Our lab studies how Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), interacts with the host; on-going studies include:
Tuberculous latency and reactivation Gene profiling studies have identified a set of Mtb genes (the dormancy regulon) that are regulated by exposure to low oxygen tension and nitric oxide, two latency-promoting environmental signals. Deletion of a dormancy regulon gene, rv2623 (a member of the USP [universal stress protein] family), results in hypervirulence in infected hosts. Rv2623 also regulates Mtb growth in vitro. The growth-regulating attribute has been linked to the ATP-binding capacity of Rv2623. Understanding how Rv2623 regulates the growth of Mtb and how members of the dormancy regulon promote latency is a focus of our laboratory.
We are collaborating with JoAnn Tufariello to study the role of the five Mtb Rpf proteins, putative peptidoglycan hydrolyases, in regulating tuberculous latency and reactivation. Mutagenesis studies showed that Mtb doubly deficient for RpfA and RpfB displays defects in persistence and reactivation, both in in vivo and in vitro models of tuberculous latency and disease recrudescence. Studies have been initiated to characterize how Mtb Rpf�s regulate mycobacterial growth.
The mechanisms that regulate the granulomatous reaction: Our Studies using the B cell-deficient mMT mouse model and specific Fcg receptor knockout mice have shown that humor immune response regulates the tuberculous granulomatous reaction and is required for optimal control of Mtb. There is also evidence that B cells can regulate T cell response in infected hosts. We are conducting experiments aimed at characterizing the roles of B cells in regulating the host granulomatous response to Mtb.
TNF is essential in controlling TB. However, TNF also contributes to the development of immunopathology. TNF neutralization reactivates TB in both mice and humans with persistent infection. We are using this TNF neutralization reactivation model to study the role of TNF in regulating the tuberculous granulomatous reaction. We are also generating cell-specific conditional TNF knockout mouse strains that will be used to decipher the relative contribution of cell-specific TNF in the protective immunity and immunopathogenesis of this cytokine in the host.
TB vaccines:We will apply the knowledge gained from the above-listed investigation to rationally design safe and effective TB vaccines in collaboration with the Jacobs and Porcelli labs. For example, understanding how to manipulate the humoral response to the advantage of the host may lead to the development of vaccines with increased efficacy. Knowing how Mtb regulates host production of TNF may lead to the design of Mtb-derived vaccines with enhanced immunogenicity.
Drumm JE, Mi K, Bilder P, Sun M, Lim J, Bielefeldt-Ohmann H, Basaraba R, So M, Zhu G, Tufariello JM, Izzo AA, Orme IM, Almo SC, Leyh TS, Chan J. 2009. Mycobacterium tuberculosis universal stress protein Rv2623 regulates bacillary growth by ATP-Binding: requirement for establishing chronic persistent infection. PLoS Pathog 5:e1000460
Russell-Goldman E, Xu J, Wang X, Chan J, Tufariello JM. 2008. A double Rpf knockout Mycobacterium tuberculosis strain exhibits profound defects in reactivation from chronic tuberculosis and innate immunity phenotypes. Infect Immun. 76:4269-81.
Maglione PJ, Xu J, Casadevall A, Chan J. 2008. Fcgamma receptors regulate immune activation and susceptibility during Mycobacterium tuberculosis Infection. J Immunol 180:3329-38.
Chakravarty SD, Zhu G, Tsai MC, Mohan VP, Marino S, Kirschner DE, Huang L, Flynn J, Chan J. 2008. Tumor necrosis factor blockade in chronic murine tuberculosis enhances granulomatous inflammation and disorganizes granulomas in the lungs. Infect Immun. 76:916-26.
Dao DN, Sweeney K, Hsu T, Gurcha, SS, Nascimento IP, Roshevsky D, Besra GS, Chan J, Porcelli S, Jacobs WR Jr. 2008. Mycolic acids of trehalose dimycolate modified by MmaA4 repress IL-12p40 production. Plos Pathogens 4(6):e1000081.
Maglione PJ, Xu J, Chan J. 2007. B cells moderate inflammatory progression and enhance bacterial containment upon pulmonary challenge with Mycobacterium tuberculosis. J Immunol 178:7222-34.
Chakravarty SD, Xu J, Lu B, Gerard C, Flynn J, Chan J. 2007. The chemokine receptor CXCR3 attenuates the control of chronic Mycobacterium tuberculosis infection in BALB/c mice. J Immunol 178:1723-35.
Hinchey J, Lee S, Jeon BY, Basaraba RJ, Venkataswamy MM, Chen B, Chan J, Braunstein M, Orme IM, Derrick SC, Morris SL, Jacobs Jr WR, Porcelli SA. 2007. Enhanced priming of adaptive immunity by a proapoptotic mutant of Mycobacterium tuberculosis. J Clin Invest 117:2279-88.;
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