Dr. John Alderette
Research & Interests
Trichomonas vaginalis, the number one, non-viral sexually transmitted organism, is the focus of our research program. The study of parasite and host cell-tissue interactions is focused on the identification of surface proteins that contribute to infection and disease pathogenesis.
We have studied several important properties of the biology of the parasite and the host-parasite interaction. These include antigenic diversity, cytoadherence, immune evasion, iron acquisition, and the dsRNA virus infection. The highly evolved and complex nature of the interrelationship between host and parasite is evidenced by the dynamics of the protein-antigen phenotypic variations and the various important protein repertoires, which have been defined. The phenotypic variation of trichomonad protein repertoires can either be coordinated, such as for the immunogens and adhesins, or be independent of one another, as seen for the proteinases. DNA sequence and the other data have been used to determine that an important phenotypically varying immunogen (P270) contains only one immunodominant epitope repeated many times, and the number of repeats varies among clinical isolates. Among most isolate trichomonads, this tandemly-repeated sequence was further found to comprise one-half of the total protein size, illustrating the complexity of the immunogen in terms of silent versus active antibody-generating domains.
The fact that trichomonads survive during phenotypic variation (without surface expression of major immunogens) does not suggest an absence of an important biofunctionality for these molecules. Biofunctional proteins, such as the epithelial cell- and erythrocyte-binding adhesins, also undergo phenotypic variation that is modulated by iron. More recently, we obtained evidence that the phenotypically varying protein plays a role in lipoprotein uptake, an important property given that trichomonads cannot synthesize lipids.
The studies on the immune evasion strategies of T. vaginalis are important for our understanding of the mechanisms of parasite survival during a host antibody response, especially when antibody readily kills the parasite in a complement-independent manner. This information may also lead to interference strategies apart from the development of vaccines to trichomonad proteins, like the adhesins. The future for pharmacologic targeting appears possible with the recent, exciting observation that proteinase activity, apart from degrading immunoglobulins and complement, is necessary for initial and sustained host parasitism.
The importance of a holistic, multidisciplinary approach to dissecting and understanding the complex host-parasite interaction is evidenced by several recent findings. Iron both up- and down-regulates transcription of genes, including adhesins and immunogens. Further, iron modulates compartmentalization and surface expression of the adhesins. Importantly, the adhesins have sequence identity to hydrogenosome metabolic enzymes, thereby invoking molecular mimicry, gene sharing, and functional diversity as important features for surface proteins of this parasite. Finally, the double-stranded RNA virus and satellite dsRNAs infecting T. vaginalis influence expression of many parasite proteins and directly correlate with the property of phenotypic variation.
Several recent new discoveries are the following: 1) There is a relationship between polyamine metabolism and the properties of cytoadherence and cytotoxicity. There is a direct relationship between polyamine depletion and enhanced adherence coupled with complete absence of host cell killing. Moreover, polyamine depletion down-regulates transcription of the cysteine proteinase known to be involved in cytotoxicity. 2) We have established an efficient transfection system that has permitted us to inhibit expression of trichomonad genes, thereby establishing a genetic approach to confirm the function of the adhesins and other virulence genes. 3) We have performed heterologous expression of functional T. vaginalis virulence genes in the bovine trichomonad Tritrichomonas foetus, and this opens exciting new approaches for examining virulence factors in a related organism. 4) We have demonstrated the up-regulation of gene expression in vaginal epithelial cells and in T. vaginalis that result immediately upon contact, showing that there are signaling events taking place in both parasites and host cells. 5) Adhesins and other trichomonad ligands for binding host molecules are among numerous metabolic enzymes of the secretome that become associated with the parasite surface for expression of function, properties that are also found among other microbial pathogens. 6) Finally, a noteworthy new finding is the relationship between seropositivity of men to T. vaginalis and prostate cancer, a finding that will establish a new paradigm for a microbial pathogen—this STD agent—as a causative agent for carcinogenesis.
Toll-like receptor 4 polymorphisms modify the assoviation between Trichomonas vaginalis serostatus and prostate cancer risk.Chen, Y-C., Y.-L. Huang, E.A. Platz, L. Zheng, J.R. Stark, J.F. Alderete, E. Giovannucci, and S. Sutcliffe. 2011. Cancer Causes & Control. Submitted.
Identification and characterization of a surface-associated subtilisin-like serine protease in Trichomonas vaginalis. Hernandez-Romano, P., R. Arroyo, J.F. Alderete, R. Hernandez, and I. Lopez-Villasenor. 2010. Parasitology.137:1621-1635. PMCID: 20602853.
Paracoccidioides brasiliensis enolase is a surface protein that binds plasminogen and mediates interaction of yeast forms with host cells. Nogueira, S.V., M.L. Rodrigues, V. Mundodi, E.A. Abi-Chacra, M.S. Winters, J.F. Alderete, and C.M. de Almeida Soares. 2010. Infect. Immun. 78:4040-4050. PMCID: 20605975.
Prospective study of Trichomonas vaginalis infection and prostate cancer incidence and mortality: Physicians' Health Study. Stark JR, Judson G, Alderete JF, Mundodi V, Kucknoor AS, Giovannucci EL, Platz EA, Sutcliffe S, Fall K, Kurth T, Ma J, Stampfer MJ, Mucci LA. J Natl Cancer Inst. 2009 Oct 21;101(20):1406-11. Epub 2009 Sep 9. PMID: 19741211
Correlates of sexually transmitted infection histories in a cohort of American male health professionals. Sutcliffe S, Kawachi I, Alderete JF, Gaydos CA, Jacobson LP, Jenkins FJ, Viscidi RP, Zenilman JM, Platz EA. Cancer Causes Control. 2009 Nov;20(9):1623-34. Epub 2009 Aug 5. PMID: 19655261
Examination for double-stranded RNA viruses in Trichomonas gallinae and identification of a novel sequence of a Trichomonas vaginalis virus. Gerhold RW, Allison AB, Sellers H, Linnemann E, Chang TH, Alderete JF. Parasitol Res. 2009 Sep;105(3):775-9. Epub 2009 May 12. PMID: 19452169
Glyceraldehyde-3-phosphate dehydrogenase is a surface-associated, fibronectin-binding protein of Trichomonas vaginalis. Lama A, Kucknoor A, Mundodi V, Alderete JF. Infect Immun. 2009 Jul;77(7):2703-11. Epub 2009 Apr 20. PMID: 19380472
Genetic identity and differential gene expression between Trichomonas vaginalis and Trichomonas tenax.Kucknoor AS, Mundodi V, Alderete J. BMC Microbiol. 2009 Mar 18;9:58. PMID: 19296850
Comparative analyses among the Trichomonas vaginalis, Trichomonas tenax, and Tritrichomonas foetus 5S ribosomal RNA genes. Torres-Machorro AL, Hernández R, Alderete JF, López-Villaseñor I. Curr Genet. 2009 Apr;55(2):199-210. Epub 2009 Mar 17. PMID: 19290527
Trichomonosis and subsequent risk of prostate cancer in the Prostate Cancer Prevention Trial. Sutcliffe S, Alderete JF, Till C, Goodman PJ, Hsing AW, Zenilman JM, De Marzo AM, Platz EA. Int J Cancer. 2009 May 1;124(9):2082-7. PMID: 19117055
Polyamine depletion down-regulates expression of the Trichomonas vaginalis cytotoxic CP65, a 65-kDa cysteine proteinase involved in cellular damage. Alvarez-Sánchez ME, Carvajal-Gamez BI, Solano-González E, Martínez-Benitez M, Garcia AF, Alderete JF, Arroyo R. Int J Biochem Cell Biol. 2008;40(11):2442-51. Epub 2008 May 24. PMID: 18586550
Characterization of the Trichomonas vaginalis surface-associated AP65 and binding domain interacting with trichomonads and host cells. Garcia AF, Alderete J. BMC Microbiol. 2007 Dec 25;7:116. PMID: 18158858
Immunogenic and plasminogen-binding surface-associated alpha-enolase of Trichomonas vaginalis. Mundodi V, Kucknoor AS, Alderete JF. Infect Immun. 2008 Feb;76(2):523-31. Epub 2007 Dec 10. PMID: 18070902
First molecular characterisation of hydrogenosomes in the protozoan parasite Histomonas meleagridis. Mazet M, Diogon M, Alderete JF, Vivarès CP, Delbac F. Int J Parasitol. 2008 Feb;38(2):177-90. Epub 2007 Jul 26. Erratum in: Int J Parasitol. 2008 Dec;38(14):1737. PMID: 17697679
Antisense RNA decreases AP33 gene expression and cytoadherence by T. vaginalis. Mundodi V, Kucknoor AS, Alderete JF. BMC Microbiol. 2007 Jul 3;7:64. PMID: 17608941
The proteins secreted by Trichomonas vaginalis and vaginal epithelial cell response to secreted and episomally expressed AP65. Kucknoor AS, Mundodi V, Alderete JF. Cell Microbiol. 2007 Nov;9(11):2586-97. Epub 2007 Jun 21. PMID: 17590165
Kang, J.H., H.O. Song, J.S. Ryu, M.H. Shin, J.M. Kim, Y.S. Cho, J.F. Alderete, M.H. Ahn, and D.Y. Min. 2006. Trichomonas vaginalis promotes apoptosis of human neutrophils by activating caspase-3 and reducing Mcl-1 expression. Parasite Immunol. 28:439-446.
Sutcliffe, S., E. Giovannucci, J.F. Alderete, T.-H. Chang, C.A. Gaydos, J.M. Zenilman, A.M. De Marzo, W.C. Willett, and E.A. Platz. 2006. Plasma antibodies against Trichomonas vaginalis and subsequent risk of prostate cancer. Cancer, Epidemiol. Biomarkers Prev. 15:939-945.
Mundodi, V., A.S. Kucknoor, and J.F. Alderete. 2006. A novel surface protein of Trichomonas vaginalis is regulated independently by low iron and contact with vaginal epithelial cells. BMC Microbiol. 6:6.
da Costa, R.F., W. de Souza, M. Benchimol, J.F. Alderete, and J.A. Morgado-Diaz. 2005. Trichomonas vaginalis perturbs the junctional complex in epithelial cells. Cell Res. 15:704-716.
Kucknoor, A., V. Mundodi, and J.F. Alderete. 2005. Adherence to human vaginal epithelial cells signals for increased expression of Trichomonas vaginalis genes. Infect. Immun. 73:6472-6478.
Kucknoor, A., V. Mundodi, and J.F. Alderete. 2005. Trichomonas vaginalis adherence mediates differential gene expression in human vaginal epithelial cells. Cell Microbiol. 7:887-897.
Garcia, A., M. Benchimol, and J.F. Alderete. 2005. Trichomonas vaginalis polyamine metabolism is linked to host cell adherence and cytotoxicity. Infect. Immun. 73:2602-2610.
Kucknoor, A., V. Mundodi, and J.F. Alderete. 2005. Heterologous expression in Tritrichomonas foetus of Functional Trichomonas vaginalis AP65 adhesin. BMC Mol. Biol. 6:5.
Tasca, T., C.D. Bonan, G.A. DeCarli, J.J. Freitas Sarkis, and J.F. Alderete. 2005. Heterogeneity in extracellular nucleotide hydrolysis among clinical isolates of Trichomonas vaginalis. Parasitol. 131:71-78.
Alderete, J.F., J. Nguyen, V. Mundodi, and M.W. Lehker. 2004. Heme-iron increases levels of AP65-mediated adherence by Trichomonas vaginalis. Microbial Pathogenesis. 36:263-271.
Mundodi, V., A.S. Kucknoor, D.J. Klumpp, and J.F. Alderete. 2004. Silencing the ap65 gene reduces adherence to vaginal epithelial cells by Trichomonas vaginalis. Mol. Microbiol. 53:1099-1108.
Lehker, M.W., M. Benchimol, and J.F. Alderete. 2004. Assigning function to putative virulence genes of Trichomonas vaginalis: utility of targeted, selectable gene-replacement. Ed. S.G. Pandalai. In Recent Res. Devel. Microbiology, 8:97-119.