Research


Our lab’s broad goal is to understand fundamental principles of host cell defense and immune dysregulation that drive pathogenesis. We are particularly interested in understanding and uncovering the innate immune and cell-intrinsic defense mechanisms that detect, signal and defend host cells against infectious pathogens. We use model bacterial pathogens with unique intracellular lifestyles to identify common as well as distinct themes in host defense. These include the bacterial pathogens Coxiella, Salmonella, Legionella that successfully manipulate host cell biology and replicate inside secure, vacuolar organelles in host cells. Coxiella burnetii, in particular, is well-adapted to the acidic and hostile environment of lysosomes. This choice of intracellular lifestyle is in contrast to most vacuolar pathogens that inhibit the fusion of their compartment with lysosomes to avoid the proteolytic environment. The mammalian Interferon-gamma (IFNγ) signaling pathway is capable of restricting the replication of C. burnetii in its lysosome-derived vacuole. Using a siRNA-based screen, my postdoctoral work demonstrated that an IFNγ-induced SNARE protein, (Soluble NSF Attachment Protein Receptor) Syntaxin 11 (STX11) negatively influences intracellular C. burnetii replication (manuscript in preparation). STX11 is well-established to mediate vesicle fusion processes, lysosomal exocytosis and granule secretion in platelets and lymphocytes, but the mechanistic basis by which it directly controls pathogen replication in the infected cell, is not defined. 
Short-term goals:The exciting immediate goal is to understand the cell-intrinsic function of STX11 by:
  • Identifying its molecular partners through proteomic approaches
  • Examining pathogenic polymorphisms of STX11 that lead to the immune disorder, familial hemophagocytic lymphohistiocytosis subtype 4 (FHL-4) through mutational analysis, cell-biological, and infection-based assays
  • Defining the localization and traffic pathway of STX11 using advanced microscopic tools
  • Identifying the function of STX11 in macrophages and other infectious disease models

Long-term goals:We also aim to identify other human genes with potentially novel antimicrobial functions against vacuolar pathogens, in order to promote the development of host-directed therapies in the future. Specific focus areas will include:
  • Role of other SNARE proteins in regulating pathogen-replication in membrane-bound organelles
  • Contribution of lysosomal biogenesis to control of intracellular pathogens 
  • Antibacterial mechanisms that operate in the placental tissue at the maternal-fetal interface 
  • The molecular composition of pathogen-containing vacuoles in immune-activated cells 

Bacterial pathogens have co-evolved nuanced secretion systems to translocate bacterial proteins into host cells and manipulate host-cell processes to their advantage. Future research will also focus on mechanisms of evasion of host-cell defense.