, Bambach AV, Cihlar RL and Calderone R (2004) The two component signal transduction protein Chk1p regulates quorum sensing in Candida albicans. Eukaryotic Cell. 3(4):1062-5.

Li D, Gurkovska V, Sheridan M, Calderone R and Chauhan N. (2004) Studies on the regulation of two component histidine kinase gene CHK1 in Candida albicans using the heterologous lac-Z reporter gene. Microbiology 150:3305-13.

Chauhan, N., Inglis, D., Roman, E., Pla, J., Li, D., Calera, J. A. and Calderone, R (2003) Candida albicans response regulator gene SSK1 regulates a subset of genes whose function is associated with cell wall biosynthesis and adaptation to oxidative stress. Eukaryotic Cell. 2(5):1018-1024.

Kruppa M, Goins T, Cutler JE, Lowman D, Williams D, Chauhan N, Menon V, Singh P, Li D and Calderone R. (2003) The role of the Candida albicans histidine kinase (CHK1) gene in the regulation of cell wall mannan and glucan biosynthesis. FEMS Yeast Res. 3(3):289-99.

BOOK CHAPTERS:

Chauhan N. (2009) Preparation of samples for proteomic analysis of Candida cell wall. In: Methods in Molecular Medicine - Candida albicans Eds: Ron Cihlar and Richard Calderone. Humana Press, USA [In Press].

Chauhan, N and Michael Kruppa. (2009) APPENDIX: Standard Growth Media and Common Techniques for use with Candida albicans. In: Methods in Molecular Medicine - Candida albicans Eds: Ron Cihlar and Richard Calderone. Humana Press, USA [In Press].

Chauhan, N and Calderone R. (2008) Molecular approaches to target discovery in human pathogenic fungi. p. 171-194. In: Pathogenic Fungi: Insights in Molecular Biology. Eds: Gioconda San-Blas and Richard Calderone. Horizon Scientific Press, UK.

Chauhan, N and Calderone, R. (2004) Adaptation to oxidative, nutrient and pH stress by human pathogenic fungi. In: Pathogenic Fungi: Cellular and Molecular Biology. Eds: Gioconda San-Blas and Richard Calderone. Horizon Scientific Press, UK.

Chauhan, N., Li, D., Singh, P., Calderone, R., Kruppa, M. (2002) The Cell wall of Candida spp. p.159-175. In: Candida and Candidiasis ed: Richard A. Calderone. ASM Press, Washington DC.






Research Funding


American Heart Association (AHA). (2006 - 2010) “Endothelial Cell Interactions”

NIH-NIAID (R21) (2008- 2010). “Triazole Hypersensitivity in Candida albicans”





Education


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