Severe spotted fever rickettsioses are life-threatening, tick-borne, emerging and re-emerging human infections caused by obligately intracellular Rickettsia including R. conorii and R. rickettsii. Excellent animal models and the available human data reveal the critical importance of IFN-gamma, CD8 cytotoxic T lymphocytes, dendritic cells (DCs) and NK cells in host protective immunity against Rickettsia. Evidence for human rickettsial infection-associated immunosuppression is supported by remarkable suppression of lymphocyte proliferation and IL-2 and IFN-gamma production by IL-10 producing CD4+CD25+ T regulatory cells in acute fatal murine spotted fever rickettsiosis compared to self-limited infection. It remains unclear why the host defense system fails to control bacterial infection in fatal rickettsiosis. The long-term goal of this research is to better understand the immune regulatory mechanisms involved in the inability of the host defense system to control infection in severe spotted fever rickettsiosis. The objective of this proposal is to determine the mechanisms by which DCs mediate defective innate and suppressed adaptive immune responses involving T regulatory 1 cells, which may lead to fatal rickettsial infection.
Our specific aim 1 is to determine the key effect of impaired DC-NK cell cross talk on promoting a defective innate immune response in severe spotted fever rickettsiosis. We will compare the defective DC-NK cell cross talk in susceptible mice, which causes progressively increased bacterial loads, with efficient DC-NK cell interaction in resistant mice, which lead to clearance of bacteria during the innate response.
Our specific aim 2 is to determine the role of immunoregulatory molecules such as PD-1/PD-L and indoleamine 2,3-dioxygenase (IDO) or cytokines such as IL-10 expressed or produced by DCs and/or T regulatory cells in suppression of T cell responses during severe spotted fever rickettsiosis. Toll-like receptors (TLRs), cytokines and chemokines that mediate the DC-NK cell interaction in specific aim 1, and the role of interactions of DCs with T regulatory cells in mediating suppressed protective effector type-1 T cells and/or apoptosis via suppressive cytokines and/or regulatory molecules including PD-1/PD-L and IDO in severe spotted fever rickettsiosis in specific aim 2 will be investigated using in vivo and in vitro approaches including flow cytometry, ELISPOT, ELISA, RT- or real time PCR, mouse TLR PCR array, immunohistochemical staining, plaque assay, HPLC as well as adoptive transfer, depletion of immune molecules and knockout mice.

Public Health Relevance

In recent years the number of cases of Rocky Mountain spotted fever, the most lethal rickettsial disease known, reported to the CDC has reached the highest level in history. This project is designed to determine what components of the immune response are responsible for failure to control bacterial growth in fatal infections to allow future immunomodulatory treatment to enhance survival.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-IDM-S (02))
Program Officer
Perdue, Samuel S
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Medical Br Galveston
Schools of Medicine
United States
Zip Code
Villano, Jason S; Rong, Fang; Cooper, Timothy K (2014) Bacterial infections in Myd88-deficient mice. Comp Med 64:110-4
Xin, Lijun; Shelite, Thomas R; Gong, Bin et al. (2012) Systemic treatment with CpG-B after sublethal rickettsial infection induces mouse death through indoleamine 2,3-dioxygenase (IDO). PLoS One 7:e34062
Jordan, Jeffrey M; Woods, Michael E; Soong, Lynn et al. (2009) Rickettsiae stimulate dendritic cells through toll-like receptor 4, leading to enhanced NK cell activation in vivo. J Infect Dis 199:236-42
Valbuena, Gustavo; Walker, David H (2009) Infection of the endothelium by members of the order Rickettsiales. Thromb Haemost 102:1071-9
Fang, Rong; Ismail, Nahed; Shelite, Thomas et al. (2009) CD4+ CD25+ Foxp3- T-regulatory cells produce both gamma interferon and interleukin-10 during acute severe murine spotted fever rickettsiosis. Infect Immun 77:3838-49
Sousa, Rita de; Franca, Ana; Doria Nobrega, Sonia et al. (2008) Host- and microbe-related risk factors for and pathophysiology of fatal Rickettsia conorii infection in Portuguese patients. J Infect Dis 198:576-85
Fang, Rong; Ismail, Nahed; Soong, Lynn et al. (2007) Differential interaction of dendritic cells with Rickettsia conorii: impact on host susceptibility to murine spotted fever rickettsiosis. Infect Immun 75:3112-23
Walker, David H (2007) Rickettsiae and rickettsial infections: the current state of knowledge. Clin Infect Dis 45 Suppl 1:S39-44
Jordan, Jeffrey M; Woods, Michael E; Feng, Hui-Min et al. (2007) Rickettsiae-stimulated dendritic cells mediate protection against lethal rickettsial challenge in an animal model of spotted fever rickettsiosis. J Infect Dis 196:629-38
Zhang, Jian-Zhi; Hao, Jun-Fang; Walker, David H et al. (2006) A mutation inactivating the methyltransferase gene in avirulent Madrid E strain of Rickettsia prowazekii reverted to wild type in the virulent revertant strain Evir. Vaccine 24:2317-23

Showing the most recent 10 out of 66 publications