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Tuberculosis

I focus my research efforts on understanding and developing treatments for the global infectious disease Tuberculosis.  Tuberculosis is caused by the bacterium Mycobacterium tuberculosis, which completes its lifecycle exclusively within the lungs of infected humans.  For an estimated 70,000 years M. tuberculosis has evolved within the niche of the human lung. 

 


Pathogenic stages of  M. marinum  infection of zebrafish. (A) Optically transparent zebrafish larva. (B) Differential interference contrast (DIC) microscopy image of infected macrophage (arrow) phagocytosing extracellular mycobacteria (arrowhead). (C) DIC image of early granulomas. (D) Epifluorescent image of C showing fluorescently labelled M. marinum inside individual macrophages. (E) Confocal microscopy image of cording  M. marinum  (red and green fluorescent strains used to emphasize cording phenotype) in a 5dpi infected larva. (F) Immunohistology of a mature granuloma in an adult infected zebrafish at 8 weeks post infection

Pathogenic stages of M. marinum infection of zebrafish. (A) Optically transparent zebrafish larva. (B) Differential interference contrast (DIC) microscopy image of infected macrophage (arrow) phagocytosing extracellular mycobacteria (arrowhead). (C) DIC image of early granulomas. (D) Epifluorescent image of C showing fluorescently labelled M. marinum inside individual macrophages. (E) Confocal microscopy image of cording M. marinum (red and green fluorescent strains used to emphasize cording phenotype) in a 5dpi infected larva. (F) Immunohistology of a mature granuloma in an adult infected zebrafish at 8 weeks post infection

Zebrafish/Mycobacterium marinum Model of Tuberculosis

The closely related bacterium, Mycobacterium marinum, causes a tuberculosis like disease in zebrafish.  All of the stages of disease progression seen in humans are evident in zebrafish upon infection with M. marinum.  With this model system we can take advantage of host and pathogen genetics to perform loss and gain of function studies to evaluate the mechanisms underlying disease pathogenesis.  Furthermore, the optical transparency of zebrafish larvae facilitate real time microscopy studies of host-pathogen interactions.  This model is a cornerstone to my research.  

 

 

 


Mycobacterial virulence lipids: immune evasion and manipulation. 

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In order to develop therapies and eventually a vaccine for Tuberculosis, we need to understand why our immune system fails to prevent infection.  My work has previously found that pathogenic mycobacteria avoid detection by host immune system.  This is accomplished by the virulence lipid phthiocerol dimycocerosate (PDIM). PDIM is localized to the outer most membrane on mycobacteria and its presence prevents conical antibacterial immune responses from recruiting activated macrophages to sites of infection. This need to avoid innate immune recognition precludes mycobacteria from establishing infection in the presence of resident microflora which are continually recognized by innate immune receptors.  Therefore, mycobacteria must initiate infection in the relatively sterile lower airways. 

Conversely, in order to thrive within hosts, mycobacteria prefer to reside in these bactericidal cells known as macrophages.  To accomplish this mycobacteria trigger their recruitment in the absence of immune activation.  Mycobacterial phenolic glycolipid (PGL) stimulates the recruitment of permissive macrophages that provide an intracellular niche for the bacteria to thrive.  My ongoing research centers around developing tools to further understand the molecular mechanisms underlying these immune modulators and on developing therapies to target and inhibit mycobacterial virulence lipids.