DESCRIPTION (provided by applicant): Many bacterial pathogens important to human health evade the immune system by living within white blood cells. Salmonella enterica, a species of gram-negative bacteria that includes the causative agent of human typhoid fever, resides within a class of white blood cells called macrophages. We have demonstrated that in mice, S. enterica subspecies Typhimurium (Salmonella) resides and replicates within hemophagocytic macrophages (HMΦ), which are macrophages that have engulfed erythrocytes, platelets, leukocytes and their precursor cells. Our long-term goal is to determine how Salmonella and HMΦs interact to cause disease. Mice infected with Salmonella are a natural host-pathogen model system encountered in the wild. Salmonella causes an acute infection in mice that typically resolves into a chronic infection, and the disease course resembles that of typhoid fever. The bacteria colonize the spleen, liver, and the lymph nodes that drain the intestine. We demonstrated the presence of HMΦs within the spleen, liver and bone marrow of Salmonella - infected mice and identified HMΦs containing Salmonella as late as eight weeks post-infection in the liver, when persistent infection has been established. In Preliminary Studies we developed a flow cytometric assay to identify and separate HMΦs from the spleen. This novel methodology along with established approaches enables new exploration of the role of HMΦs in disease. The objectives of the current application are to 1) Determine the immunological requirements for hemophagocytosis and the effect of HMΦ accumulation on the course of murine typhoid fever, 2) Establish whether HMΦs formed in response to Salmonella infection in vivo or in culture become anti-inflammatory and whether anti-inflammatory macrophages are permissive for bacterial replication, and 3) Identify regulatory pathways within HMΦs needed to make them permissive for Salmonella replication. Completion of these Aims has the potential to elucidate whether hemophagocytosis benefits the host as well as Salmonella. In addition, the information we acquire has potential use in the development of treatments that modulate hemophagocytosis and influence the course of inflammation in infectious and non-infectious circumstances.

The work proposed within has the potential to define novel and important mechanisms of host-pathogen interactions not only for Salmonella, but by inference for other microbes that trigger HMΦ accumulation, including Mycobacterium tuberculosis, Leishmania species, and Histoplasma capsulatum. The long-term significance of the proposed work is its potential to suggest novel therapeutic approaches to infectious and non-infectious diseases in which HMΦs accumulate.