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The Role of Macrophages and the Th1 Transcription Factors STAT1 and STAT4 During Visceral Leishmaniasis

Steinkamp, Heidi Marie
http://rave.ohiolink.edu/etdc/view?acc_num=osu1338335780

Abstract Details

2012, Doctor of Philosophy, Ohio State University, Oral Biology.
Leishmaniasis is a tropical disease caused by protozoan parasites. Leishmania donovani causes visceral disease with tropism for reticuloendothelial organs. Left untreated, L. donovani infections are fatal, often due to secondary bacterial infections and complications resulting from profound hepatosplenomegaly. Although Leishmania species are capable of parasitizing several different mammalian cell types, recent research has suggested that neutrophils may serve as early silent vectors for parasite entry into tissue macrophages, which are the definitive host cells and sites of parasite replication. Proper macrophage activation and parasite clearance is contingent upon hosts mounting type I CD4+ T cell (Th1) responses associated with the production of interleukin-12 and interferon-gamma (IFN-gamma). Signal transducer and activator of transcription 1 (STAT1) mediates the biological functions of IFN-gamma while STAT4 mediates the biological functions of IL-12. Interestingly, we found that while STAT1-deficient mice on a susceptible BALB/c background failed to mount protective Th1 responses, they were highly resistant to infection and developed little or no immunopathology compared with WT controls. We further found that STAT1 signaling in T cells was not involved in mediating immunopathology or susceptibility to L. donovani, suggesting that non-T cells recruited to the liver via STAT1-depdendent mechanisms may be involved in the pathogenesis of visceral leishmaniasis. We further found that phagocytes from STAT1-deficient mice had significant impairments in trafficking and parasite uptake compared with WT controls. These studies suggest that STAT1 signaling may mediate susceptibility by facilitating parasite uptake into host phagocytes. Similar to STAT1-deficient animals, STAT4-deficient mice were also unable to mount Th1 immune responses. However, STAT4 mice had significantly higher parasite burdens in their livers and spleens compared to WT animals. Additionally, STAT4-deficient animals exhibited temporal delays in hepatic and splenic inflammatory responses. These studies indicate that STAT4 signaling is critical in both the control of parasite growth and in the inflammatory response mounted against L. donovani infection. Macrophages in the organs of reticuloendothelial system are the principle effector cells involved in eliminating L. donovani, but they are also the cells which mediate inflammatory pathology and are used by the parasite for its survival as well as replication within the host. We found that transient depletion of macrophages in susceptible BALB/c mice after L. donovani infection by a single injection of liposome encapsulated bisphosphonate led to rapid clearance of parasites from the liver and spleen and also resulted in a reduction in liver and spleen pathology. Clodronate liposomes were found to be as effective as sodium stibogluconate (SSG) in reducing liver parasite loads, and were significantly better than SSG in clearing parasites from the spleen. Combination therapies with SSG and clodronate liposomes were even more effective in reducing parasite loads in reticuloendothelial organs than either drug alone. These findings indicate that liposome encapsulated bisphosphonates, which are already in clinical use, could be potential new drugs for treatment of visceral leishmaniasis. Additionally, the data demonstrate that combination therapy induces significantly better parasite clearance from the spleen, which is difficult to achieve with SSG alone.
Abhay Satoskar, MD,PhD (Advisor)
John Sheridan, PhD (Committee Member)
William Lafuse, PhD (Committee Member)
Michael Bailey, PhD (Committee Member)
201 p.
Immunology
Leishmania; infectious disease; immunology; parasitology; STAT1; STAT4; clodronate liposomes; macrophages; innate immunity

Recommended Citations

Citations

  • Steinkamp, H. M. (2012). The Role of Macrophages and the Th1 Transcription Factors STAT1 and STAT4 During Visceral Leishmaniasis [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1338335780

    APA Style (7th edition)

  • Steinkamp, Heidi. The Role of Macrophages and the Th1 Transcription Factors STAT1 and STAT4 During Visceral Leishmaniasis. 2012. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1338335780.

    MLA Style (8th edition)

  • Steinkamp, Heidi. "The Role of Macrophages and the Th1 Transcription Factors STAT1 and STAT4 During Visceral Leishmaniasis." Doctoral dissertation, Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1338335780

    Chicago Manual of Style (17th edition)

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© 2012, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.