Type I interferons on trypanosoma cruzi infection
By: by Anne-Danielle Celia Chessler
Published: 2009
Language: eng
Number of pages: 163
Description: The innate immune response to pathogens is critical to host control of infection. Trypanosoma cruzi induces a robust type I interferon (IFN) response in a wide variety of cell types. We demonstrate that T. cruzi engages a novel signaling pathway that converges on TBK1 and IRF3 to induce IFNβ in isolated macrophages and fibroblasts. Additionally, T. cruzi triggers a type I IFN response in vivo, at a local infection site. Robust induction of type I IFN-stimulated genes is observed in excised skin 24 hours post-infection where the level of induction is parasite strain-dependent, with a low virulence strain triggering a muted IFN response. Significant induction of a type I IFN response both in vitro and at the site of infection in vivo suggests a role for this family of cytokines in T. cruzi infection. Although previous attempts to characterize the role of type I IFNs in T. cruzi using mice deficient in type I IFN signaling (IFNAR -/- ) have yielded conflicting results, a more systematic examination of the parameters of strain and dose on T. cruzi infection in WT and IFNAR -/- mice demonstrates that the effects of type I IFN in the context of T. cruzi infection are dependent on infective dose. Specifically, mice deficient in type I IFN signaling are protected from lethal infection while the mice of the same genetic background infected with a sub-lethal dose of T. cruzi show no significant differences in morbidity or mortality. Although the mechanism for this detrimental effect of type I IFNs is not clear, gross differences in pathology, infiltrating cell types, levels of apoptosis, or cytokine profiles are not observed. Taken together, these results suggest a complex immunomodulatory role for type I IFNs that could influence infection and pathology during T. cruzi infection.

Further characterization of the signaling pathways upstream of T. cruzi -induced IFNβ production and the mechanisms by which type I IFNs are detrimental during T. cruzi infection will provide valuable insight into the complex signaling networks and immunomodulatory effects of this family of cytokines in the control of intracellular pathogens.
Notes: "January 2009."

Thesis (Ph.D., Dept. of Biological Sciences and Public Health)--Harvard University, 2009.

Includes bibliographical references.