Salmonella enterica subspecies Typhimurium is a natural pathogen of mice that establishes persistent, systemic infection. Salmonella generally reside within professional phagocytes, typically macrophages, which is critical for the development of chronic infection. However, it is unclear how Salmonella can survive within a cell-type that evolved to destroy pathogens. Our lab has demonstrated that during persistent murine infections, S. Typhimurium can reside within macrophages that are hemophagocytic. Hemophagocytic macrophages (HM?s) are characterized by the ingestion of viable cells of the hematopoietic lineages, and are clinically associated with human Typhoid fever. We have also observed that by three weeks post-infection, activated macrophages, and possibly HM?s, coalesce into granulomas that harbor and appear to protect bacteria from the host immune system, potentially establishing a site at which the bacteria can survive long-term. The goal of this proposal is to determine how S. Typhimurium exploits macrophages, including HM?s and macrophages within granulomas, to withstand host defenses during acute and chronic infection. We are modeling HM?s and granulomas and the following two aims will address key questions regarding how bacteria establish and maintain colonization of tissues within HM?s and granulomas: 1) How does S. Typhimurium acquire iron from macrophages? and 2) How does S. Typhimurium survive in granulomas? How granulomas form and acquire and maintain bacteria such as Salmonella remains a poorly understood area that may be able to be targeted with therapeutics.
The proposal is directly relevant to public health because it aims to establish how a bacterial pathogen survives within different kinds of macrophages to cause chronic infection. Long-term survival within macrophages is a characteristic of major human pathogens, including not only Salmonella enterica, but also Mycobacterium tuberculosis and M. leprae, Brucella abortus, and species of the eukaryotic pathogen, Leishmania. A molecular understanding of how one pathogen, S. enterica, exploits macrophages has the potential to suggest new therapeutic avenues effective against other pathogens that live within macrophages to cause chronic disease.
| Courtney, Colleen M; Goodman, Samuel M; Nagy, Toni A et al. (2017) Potentiating antibiotics in drug-resistant clinical isolates via stimuli-activated superoxide generation. Sci Adv 3:e1701776 |
