Juan Martinez, Ph.D.

The long-term goals of my research program are to elucidate the molecular mechanisms of spotted fever group (SFG) rickettsia adhesion and invasion of target human cells and to identify putative targets that can be exploited for the development of novel anti-microbial therapies. Rickettsia conorii, an obligate intracellular, tick borne bacterial pathogen is the causative agent of Mediterranean spotted fever. Upon transmission by its arthropod vector, which inoculates the pathogen into human body fluids, R. conorii bind to and invade target host cells, typically endothelia of blood vessels. Aerosol transmission of rickettsia can also occur and represents a bioterrorist threat for the United States. R. conorii survives within infected cells and inhibits cellular apoptosis, a pathogenic strategy that is not only essential for microbial replication but also provides for a protective niche, away from host defenses. Subsequent endothelial inflammation and release of pro-inflammatory cytokines IL-1a, IL-6 and IL-8 generate the pathological-anatomical substrates of Mediterranean spotted fever. A recent report has identified at least 5 genes in the R. conorii genome that are part of a family of surface cell antigens (sca), two of which Sca0 (rOmpA) and Sca5 (rOmpB) are thought to be involved in bacterial adhesion and invasion of non-phagocytic mammalian cells. However, the host cell receptors recognized by these two ligands have thus far not been identified. We have demonstrated that molecular interactions between Ku70, a mammalian host cell protein, and the bacterial outer-membrane protein, rOmpB, are important for the establishment of rickettsial infection in human cells. This hypothesis is supported by several observations. During in vitro infection, R. conorii, but not other invasive pathogens, interact with a complex of host surface proteins, including Ku70. Ku70 is recruited to sites of bacterial entry and inhibition of endogenous Ku70 expression in various model cell lines effectively inhibits R. conorii entry. rOmpB specifically interacts with Ku70 in vitro. Interestingly, rOmpB from R. japonica, a closely related SFG rickettsia, mediates invasion of non-phagocytic mammalian cells when expressed in non-invasive strains of E. coli, suggesting that the interaction of rOmpB with Ku70 may be critical to the rickettsial entry process. C-Cbl, a ubiquitin ligase involved in regulating endocytosis, ubiquitinates Ku70 during rickettsial invasion. R. conorii also initiates signaling cascades during the entry process that involve tyrosine phosphorylation of focal adhesion kinase (FAK) and other host proteins as well as activation of phosphoinositide-3 kinase (PI 3-kinase). These signaling events are thought to recruit the host cell endocytic machinery to contribute to the bacterial entry process. Currently, there are several projects in my laboratory to define the roles of Sca proteins and host cell receptors in the progression of SFG rickettsial pathogenesis using in vitro and in vivo models.

Selected Papers

Martinez JJ and Cossart P. (2004). Early signaling events involved in the entry of Rickettsia conori into mammalian cells. The Journal of Cell Science 117 : 5097-5106.

Martinez JJ, Seveau S, Veiga E, Matsuyama S and Cossart P. (2005). Ku70, a component of DNA-depedent protein kinase, is a mammalian receptor for Rickettsia conorii. Cell 123(6):1013-23.