Bartonella virulence mechanisms in patients with AIDS
Jane E. Koehler, University of California, San Francisco
Bartonella henselae (BH) and B. quintana (BQ) are arthropod-borne, emerging, gram- negative pathogens that cause bacillary angiomatosis (BA), a unique, potentially lethal, vascular proliferative lesion affecting HIV-infected patients. Relapsing and/or persistent bloodstream infection is another manifestation of Bartonella infection that occurs in patients at all stages of HIV infection. Bartonella infections represent a threat to the health of AIDS patients in California, where the majority of the US cases of HIV-associated Bartonella infection have been diagnosed; BQ disproportionately affects the HIV-infected homeless population in California. Because Bartonella infection was only identified in the US in the past 15 years, almost nothing is known about how Bartonella causes infection in humans. The goal of our research is to identify virulence genes and mechanisms of pathogenesis utilized by BQ to infect and persist in the immunocompromised human host.
We are currently focusing our research on a virulence pathway of BQ, the obligatory acquisition of iron in the form of hemin or heme. Heme is the nonprotein, ferrous component of hemoglobin that carries oxygen; hemin is the ferric chloride form of heme. Both hemin and heme are utilized by BQ as a source of iron. The Specific Aims of this pilot project are: 1) identification and characterization of genes involved in the transport of hemin in BQ; and 2) identification of environmental signal-mediated regulation of hemin transport in BQ. We have identified an unusual phenotype during a forward genetic screen for hemin uptake; analysis of these mutants has implicated two transporter genes in the export of hemin. We will further characterize these mutants functionally in vitro by generating null mutants for each gene, and by heterologous reconstitution of the transport system in E. coli. Contribution of these genes to virulence of BQ in vivo will also be tested. We will also continue to screen for additional hemin transport mutants in BQ.
Studying these mutants further will likely reveal how BQ is able to survive toxic levels of hemin while residing in the intestinal tract of the body louse vector, as well as while circulating within erythrocytes in the bloodstream of the mammalian host. BQ occupies these two very unusual niches, and information about the associated virulence strategies of BQ will likely provide insight into the cellular processes of the human host, as well as into the biology of the arthropod. Ultimately, this information will lead to potential strategies for improved treatment of HIV-infected patients (e.g., preventing relapse in the bloodstream) and prevention of infection (e.g., eradicating BQ from the body louse gut).