James B. Bliska

Research Interests (continued)

YPTB and YP are classified as facultative intracellular pathogens.  They are able to survive within host cells such as macrophages.  Alternatively, YPTB and YP can replicate in an extracellular form in host tissues.  During infection of human or animal hosts these bacteria are likely to exist transiently in macrophages at early stages of pathogenesis, followed by extensive extracellular growth at later stages of disease. 

We are investigating the interaction of YPTB and YP with macrophages during the intracellular and extracellular stages of pathogenesis.  During the intracellular stage of pathogenesis the bacteria survive in a macrophage phagosome that appears to interact with the endocytic pathway, but fails to acidify.  Macrophages can internalize Yersinia by several different phagocytic pathways but the phagosome fails to acidify and the bacteria survive regardless of which pathway is used.  Studies are being undertaken to determine why the Yersinia-containing vacuole (YCV) fails to acidify and to identify bacterial gene products that are required for this block in the normal phagosome maturation process. 

YP and YPTB encode a specialized protein export pathway known as a type III secretion system (T3SS). Interesting, a large number of pathogenic bacteria utilize a T3SS during infection of host cells. The T3SS functions to deliver bacterial proteins to the plasma membrane or cytosol of the infected host cell.  Each pathogen encodes a unique set of proteins that are secreted by the T3SS.  In Yersinia the proteins secreted by the T3SS are known as Yops, and they form two major classes (translocators and effectors).  The Yop translocators function to insert a channel (translocon) into the plasma membrane of the host cell.  The Yop effectors are delivered through the translocon into the cytoplasmic space of the macrophage, where they interfere with signaling cascades. The effectors function to paralyze the phagocyte, alter its ability to produce cytokines, and then kill it.

Several lines of investigation are underway to better understand the function of the T3SS.  First, we are interested in characterizing the essential components of the translocon.  As part of this work we aim to devise strategies (e.g. the use of neutralizing monoclonal antibodies) to interfere with translocon function.  Second, we are carrying out structure and function analysis of several Yop effectors to better define their precise biological functions.  Third, we are interested in uncovering mechanisms of host resistance to infection that rely on sensing the components of the T3SS.  For example, deployment of the T3SS during phagocytosis reduces survival on YPTB within macrophage phagosomes, and we are currently investigating the cellular and molecular basis for this phenomenon.

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