|
Faculty
My laboratory studies the opportunistic pathogenic fungus Candida albicans. C. albicans is part of the normal human microbiota. However, as an opportunistic pathogen it is capable of causing overt disease (candidiasis), but usually only in hosts with defective immunity. The frequency of candidiasis has increased dramatically in the last decades as a result of an expanding population of immunocompromised patients. As a result, candidiasis is now the fourth most common nosocomial infections. The seriousness of this problem is heightened by the fact that, even with treatment using available antifungal agents, mortality rates lie in the 30- 40% range for these infected patients. As an opportunistic pathogen, it is clear that mechanisms of host immunity and pathogen virulence intertwine, giving rise to the highly complex nature of host-fungus interactions. However, the interplay between host immunity and fungal virulence has traditionally been ignored and most investigations into these topics are overwhelmingly “one-sided” which has resulted in a dangerous dichotomy between “microorganism-centered” and “host-centered” views of candidal pathogenesis. Thus, studies in my laboratory try to integrate these two facets to better understand and offer a more global perspective of C. albicans pathogenesis. Results have already provided new paradigms in the host-fungus relationship during candidiasis. Some of the highlights of this research program are: 1) Role of filamentation in virulence. C. albicans is able to undergo reversible morphological transitions between a variety of unicellular and filamentous forms, and this is considered a major virulence factor, but until now most studies used mutant strains that are locked in one morphlogy or another. We have constructed a genetically engineered C. albicans regulatable strain in which morphogenetic conversions and virulence can be externally manipulated both in vitro and in vivo. Studies with this strain have provided the most compelling evidence to date linking fungal morphogenesis and virulence and opened new avenues of research that were not possible in the past. They have forced many to reconsider some of the previous “dogmas” in the field. These experiments are in collaboration with Dr. Stephen P. Saville, a former postdoc in my lab and currently a Research Assistant Professor here at UTSA. 2) Biofilms. Our perception of microorganisms as unicellular life forms is primarily based on the pure-culture mode of growth. Since microorganisms can be diluted to a single cell and studied in liquid culture, this mode of growth has overwhelmingly predominated in the study of microbial physiology and pathogenesis in the research laboratory. However, the majority of microbes in their natural habitats persist attached to surfaces within a structured biofilm ecosystem and not as free-floating (planktonic) organisms. Recently, there has been an increasing recognition of the role that microbial biofilms play in human medicine and it has been estimated that about 65% of all human microbial infections involve biofilms. Biofilm formation carries important consequences since sessile cells in biofilms display phenotypic traits that are dramatically different from their planktonic counterparts, such as increased resistance to anti-microbial agents and protection form host defenses. Thus, biofilms represent one of the evolving paradigms of modern microbiology. A variety of manifestations of candidiasis are associated with biofilm formation on the surface of different types of biomaterials. Our group has taken a leading role in the development of in vitro Candida biofilms models, advanced visualization tools, the examination of their susceptibility patterns to antifungal agents and resistance mechanisms, and the application of state of the art genomic and proteomic techniques to study gene expression associated with the biofilm life-style. |
|
|
|
3). Development of novel immune-based strategies to combat candidiasis. We are interested in the development of vaccines and serum-therapies as alternative (or complementary) approaches for the management of candidiasis. We have identified immunodominant antigens during candidiasis. We have developed a subunit vaccine that provides excellent protection in murine models of hematogenously disseminated candidiasis. We have generated a battery of monoclonal antibodies, some of which confer protection to naïve mice when passively administered prior to infections. Most of these reagents (vaccine formulations and Mabs) have been patented. |
|
The amino acid sequence of the protein portion of mp58 as deduced from the DNA sequence of its encoding gene (FBP1/PRA1) was used to synthesize a complete set of overlapping dodecapeptides (overlap 7, offset 5) covalently attached to the surface of derivatized polyethylene pins. The pin-coupled peptides were used in a modified enzyme-linked immunosorbent assay to identify continuous epitopes recognized by a number of antiserum preparations containing anti-mp58 antibodies.Figure shows IgG reactivity of hyperimmune sera from mice immunized with electrophoretically purified mp58 with dodecapeptides spanning the entire sequence of the protein portion of C. albicans mp58.
|
|
Serum therapy experiments. Protection of Mab 3H3-treated mice against hematogenously disseminated candidiasis assessed as survival proportions. Mab 3H3 recognizes the C-terminal epitope of C. albicans mp58.
|
|
4) Other areas of interest. Genomics and proteomics, cell wall and adhesion, antifungal drug resistance, development of diagnostic techniques for candidiasis and high throughput screening of small molecule libraries to study complex processes during candidiasis (with an emphasis on filamentation and biofilm formation). |
|
|
|
Proteomics to study C. albicans |
|
Northern blots of total RNA from |
|
Recent Publications Viudes, A., S. Perea, J.L. López-Ribot. 2001. Identification of Continuous B-Cell Epitopes on the Protein Moiety of the 58-kiloDalton Cell Wall Mannoprotein of Candida albicans Belonging to a Family of Immunodominant Fungal Antigens. Inf. Immun. 69:2909-19. Redding, S.W., C.L. Bailey, J.L. López-Ribot, R.K. McAtee, W.R. Kirkpatrick, A.W. Fothergill, M. Rinaldi, T.F. Patterson. 2001. Candida dubliniensis in Radiation Induced Oropharyngeal Candidiasis. Oral surgery, oral medicine, oral pathology and oral radiology endodontics. 91:659-662. Perea, S., J.L. López-Ribot, W. R. Kirkpatrick ,R. K. McAtee , R.A. Santillan, M. Martinez, D. Calabrese, D. Sanglard, T. F. Patterson. 2001. Prevalence of resistance mechanisms to azole antifungal agents in Candida albicans isolates displaying high-level fluconazole resistance from HIV-infected patients. Antimicrob. Agents Chemother. 45:2676-2684. Ramage, G., K. VandeWalle, B L. Wickes, J.L. López-Ribot. 2001. A standardized method for in vitro antifungal susceptibility testing of Candida albicans biofilms. Antimicrob. Agents Chemother. 45:2474-2479. Ramage, G., K. VandeWalle, B. L. Wickes J.L. López-Ribot. 2001. Biofilm formation by Candida dubliniensis. J. Clin. Microbiol. 39:3234-3240. Ramage, G., K. VandeWalle, B. L. Wickes J.L. López-Ribot. 2001. Characteristics of biofilm formation by Candida albicans. Rev. Iberoam. Micol. 18: 163-170. Martinez, M., J.L. López-Ribot, W. R. Kirkpatrick, S.P. Bachmann, S. Perea, M.T. Ruesga, T. F. Patterson. 2002. Heterogeneous Mechanisms of Azole Resistance in C. albicans Clinical Isolates from an HIV-Infected Patient on Continuous Fluconazole for Oropharyngeal Candidosis. J. Antimicrob. Chemother. 49:515-524. Perea, S., J.L. López-Ribot, B.L. Wickes, W. R. Kirkpatrick, O. P. Dib, S.P. Bachmann, S.M. Keller, M. Martinez, Thomas F. Patterson. 2002. Molecular mechanisms of fluconazole resistance in Candida dubliniensis isolates from HIV-infected patients with oropharyngeal candidiasis Antimicrob. Agents Chemother. 46:1695-1703. Viudes, A, J. Pemán, E. Cantón, M. Salavert, P. Ubeda, J.L. López-Ribot, M. Gobernado. 2002. Fungemia caused by Candida lusitaniae: report of two cases and review of the literature. Eur. J. Clin. Microbiol. Inf. Dis. 21:294-299. Ramage, G., S. P. Bachmann, T.F. Patterson, B. L. Wickes J.L. López-Ribot. 2002. Investigation of multidrug efflux pumps in relation to fluconazole resistance in Candida albicans biofilms. J. Antimicrob. Chemother. 49:973-980. Bachmann, S.P., T. F. Patterson, J.L. López-Ribot. 2002. In vitro activity of Caspofungin (MK-0991) against Candida albicans clinical isolates displaying different mechanisms of azole resistance. J. Clin. Microbiol. 40:2228-2230. Ramage, G., K. VandeWalle, J.L. López-Ribot, and B. L. Wickes. 2002. The filamentation pathway regulated by Efg1p is required for biofilm formation and development in Candida albicans. FEMS Microbiol. Lett. 214:95-100. Martinez, M., J.L. López-Ribot, W. R. Kirkpatrick, B. Coco, S.P. Bachmann, and T. F. Patterson. 2002. Replacement of Candida albicans by C. dubliniensis in HIV-infected patients with oropharyngeal candidiasis treated with fluconazole. J. Clin. Microbiol. 40:3135-3139. Bachmann, S.P., K. VandeWalle, Ramage, G., T.F. Patterson, B. L. Wickes, J.R. Graybill, J.L. López-Ribot. 2002. In vitro activity of caspofungin against Candida albicans biofilms. Antimicrob. Agents Chemother. 46:3591-6. Ramage, G., K. VandeWalle, S. P. Bachmann, B. L. Wickes and J.L. López-Ribot. 2002. In vitro pharmacodynamic properties of three antifungal agents against preformed C. albicans biofilms determined by time-kill studies. Antimicrob. Agents Chemother. 46:3634-6. Ramage, G., S.P. Saville, B.L. Wickes and J.L. López-Ribot. 2002. Inhibition of Candida albicans biofilm formation by farnesol, a quorum sensing molecule. Applied and Environmental Microbiology. 68:5459-63. Viudes, A., J. Peman, E. Canton, P. Ubeda, J.L. López-Ribot, and M. Gobernado. 2002. Candidemia at a tertiary-care hospital: Epidemiology, treatment, clinical outcome and risk factors for death. Eur. J. Clin. Microbiol. Inf. Dis. 21:767-74. Redding, S.W., W. R. Kirkpatrick, S.P. Saville, B. Coco, W. S. White, T.F. Patterson and J.L. López-Ribot. 2003. Multiple Resistance Mechanism Patterns in a Patient with Candida glabrata Oropharyngeal Candidiasis Receiving Head and Neck Radiation. J. Clin. Microbiol. 41:619-622. Saville, S.P., A. Lazzell, C. Monteagudo, J.L. Lopez-Ribot. 2003. Engineered control of cell morphology in vivo reveals distinct roles for yeast and filamentous forms of Candida albicans during infection. Eukaryotic Cell. 2:1053-1060. Bachmann, S.P., G. Ramage, K. VandeWalle, T. F. Patterson, B. L. Wickes and J.L. López-Ribot. 2003. Combination of Antifungal Agents Against Biofilms of Candida albicans In Vitro. Antimicrob. Agents. Chemother. 47:3657-9. Li, X., N. Brown, A. S. Chau, J.L. López-Ribot, M. T. Ruesga, G. Quindos, C. A. Mendrick, R. S. Hare, D. Loebenberg, B. DiDomenico, P. M. McNicholas. 2004. Changes in susceptibility to Posaconazole in clinical isolates of Candida albicans. J. Antimicrob. Chemother. 53:74-80. Viudes, A., A. Lazzell, S. Perea, W. R. Kirkpatrick, J. Peman, T. F. Patterson, and J.L. López-Ribot. 2004. The C-terminal Antibody Binding Domain of Candida albicans mp58 Represents a Protective Epitope during Candidiasis. FEMS Microbiol Lett. 232:133-138. Hernandez, S., J.L. López-Ribot, L. K. Najvar, R. Bocanegra, and J. R. Graybill. 2004. Caspofungin Resistance in Candida albicans: Correlating Clinical Outcome with Laboratory Susceptibility Testing of Three Isogenic Isolates Serially Obtained from a Patient with Progressive Candida Esophagitis Antimicrob. Agents. Chemother. 48:1382-1383. Ramage, G., K. Tomsett, B. L. Wickes, J.L. López-Ribot, S. W. Redding. 2004. Denture stomatitis: a role for Candida biofilms. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 98:53-59. Monteagudo, C., A. Viudes, A. Lazzell, J.P. Martinez, and J.L. Lopez-Ribot. 2004. Tissue invasiveness and non-acidic pH in human candidiasis correlate with “in vivo” expression by C. albicans of the carbohydrate epitope recognized by a new monoclonal antibody 1H4. Am. J. Clin Pathol. 57:598-603. Ullmann, B.D, H. Myers, W. Chiranand, A.L. Lazzel, Q. Zhao, L.A. Vega, J.L. Lopez-Ribot, P.R. Gardner, M.C. Gustin. 2004. An inducible defense mechanism against nitric oxide in Candida albicans. Euk. Cell. 3:715-723. Sánchez-Vargas, L.O., N. G. Ortiz-López, M. Villar, M. D. Moragues, J. M. Aguirre, M. Cashat-Cruz, J.L. Lopez-Ribot, L. A. Gaitán-Cepeda, G. Quindós. 2005. Oral Candida isolates colonizing or infecting Mexican HIV-infected and healthy persons. J. Clin. Microbiol. 43:4159-62. Sánchez-Vargas, L.O., N. G. Ortiz-López, M. Villar, M. D. Moragues, J. M. Aguirre, M. Cashat-Cruz, J.L. Lopez-Ribot, L. A. Gaitán-Cepeda, G. Quindós. 2005. Point prevalence, microbiology and antifungal susceptibility patterns of oral Candida isolates colonizing or infecting Mexican HIV/AIDS patients and healthy persons. Rev. Iberaom. Micol. 22:83-92. Chamilos, G., M.S. Lionakis, R.E. Lewis, J.L. Lopez-Ribot, S.P. Saville, N.D. Albert, G. Halder and D.P. Kontoyiannis. Drosophila melanogaster is a facile model for large-scale studies of virulence mechanisms and antifungal drug efficacy in Candida. J. Infect. Dis. In press. Saville, S.P., D.P. Thomas and J.L. Lopez-Ribot. 2006. A Role for Efg1p in Candida albicans Interactions with Extracellular Matrices. FEMS Microbiol Lett. 256:151-158. b) Invited Reviews: Martínez, J.P., M.L. Gil, J.L. López-Ribot, and W. L. Chaffin. 1998. Serologic response to cell wall proteins and mannoproteins of Candida albicans. Clinical Microbiology Reviews. 11:121-141. Chaffin, W.L., J.L. López-Ribot, M. Casanova, D. Gozalbo, and J.P. Martínez. 1998. Cell wall and secreted proteins of Candida albicans: identification, function and expression. Microbiology and Molecular Biology Reviews. 62:130-180. Viudes, A., J. Peman, E. Canton, J.L. López-Ribot, and M. Gobernado. 2001. Actividad de las asociaciones de antifungicos sistemicos. Rev. Esp. Quimioterap. 14:30-39. Ramage, G., B.L. Wickes J.L. López-Ribot. 2001. Biofilms of Candida albicans and their associated resistance to antifungal agents. American Clinical Laboratory. 20:42-44. Viudes, A., E. Canton, J. Peman, J.L. López-Ribot, and M. Gobernado. 2002. Correlación entre las pruebas de sensibilidad in vitro a los antifúngicos y la evolución clínica de los pacientes con candidiasis y criptococosis. Rev. Esp. Quimioterap. 15:32-42. López-Ribot, J.L., M. Casanova, A. Murgui, and J.P. Martínez. 2004. Serologic response to Candida albicans cell wall antigens: protective and diagnostic value. FEMS Immunol. Med. Microbiol. 41:1871-96. Carrillo-Munoz, A.J., G. Quindos and J.L. López-Ribot. 2004. Current developments in antifungal agents. Current Medicinal Chemistry: Anti-Infective Agents. 3:297-323. Ramage, G., S.P. Saville, D.P. Thomas and J.L. López-Ribot. Candida biofilms: an update. 2005. Eukaryotic Cell. 4:633-638. Saville, S.P., D.P. Thomas and J.L. López-Ribot. 2005. Use of genome information for the study of the pathogenesis of fungal infections and the development of diagnostic tools. Rev. Iberoam. Mycol. 22:238-241. López-Ribot, J.L. 2005. Candida albicans Biofilms: More than Filamentation. Current Biology. 15:R453-5. Thomas, D.P., A. Pitarch, L Monteoliva, C Gil, J.L. Lopez-Ribot. Proteomics to Study Candida albicans Biology and Pathogenicity. Current Drug Targets-Infectious Disorders. Submitted. Ramage, G., J.P. Martinez and J.L. López-Ribot. Candida biofilms: a clinically significant problem. FEMS Yeast Research. Submitted. c) Book chapters: Thomas, J., G. Ramage and J.L. López-Ribot. Biofilms and Implant Infections. 2004. In Microbial Biofilms (G. O’Toole and M. Ghanoum eds.) ASM Press. Ramage, G. and J.L. López-Ribot. Fungal Biofilms and Drug Resistance. 2004. In Pathogenic Fungi: Cellular and Molecular Biology (G. San Blas and R.A. Calderone, eds.). Horizon Scientific Press. Ramage, G. and J.L. López-Ribot. 2005. Techniques for Antifungal Susceptibility Testing of Candida albicans Biofilms. In Methods in Molecular Medicine (P.D. Rogers, ed.). Humana Press. López-Ribot, J.L. and T.F. Patterson. 2005. Non-invasive and serodiagnostic techniques for fungal infections. In Fungal Infections in Immunocompromised Patients (J.R. Wingard and E.J. Anaissie, eds.). Marcel Dekker Inc. López-Ribot, J.L. Blastomicosis. Tratado SEIMC. Editorial Medica Panamericana. In press. Ramage, G., M. Ghanoum and J.L. López-Ribot. Fungal biofilms: agents of disease and drug resistance. In Molecular Principles of Fungal Pathogenesis (J.Heitman, A. Mitchell, S. Filler eds.) ASM Press. In press. López-Ribot, J.L. and T.F. Patterson. Fungal Drug Resistance: Azoles. In Antimicrobial Drug Resistance Handbook. (D.L. Mayers ed.) Humana Press. Submitted. López-Ribot, J.L., R. Diaz-Orejas and C. Gil. Antibodies. In Immunity against Fungal Pathogens (Brown and Netea eds.). Elsevier Press. Submitted. Pitarch, A., G. Molero, L. Monteoliva, D. P. Thomas, J.L. López-Ribot, C. Nombela and C. Gil. Proteomics in Candida species. In Candida: comparative and functional genomics (C. d’Enfert, ed.). Horizon Press.
|
|
|
Jose L. Lopez-Ribot, Ph.D.
