Rickettsiae are intracellular bacteria that potentially cause life-threatening diseases all over th world. Rickettsiae possess the ability to invade host cells, quickly escape phagosomal vacuoles, and replicate in the cytoplasm. Autophagy targets cytoplasmic constituents in the autophagosomes and degrades them in the autolysosomes/lysosomes. Autophagy is now considered as a cornerstone of the intracellular surveillance system. The objective of the proposed project is to determine the interaction of rickettsiae with autophagy and its contribution to host control of fatal rickettsial diseases. We hypothesize that rickettsiae induce autophagy at the early stage of infection, which mediates degradation of cytosolic rickettsiae resulting in efficient host protective immunity of fatal rickettsial diseases. In the first Aim, we will determie whether autophagy is induced by rickettsiae and whether autophagy contributes to host control of fatal rickettsial diseases using a mouse model. In the second aim, we will identify how autophagy regulates the IL-1 response during fatal rickettsial diseases. The successful completion of the project will highlight the role of autophagy in host control of intracellular pathogens. The proposed project will provide important information on targeting autophagy for preventive and therapeutic interventions of fatal infectious diseases caused by intracellular microbes.

Public Health Relevance

Rickettsiae have potential to cause life-threatening diseases and to be used as biological weapons, which poses a serious public health problem. The proposed project will study how autophagy eliminates rickettsiae and how this event regulates inflammatory response. The findings of these studies will provide novel strategies for control of severe diseases caused by intracellular pathogens.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI101413-02
Application #
8829741
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Perdue, Samuel S
Project Start
2014-04-01
Project End
2017-03-31
Budget Start
2015-04-01
Budget End
2017-03-31
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Pathology
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Bechelli, Jeremy; Smalley, Claire; Zhao, Xuemei et al. (2016) MyD88 Mediates Instructive Signaling in Dendritic Cells and Protective Inflammatory Response during Rickettsial Infection. Infect Immun 84:883-93
Smalley, Claire; Bechelli, Jeremy; Rockx-Brouwer, Dedeke et al. (2016) Rickettsia australis Activates Inflammasome in Human and Murine Macrophages. PLoS One 11:e0157231
Bechelli, Jeremy; Smalley, Claire; Milhano, Natacha et al. (2015) Rickettsia massiliae and Rickettsia conorii Israeli Spotted Fever Strain Differentially Regulate Endothelial Cell Responses. PLoS One 10:e0138830
Desai, Mayura; Fang, Rong; Sun, Jiaren (2015) The role of autophagy in microbial infection and immunity. Immunotargets Ther 4:13-26