Characterization and analyses of the tuberculous granuloma and its immunomodulation
Chakravarty, Soumya Darshan
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Multiple studies to further our understanding of the architectural and spatial characteristics of the tuberculous granulomatous response and the host immunity---pathogen interaction were completed. Characterization of the pulmonic granulomatous responses of tuberculous mice and humans revealed that granulomatous tissues are highly organized structures, formed by an orderly recruitment of specific immunocytes displaying distinctive spatial relationships, including B lymphoid aggregates. Additionally, murine granulomatous tissues were found to be relatively aerobic, implying that mouse models of persistent tuberculosis may not be appropriate for studying hypoxic responses in M. tuberculosis infection.;Studies to elucidate possible mechanisms for how the neutralization of TNFalpha disrupts the granuloma, induces reactivation of latent infection, and causes greater inflammation and pathology, demonstrated marked dysregulation in the structure of B cell aggregates and macrophages. In addition, there was increased expression of immunoregulatory molecules in the lungs of chronically infected mice neutralized for TNFalpha, such as IFNgamma, as well as chemokine/chemokine receptors involved in Th1 immunity, such as CXCR3. Thus, being essential for normal granuloma formation, TNFalpha serves to regulate chemokine/chemokine receptor expression and that its neutralization can lead to a pro-inflammatory granulomatous environment.;Investigations into the role of CXCR3 in controlling tuberculous infection found that a murine model deficient for CXCR3 was better able to control tubercle bacilli than the parental BALB/c strain in the chronic phase of infection. Histopathology of infected pulmonic tissues obtained from CXCR3-/- and wild-type animals were comparable, but immunophenotypic analyses targeting leukocyte subsets showed significant differences in the cellular composition of the lung granulomatous tissues. Hence, CXCR3 plays a role in modulating the cellular composition of tuberculous granulomas and that deficiency of CXCR3 unmasks the ability of the host to kill or inhibit the growth of M. tuberculosis in the chronic phase of infection. To understand possible mechanisms underlying the chronic infection-specific resistance observed, studies examining the role of plasmacytoid dendritic cells (pDCs) were initiated. Preliminary results have indicated that pDCs are capable of mobilizing into the peripheral circulation in response to systemic M. tuberculosis infection and present in the LNs and lungs of aerogenically infected BALB/c mice.