Biology subjects

Kaushal, D.

Publications and source records attributed to Kaushal, D..

3 recordsLinked to original sources

bioRxiv2020

Control of Mycobacterium tuberculosis Infection in Lungs is Associated with Recruitment of Antigen-Specific Th1 and Th17 cells Co-expressing CXCR3 and CCR6.

Mycobacterium tuberculosis (Mtb)-specific T cell responses associated with immune control during asymptomatic latent tuberculosis infection (LTBI) remain poorly understood. Using a non-human primate (NHP) aerosol model, we studied the kinetics, phenotypes and functions of Mtb antigen-specific T cells in peripheral and lung compartments of Mtb-infected asymptomatic rhesus macaques by longitudinally sampling blood and bronchoalveolar lavage (BAL), for up to 24 weeks post-infection. We found significantly higher frequencies of Mtb-specific effector and memory CD4 and CD8 T cells producing IFN-{gamma} in the airways compared to peripheral blood, which were maintained throughout the study period. Moreover, Mtb-specific IL-17+ and IL-17/IFN-{gamma} double-positive T cells were present in the airways but were largely absent in the periphery, suggesting that balanced mucosal Th1/Th17 responses are associated with LTBI. The majority of Mtb-specific CD4 T cells that homed to the airways expressed the chemokine receptor CXCR3 and co-expressed CCR6. Notably, CXCR3+CD4+ cells were found in granulomatous and non-granulomatous regions of the lung and inversely correlated with Mtb burden. Our findings provide novel insights into antigen-specific T cell responses associated with asymptomatic Mtb infection that are relevant for developing better strategies to control TB.

immunology↗

bioRxiv2020

ClgR contributes to pulmonary pathology but not bacterial growth in Mycobacterium tuberculosis infection

BackgroundThe Clp proteases regulator, ClgR, is encoded in the Mycobacterium tuberculosis (Mtb) genome by Rv2745c gene (clgR). ClgR is required to clear damaged proteins, thereby preventing their accumulation in the cell. It also controls the availability of key enzymes or regulators via conditional degradation mechanism of proteolytic activity in Mtb [1,2]. MethodsIt has been previously reported that Mtb clgR gene is induced in a sigma factor SigH-dependent manner and a deletion mutant of clgR is susceptible to growth in a hypoxic environment. Whether hypoxia is indeed a restriction factor and ClgR is required for Mtb growth in that environment remains unelucidated. We began to address this hypothesis in the C57/BL6 mouse model of TB where Mtb infected lungs do not form granuloma and the lung environment is considerably non-hypoxic. ResultsOur results demonstrate that despite not having a deficit in growth in either murine lungs or primary macrophages, in comparison to wild type, the{Delta} clgR mutant failed to induce pulmonary pathology. ConclusionWe propose that ClgR is required for the pathogenesis of Mtb.

microbiology↗

bioRxiv2019

Tuberculosis-associated IFN-I induces Siglec-1 on tunneling nanotubes and favors HIV-1 spread in macrophages

While tuberculosis (TB) is a risk factor in HIV-1-infected individuals, the mechanisms by which Mycobacterium tuberculosis worsens HIV-1 pathogenesis remain poorly understood. Recently, we showed that HIV-1 infection and spread are exacerbated in macrophages exposed to TB-associated microenvironments due to tunneling nanotube (TNT) formation. To identify molecular factors associated with TNT function, we performed a transcriptomic analysis in these macrophages, and revealed the up-regulation of the lectin receptor Siglec-1. We demonstrate Siglec-1 expression depends on TB-mediated production of type I interferon. In co-infected non-human primates, Siglec-1 is highly expressed by alveolar macrophages, whose abundance correlates with pathology and activation of the type I interferon/STAT1 pathway. Intriguingly, Siglec-1 expression localizes exclusively on microtubule-containing TNT that are long and carry HIV-1 cargo. Siglec-1 depletion in macrophages decreases TNT length, diminishes HIV-1 capture and cell-to-cell transfer, and abrogates TB-driven exacerbation of HIV-1 infection. Altogether, we uncover a deleterious role for Siglec-1 in TB-HIV-1 co-infection, and its localization on TNT opens new avenues to understand cell-to-cell viral spread.

cell biology↗