Public Health Research Institute Center and
UMDNJ - New Jersey Medical School
225 Warren Street
Newark, New Jersey 07103

Phone: (973) 854-3262
e-mail: fontanpa@umdnj.edu



Research Summary

Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis, a disease, which is still one of the most significant causes of morbidity and mortality in the world. Mtb is able to silently survive for years inside the lung of an immune-competent host. Bacteria may remain in this stage of persistence until a failure in the immune defenses of the host takes place, as in the case of HIV patients, aged individuals or patients under immune-suppressive therapies. Patients with a reactivated infection can transmit the disease to other individuals in the population. It has been estimated that the lungs of one third of the world population are Mtb reservoirs and therefore the development of new strategies to combat the bacteria in the persistence phase prior to reactivation of the infection is imperative. Experiments in the mouse model of infection have shown that persistent Mtb does not divide or divides very slowly but maintains an active although, restricted metabolism and it is tolerant to antibiotic treatment. This state is usually referred as “non-replicating persistence”. However, the mechanisms required for the entrance of Mtb into such a “persistent state” remain to be determined. Toxin-Antitoxin systems (TAs) can control bacterial growth by regulating the synthesis of macromolecules. It has been proposed that the reversible activation of the toxins can cause a transient growth arrest as part of a global cell response to stress, which would be beneficial to bacterial survival by saving energy. Orthologs of the TAs have been identified in the genome of Mtb. We have focused our study on the VapBC family of TAs since we observed the expression of these genes differentially regulated in Mtb during infection of macrophages. We have obtained data indicating that the over-expression of some of the VapBC genes induces growth arrest specifically in mycobacteria. Moreover, we have observed that these systems are required for the survival of Mtb during chronic infection in mice and for the development of antibiotic tolerance in vitro. We hypothesize that these toxin-antitoxin systems may be bacterial growth regulator factors involved in the development of the persistent state of Mtb during infection. The study of the role of the Toxin-Antitoxin systems of Mycobacterium tuberculosis may lead to new approaches to find more effective chemotherapy and to achieve a quicker eradication of the bacteria. Inhibition of the Toxin-Antitoxin systems of Mycobacterium tuberculosis could possible prevent the entrance of Mycobacterium tuberculosis into persistence thereby improving the effectiveness of the available anti–tuberculosis drugs that target actively replicating microorganism. The Toxin-Antitoxin systems can be targets for new anti-tubercular therapies against the problem of antibiotic tolerance and also may be useful controlling latent tuberculosis.




Selected Publications


Fontán PA, Voskuil MI, Gomez M,Tan D, Pardini M, Manganelli R, Fattorini L, Schoolnik GK and Smith I.
The Mycobacterium tuberculosis sigma factor B is required for full response to cell envelope stress and hypoxia in vitro but it is dispensable for in vivo growth.
J Bacteriol June 2009 (in press).

Fontán P, Aris V, Alvarez M, Ghanny S, Cheng J, Soteropoulos P, Trevani A, Pine R, Smith I.
Mycobacterium tuberculosis SigE regulon modulates the host inflammatory response.
J. Infect. Dis. 198:877-885, 2008.

Fontán P, Aris V, Ghanny S, Soteropoulos P, Smith I.
Global transcriptional profile of Mycobacterium tuberculosis during THP-1 human macrophage infection.
Infect Immun. 76:717-25, 2008.

Rehren G., Walters S., Fontán P., Smith I., Zarraga A.M.
Differential gene expression between Mycobacterium bovis and Mycobacterium tuberculosis.
Tuberculosis (Edinb)., 87(4):347-59, 2007.

Pancholi V., Fontán, P. and Jin, H.
Plasminogen-mediated group A streptococcal adherence to and pericellular invasion of human pharyngeal cells.
Microb Pathog. , 35:293-303, 2003.

Dubnau E., Fontán PA, Manganelli R., Soares-Appel S., Smith I.
Identification of Mycobacterium tuberculosis genes induced during infection of human macrophages.
Infect Immun., 70(6):2787-95, 2002.

Maskin B., Fontán PA., Spinedi E.G., Gammella D., Badolati A.
Evaluation of endotoxin release and cytokine production induced by antibiotics in patients with Gram-negative nosocomial pneumonia.
Crit. Care Med., 30(2):349-354, 2002.

Fontán PA, Pancholi V, Nociari MM, and Fischetti VA.
Anti-SEN (streptococcal surface enolase) antibodies react with the human - enolase: Implications in post-streptococcal autoimmune diseases.
J. Infect. Dis., 182:1712-1721, 2000.

Rosenow C, Ryan P, Wiser JN, Johnson S, Fontán PA, Ortqvist A and Masure HR. Contribution of novel choline-binding proteins to adherence, colonization and immunogenicity of Streptococcus pneumoniae.
Molec. Microbiol., 25:819-829, 1997.




Research Grants


2009 – 2010    Seed Grant. UMDNJ foundation. Analysis of the molecular mechanisms of drug tolerance in Mycobacterium tuberculosis.

2008 – 2010    Grant-in-aid. STONY WOLD – HERBERT FUND, INC. Toxin-antitoxins of Mycobacterium tuberculosis in the development of persistence.

2005 – 2006    CFAR Pilot Project Award. New York University. Effect of Mycobacterium tuberculosis sigma factor E on the macrophage transcriptome.

2004 – 2009    National Institute of Health K01 Award (HL76632). Mechanisms of cell growth arrest in tuberculosis.






C.V.


2006 –             Assistant Professor, Public Health Research Institute at the International Center for Public Health, New Jersey Medical School-UMDNJ.

2004 – 2006     Research Associate Member, Public Health Research Institute at the International Center for Public Health, New Jersey Medical School-UMDNJ.

2000 – 2004     Post-doctoral Fellow, Department of Microbiology. Public Health Research Institute, New York.

1997 – 2000     Post-doctoral Fellow, Laboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, New York.

1996 – 1997     Post-doctoral Fellow, Laboratory of Molecular Infectious Diseases. The Rockefeller University, New York.

1995 – 1999     Assistant Researcher, Department of Microbiology, School of Medicine University of Buenos Aires, National Research Council (CONICET), Buenos Aires, Argentina.

1992 – 1995     Post-doctoral Fellow, Department of Microbiology, School of Medicine University of Buenos Aires, National Research Council (CONICET), Buenos Aires, Argentina.

1990 – 1992     Advanced Graduate Fellow, Department of Microbiology, School of Medicine University of Buenos Aires, National Research Council (CONICET), Buenos Aires, Argentina.

1988 – 1990     Graduate Fellow, Department of Microbiology, School of Medicine University of Buenos Aires, National Research Council (CONICET), Buenos Aires, Argentina.