Epidemic typhus, also known as Gaol fever, Jail fever, or Famine fever, is caused by the Gram-negativebacterium Rickettsia prowazekii. This louse-borne disease has been responsible for devastating widespreadepidemics throughout history, especially during and after the wars, famine, and poor socio-economicconditions, and is the only known rickettsiosis that can recur after a long period of latency (Brill-Zinsserdisease). R. prowazekii is classified as a CDC/NIAID Category B biological warfare pathogen, the entiregenome for which was the first to be sequenced among all known Rickettsia species. Despite considerablerestrictions imposed by obligate intracellular parasitism, tremendous strides have recently been made in thegenetic manipulation of R. prowazekii. Strikingly, the knowledge of molecular aspects of interactions with thevascular endothelium, the preferred cell type infected during human infections, still remains in its infancy. It isnoteworthy that endothelial cells, which are intimately involved in the manifestations of rickettsial infections,have emerged as key immunoreactive cells involved in host defense and inflammation. On the basis ofinteractions of host endothelial cells with R. prowazekii and R. typhi (the etiologic agent of endemic typhus), wehave identified activation of nuclear factor kappa B (NF- B) and stress-activated p38 protein kinase as criticallyimportant regulatory signaling mechanisms that contribute to host cell activation and responses to infection.
The first aim of this exploratory grant application is designed to define the extent and kinetics of the activationof NF- B and MAP kinase signaling pathways after R. prowazekii infection of vascular endothelial cells in vitroand to test the hypothesis that potential differences in intracellular signaling mechanisms determine theintensity of host cell activation in response to virulent Breinl versus attenuated Madrid E strains of R.prowazekii.
Aim 2 will focus on establishing and characterizing a mouse model of R. prowazekii infection thatclosely mimics the major pathological features, i.e. disseminated endothelial infection and vascularinflammation, of epidemic typhus disease in humans. The long-term objective of this project is to lay thefoundation for comprehensive understanding of epidemic typhus pathogenesis by identifying specializedvascular cell signaling pathways activated in vitro and subsequent detailed analysis of their involvement indetermination of innate and adaptive immune responses with an aim to develop unique chemotherapeuticstrategies focused at targeted intervention. In addition, detailed characterization of a small animal model ofinfection akin to disease in humans will allow us to define unique features of epidemic typhus pathogenesisand virulence factors of R. prowazekii, to expand our understanding of in vivo host immune responses, and totest the efficacy of novel antibiotics and vaccine candidates.

Public Health Relevance

Rickettsial diseases have been a scourge of humankind throughout history. Typhus epidemics due to louse- borne Rickettsia prowazekii have caused more deaths than all the wars combined and recent epidemiological evidence documents the reemergence of epidemic typhus in different geographic locations of the world. Despite considerable progress in the recent past regarding genomics, proteomics, and other important aspects of rickettsial biology, the relative paucity of the knowledge of basic molecular and cellular concepts of epidemic typhus pathogenesis is rather astonishing. Specifically, the knowledge pertaining to the interactions of typhus rickettsiae with their preferred target in the human host, i.e. vascular endothelium, is still in its infancy and first description of a convenient laboratory model of in vivo R. prowazekii infection has become available only recently. Since vascular dysfunction/damage are the major culprits for complications of human disease, obtaining a definition of signaling interactions between endothelial cells and R. prowazekii strains of varying virulence and detailed characterization of a mouse model of disseminated infection of the vasculature represent major steps in advancing our understanding of typhus pathogenesis, that will ultimately lead to the development of novel therapeutic/immunologic strategies to combat this debilitating rickettsial disease.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-IDM-A (90))
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Perdue, Samuel S
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University of Texas Medical Br Galveston
Schools of Medicine
United States
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