The major research theme of our team is deciphering the immunological and molecular factors responsible for tuberculosis (TB) disease with or without co-infection with HIV. Our laboratory pursues both basic and application-oriented approaches to resolve these issues. We study immune responses in the settings of mono- or co- infection with Mycobacterium and HIV with a long-term goal of developing novel therapeutic and diagnostic modalities. One –third of the world population carries latent TB infection (LTBI); an immune imbalance in individuals with LTBI results in Mycobacterium tuberculosis (Mtb) reactivation and TB disease. Therefore, it is important to identify prognostic markers that can predict clinical TB in LTBI for timely control of occult disease. By twinning clinical outcome and utilizing combination of multiple immunological, molecular and genomic approaches we are trying to understand the dynamics of host-pathogen interaction and the risk factors associated with occult TB and HIV disease.

The major on-going studies in the lab are:

  1. Role of Myeloid Derived Suppressor Cells (MDSC) in M tuberculosis and HIV infection

Myeloid derived suppressor cells (MDSC) are a heterogeneous population of cells and precursors of myeloid cells (macrophages, dendritic cells and granulocytes). In human 0.5% of the peripheral blood mononuclear cells are MDSC. These cells express CD33+ and CD11b+ and do not express HLA-DR. A block in the differentiation of immature myeloid cells to mature myeloid cells results in the expansion of MDSC. These cells can prevent autoimmunity, inhibit transplant graft rejection and suppress immune response to tumors. MDSC influence the immune response to parasitic, bacterial, viral and fungal pathogens. Our recently published studies indicate increased number MDSC are present in untreated HIV-infected individuals and exhibit suppressed innate immunity to Mtb. We have recently observed that MDSC do not expand in vitro in presence of M bovis BCG, but surprisingly expand in the presence of virulent M tuberculosis antigens. This suggests that MDSC can be beneficial or harmful depending on the pathogen and infection state. Limited or almost no information is available about MDSC in HIV-Mtb infection. We are interested in studying the role of MDSC in these disease condition

2. Role of IL-27 in M tuberculosis infection with and without co-infection with HIV

Tuberculosis (TB) remains a major health hazard and leading cause of death from infectious organism worldwide. HIV affects Mtb at all disease stages, even when CD4 T cells have recovered and viral replication suppressed as a result of successful HAART. Co-infection with HIV-infection increases the risk of primary TB or Mtb reactivation by 30 fold. We believe that HIV-Mtb co-infected individuals with suppressed viral replication exhibit an immune state that is able to control HIV replication but is detrimental for Mtb. We have recently observed that cytokine IL-27 exhibits a negative correlation with HIV viral load, positive correlation with CD4 T cells and inhibit HIV replication in vitro. Importantly, this cytokine inhibits phagosomal acidification by blocking vacuolar ATPases, compromises control of Mtb growth and modulates anti-Mtb effector functions. We are investigating the mechanism by which this cytokine causes TB disease.

3. Mechanism of lymphopenia in SARS CoV2 infection

The pandemic coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is rapidly spreading across the globe. The clinical manifestations of COVID-19 are highly variable, ranging from asymptomatic infection to acute respiratory failure and death.However, it is well established that lymphocyte count is a predictor of disease severity and T cell lymphopenia is a prominent feature of critically ill patients. The mechanism(s) for T cell destruction and association of T cell lymphopenia with disease prognosis remains ill defined. We are interested to decipher the mechanism that leads to T cell destruction, and ways to rescue it.

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