Wednesday, April 2, 2025
4/2/2025
At the site of the bite: Immune Response to tick-transmitted Rickettsiae - PROJECT SUMMARY/ABSTRACT Advancements in understanding the human immune response to spotted fever rickettsiosis (SFR) require a translational animal model demonstrating clinical rickettsiosis after tick transmission of the spotted fever group Rickettsia spp. (SFGR) agents of SFR. The guinea pig is an ideal model for studying SFR because it recapit- ulates the disease after tick transmission, has an immune system demonstrably closer to that of a human than a mouse, and allows for antemortem sample collection for multiple assays at sequential time points in longitu- dinal studies. The latter characteristic makes the guinea pig uniquely informative because such sample collec- tions from murine models would not be feasible. Here, we utilize the guinea pig-tick-SFGR system, methods tailored to the model system, and the inclusion of three SFGR, Rickettsia rickettsii, R. parkeri, and R. am- blyommatis, that overlap in geographic distribution but range in their ability to cause human disease. The most virulent SFGR in our system is Rickettsia rickettsii, the agent of Rocky Mountain spotted fever (RMSF), a potentially fatal SFR. Rickettsia parkeri was confirmed as an agent of SFR approximately 20 years ago and causes a milder SFR than RMSF. The third SFGR in our proposed studies is R. amblyommatis, which is not a known SFR agent but may be associated with mild symptoms and confound SFR diagnosis. While all three SFGR overlap in their eastern US range, R. parkeri, in its Amblyomma maculatum tick vector, and R. am- blyommatis, in its A. americanum tick vector, are more commonly encountered compared to R. rickettsii in its Dermacentor variabilis tick vector. The long-term goal of our research is to elucidate the immune response to SFGR and determine the mechanisms that lead to the development of SFR using a relevant experimental system. Our objectives for this R01 resubmission are to differentiate immune effector profiles in the skin after tick transmission of SFGR associated and not associated with SFR and to identify acute disease biomarkers. We address the hypotheses that unique local immune profiles are generated from guinea pigs exposed to tick- transmitted SFGR that differ in virulence. These unique profiles may reveal potential mechanisms driving the immune response to SFGR under natural conditions. Further, biomarkers identified during acute infection will inform SFR progression and clearance. Our rationale is that immune effectors and biomarkers in a relevant model system will best clarify SFR and provide reliable approaches to treatment and diagnostics. The pro- posed research is significant because it will position the guinea pig-tick-SFGR system to address more pro- found mechanistic questions and thus better inform future development of therapeutics and diagnostics com- pared to the use of the murine model. This proposal is innovative by combining expertise in the uniquely translational guinea pig-tick-SFGR system and immunology, including assay development, with studies of SFR agents and potential confounders of SFR diagnosis in the US.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).