Laboratory Websites

Current Research

Leprosy

Example 2
T cells are required for protection against intracellular infections, such as leprosy and tuberculosis; however, the mechanisms by which T cells contribute to host immunity remain unresolved. Leprosy, caused by the intracellular pathogen Mycobacterium leprae (mLEP), represents an accessible model to investigate human immune responses to intracellular bacterial infection. The spectrum of clinical manifestations of leprosy correlates with the immune response to mLEP. Patients with tuberculoid leprosy (T-lep) develop protective immunity and eliminate the infection, whereas those with lepromatous leprosy (L-lep) sustain a progressive infection. We established that T-cell subsets differed dramatically between blood and lesions, indicating the importance of studying the immune response at the site of disease. We seek to characterize antimicrobial T cells and their roles in reducing the viability of intracellular pathogen.

Potential projects:

  1. Elucidate mechanisms by which CD8+ cytolytic T lymphocytes (CTL) are triggered via TCR-dependent and/or -independent antimicrobial response
  2. Define the heterogeneity within the Th17 compartment of patients with T-lep and L-lep to map the IL-1β-mediated antimicrobial response
  3. Identify the innate pathways that induce antimicrobial T-cell differentiation in leprosy

Acne: A Disease of Lipid Metabolism, Microbiome, and the Immune Response

Example 2
Using acne as a model to study the interaction between the microbiome and the local immune response, we aim to investigate how crosstalk among molecular gene programs, distinct phylotypes of commensal bacteria Cutibacterium acnes (C. acnes), and surrounding cells in the microenvironment promote inflammatory innate and adaptive immune response.

Potential projects:

  1. Determine how metabolites and molecular signals released during inflammation affect the acne cellular microenvironment
  2. Investigate the mechanisms of distinct C. acnes phylotypes to promote inflammation or maintain homeostasis
  3. Identify specific genetic elements of commensal C. acnes that are responsible for the differential induction of cytokine and immune signaling 
  4. Defining the influence of lipid metabolism in immune cell fate and function

Pulmonary TB granuloma

Example 2
The emergence of multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis strains is an emerging global public health crisis that underscores the urgent need to understand immune mechanisms in human tuberculosis (TB), with the ultimate goal of developing new strategies for its prevention and treatment. Our study focuses on investigating TB granuloma heterogeneity and its role in disease outcome, as well as the potential for identifying biomarkers that can reliably predict response to chemotherapy.

Potential projects:

  1. Determine the cell subpopulations and molecular architecture of TB granuloma and correlate the presence of cellular subtypes with response of chemotherapy in responder and resistant patients with TB
  2. Identify the role of macrophage subpopulations in TB granulomas that promote antimicrobial responses against M. tuberculosis and the mechanisms by which macrophage kill intracellular M. tuberculosis
  3. Determine the contribution of T cell subpopulation to regulate surrounding macrophages repolarization and the effects of M. tuberculosis antimicrobial activity

IL-26

Example 2
Th17 cells defend the host against extracellular bacteria by releasing cytokines that recruit and activate a variety of other cells. Th17 cells mediate host defense against extracellular bacteria by releasing the antimicrobial protein interleukin (IL)-26 that kills bacteria in axenic cultures. Previous studies in our laboratory indicated that IL-26 expression in leprosy lesions significantly correlates with elimination of bacteria over time. In addition, we showed that IL-26 enters Mycobacterium leprae-infected macrophages, induces autophagy and phagolysosome fusion, colocalizes with the intracellular bacteria, and reduces bacterial viability. Our study aims to identify how IL-26 released by the activation of Th17 cells contribute to host defense intracellular bacteria such as bacterium M. leprae.

Potential projects:

  1. Determine how the extracellular IL-26 gain access to intracellular pathogens within macrophages and trigger an antimicrobial response
  2. Determine how IL-1b-activated secretion of IL-26 by Th17 cells contributes to the antimicrobial response against intracellular M. leprae and identify additional producers of IL-26
  3. Asses the role of IL-26 in host defense against various intracellular bacteria and whether distinct subcellular compartments are required for IL-26 antimicrobial activity

CD1-restricted T cell Responses in Skin

Example 2
One crucial barrier mechanism via which the skin defends against microbial infection involves Langerhans cells (LCs), which are a skin-specific resident dendritic cell (DC) subset in the epidermis. Previous studies in our laboratory found that LCs contribute to the cutaneous immune response to Mycobacterium leprae, the causative agent of leprosy, via a langerin-dependent, CD1a-restricted antigen presentation pathway to T cells. We uncovered new paradigms of CD1 immunobiology, including defining the lipid-containing CD1-restricted T cell antigen structure and mechanisms of CD1 antigen presentation, mechanisms via which CD1 expression is regulated in skin, and the first evidence for direct T cell-mediated antimicrobial activity. To build on these findings, we aim to examine the role of CD1a-restricted T cell and LC in host defense in skin.

Potential projects:

  1. Determine specific pathways by which activated LCs kill intracellular bacteria as well as microbial ligands and their role in LC-mediated antimicrobial response
  2. Investigate mechanisms by which CD1a-restricted T cells kill intracellular pathogens in LCs
  3. Define mechanisms by which LCs process and present CD1a-restricted bacterial peptides to T cell

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