Murine typhus is a febrile, flea-borne rickettsial disease caused by an obligate intracellular bacterium, Rickettsia typhi. The illness is accompanied by fever, headache, chills, vomiting, nausea, myalgia, and rash and leads to disseminated multisystem disease. Due to its resemblance to diseases like typhoid- or dengue fever it is often misdiagnosed and under reported. Murine typhus is a debilitating disease with over 70% of patients requiring hospitalization. Since the disease does not effectively respond to broad-spectrum antibiotics misdiagnosis and treatment delays increase the risk for complications (i.e., seizures, respiratory and kidney failure, and persistent frontal and temporal lobe dysfunction) or death. Murine typhus is prevalent worldwide and its transmission is closely associated with the human habitations. Importantly murine typhus is endemic in the continental US and in particular is re-emerging in southern Texas and California where the current level of reported human cases is continuing to occur with high prevalence. Murine typhus cases are also on the rise among urban homeless populations, as well as returning travelers from endemic areas. During the previous funding period, we have made several important discoveries concerning the characterizations and functional analysis of R. typhi secreted proteins and host innate immune responses to rickettsial colonization. Our proposed research in this renewal application underscores the role of the R. typhi secretory proteins in the host during the infectio process.
The aims of this competitive renewal are now narrowly focused on defining the role of R. typhi secretory proteins that facilitate rickettsial colonization and survival in both flea and at hosts (Aim 1). Based on our published work and preliminary data, we will target R. typhi surface cell antigens, ankyrin repeat proteins and patatin-like phospholipases. Our investigation will cover the infection process in both flea and rat hosts. The two host systems (invertebrate and vertebrate) provide unique insight into dynamics of molecular interactions by which R. typhi target, colonize and survive within the epithelial cells in fleas and endothelial cells in the mammalian host.
Specific Aim 2 will explore further how microbe-associated molecular patterns and downstream immune effectors affect Rickettsia typhi colonization in flea hosts. Since differential immune response in infected flea supports the symbiotic stability between this arthropod vector and R. typhi we hypothesize that disrupting the molecular balance between R. typhi and the flea vector should affect flea fitness during infection.

Public Health Relevance

Murine typhus is a febrile disease caused by Rickettsia typhi. The disease is prevalent worldwide and is closely associated with human habitations, commensal rodents, opossums and fleas. Murine typhus is re-emerging in many coastal regions, urban and rural communities worldwide. The illness is accompanied by clinical symptoms resembling diseases like typhoid- or dengue fever and as a result it is often misdiagnosed and underreported. The disease is endemic in the continental U.S. particularly, in southern Texas and California. Cases are also on the rise among urban homeless populations as well as returning travelers from murine typhus endemic areas. This proposed research underscores major concepts in rickettsial virulence and pathogenesis by targeting rickettsial secretory proteins that facilitate rickettsial survival in prokaryotic hosts. Identification of rickettsial proteins interacting with the mammalian hosts will advance our understanding of the biology of R. typhi and provide information on pathogen proteins that could be used in developing better rickettsial vaccines and/or therapeutics.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AI017828-31
Application #
8668876
Study Section
Vector Biology Study Section (VB)
Program Officer
Perdue, Samuel S
Project Start
Project End
Budget Start
Budget End
Support Year
31
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Gillespie, Joseph J; Kaur, Simran J; Rahman, M Sayeedur et al. (2015) Secretome of obligate intracellular Rickettsia. FEMS Microbiol Rev 39:47-80
Pelc, R S; McClure, J C; Sears, K T et al. (2014) Defending the fort: a role for defensin-2 in limiting Rickettsia montanensis infection of Dermacentor variabilis. Insect Mol Biol 23:457-65
Kang, Yan-Jun; Diao, Xiu-Nian; Zhao, Gao-Yu et al. (2014) Extensive diversity of Rickettsiales bacteria in two species of ticks from China and the evolution of the Rickettsiales. BMC Evol Biol 14:167
Rahman, M Sayeedur; Gillespie, Joseph J; Kaur, Simran Jeet et al. (2013) Rickettsia typhi possesses phospholipase A2 enzymes that are involved in infection of host cells. PLoS Pathog 9:e1003399
Driscoll, Timothy; Gillespie, Joseph J; Nordberg, Eric K et al. (2013) Bacterial DNA sifted from the Trichoplax adhaerens (Animalia: Placozoa) genome project reveals a putative rickettsial endosymbiont. Genome Biol Evol 5:621-45
Gillespie, Joseph J; Joardar, Vinita; Williams, Kelly P et al. (2012) A Rickettsia genome overrun by mobile genetic elements provides insight into the acquisition of genes characteristic of an obligate intracellular lifestyle. J Bacteriol 194:376-94
Ceraul, Shane M; Chung, Ashley; Sears, Khandra T et al. (2011) A Kunitz protease inhibitor from Dermacentor variabilis, a vector for spotted fever group rickettsiae, limits Rickettsia montanensis invasion. Infect Immun 79:321-9
Sutten, Eric L; Norimine, Junzo; Beare, Paul A et al. (2010) Anaplasma marginale type IV secretion system proteins VirB2, VirB7, VirB11, and VirD4 are immunogenic components of a protective bacterial membrane vaccine. Infect Immun 78:1314-25
Rahman, M Sayeedur; Ammerman, Nicole C; Sears, Khandra T et al. (2010) Functional characterization of a phospholipase A(2) homolog from Rickettsia typhi. J Bacteriol 192:3294-303
Gillespie, Joseph J; Brayton, Kelly A; Williams, Kelly P et al. (2010) Phylogenomics reveals a diverse Rickettsiales type IV secretion system. Infect Immun 78:1809-23

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