Severe rickettsial infections can be life-threatening with pre-antibiotic case-fatality rates reported as high as 65%-80% in some case series. Increased endothelial permeability is a major component of the pathophysiology of severe rickettsial diseases. However, the key mechanisms by which rickettsiae mediate severe diseases targeting endothelial cells (ECs) remains elusive. Our long term goal is to develop a novel therapeutic strategy that can effectively treat patients at even a late stage of infection to address the public health problems due to this disease. The objectives of this proposal are to understand the mechanisms mediating increased EC permeability by rickettsiae and to correct this disorder by counteracting the specific mechanism. The hypothesis to be tested in this proposal is that rickettsiae increase EC permeability via activating NLRP3 inflammasome. This hypothesis will be tested by accomplishment of two Specific Aims.
Aim 1 is to determine the activation of NLRP3 inflammasome by rickettsiae in ECs. NLRP3-knock (KO) mice and NLRP3-specific short hairpin RNA (shRNA) will be employed to study the activation of NLRP3 inflammasome in R. australi-infected mouse brain microvascular ECs and R. conorii-infected human ECs. The cooperation of NLRC5 with NLRP3 inflammasome activation will be examined.
Aim 2 is to determine the contribution of NLRP3 inflammasome to mediating EC hyperpermeability in severe rickettsioses. We will determine both the in vivo and in vitro role of NLRP3 inflammasome in mediating EC hyperpermeability. Casp-1 pharmaceutical inhibitors will be employed in R. conorii-infected C3H/HeN mice to amend the EC hyperpermeability in vivo. It is believed that accomplishment of the specific aims of this proposal may provide novel insights into therapeutic interventions targeting increased microvascular permeability.

Public Health Relevance

Rickettsioses can be life-threatening if it is diagnosed too late due to the lack of effective treatment at the late stage of infection. The proposed project aims to address this problem by development of novel treatment based on understanding of mechanisms of endothelial dysfunction-related pathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI133359-02
Application #
9701899
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Perdue, Samuel S
Project Start
2018-05-24
Project End
2021-04-30
Budget Start
2019-05-01
Budget End
2021-04-30
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Texas Med Br Galveston
Department
Pathology
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555