Investigation of human immune responses in acute rickettsioses: towards development of host response-based diagnostics

The National Institute of Allergy and Infectious Diseases awarded Duke University $807,481 on September 1, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate human immune responses in acute spotted fever group rickettsioses and develop host response-based diagnostics.

The project characterizes the human immune response to spotted fever group rickettsioses across three distinct geographic settings—Sri Lanka, Tanzania, and the United States—and develops transcriptomic and proteomic host response diagnostic classifiers to improve early recognition of the disease. Spotted fever group rickettsioses are tick-borne bacterial infections endemic to all continents except Antarctica that can cause severe febrile illness requiring hospitalization. The disease is treatable with tetracycline antibiotics if recognized within five days of illness, but delayed diagnosis is common worldwide due to non-specific clinical manifestations and lack of accurate diagnostics on readily obtainable specimens such as blood samples. The project aims to advance timely recognition and reduce preventable morbidity and mortality attributable to diagnostic delay.

Duke University's Office of Research Administration, based in Durham, North Carolina, is the recipient. The period of performance runs from September 1, 2026, through August 31, 2027. Work is performed in Durham, North Carolina. The assistance type is a Project Grant.

Abstract

Spotted fever group rickettsioses (SFGR) are tick-borne bacterial diseases endemic to all continents save antarctica. They can cause severe febrile illness (SFI) that requires hospitalization. In the US, the highest incidence of SFGR is in south-central and southeastern states. Our collaborative research in SRI lanka and in tanzania has identified SFGR as the cause of illness in nearly 10% of patients presenting to hospital with SFI. The rickettsia SPP. That cause SFGR in SRI lanka, tanzania, and the US-the three settings contributing to this project-are at once potentially fatal yet also highly treatable if the disease is recognized and treated with tetracycline antibiotics in the first five days of illness. However, the crucial problem is that SFGR treatment delays beyond five days of illness are common worldwide, including in our three settings. This delayed recognition stems from the non-specific clinical manifestations of SFGR, which include fever, malaise, headache, and usually a rash; delayed recognition also stems from the lack of accurate diagnostic tests that can be run on readily obtainable specimens (i.e., blood samples as opposed to skin biopsies) in the initial days of illness. This diagnostic challenge leads to under-treatment and excess preventable morbidity and mortality due to SFGR. Through characterization of the human host immune response to SFGR in these three distinct settings (aim 1) and through development of transcriptomic and proteomic host response diagnostic classifiers (aims 2 and 3), the project seeks to advance the long-term goal of improving timely recognition of SFGR in the initial days of illness. SFG rickettsia have a tropism for infecting vascular endothelial cells and causing a vasculitis- like inflammatory process characterized by endothelial activation and vascular permeability. We hypothesize that the host response to SFGR is sufficiently distinct from other common SFI, allowing for diagnostic host biomarkers to be identified in the acute phase of illness-biomarkers identified by whole blood mrna gene expression analysis (aim 2) or by plasma and extracellular vesicle proteomic analysis (aim 3). The experiments in aim 1 address a related and important question: whether the human immune response to SFGR is conserved across species and geographic locations. Answering this question will determine whether host response-based diagnostics for SFGR will be globally generalizable or will require setting/species-specific optimization. To achieve these aims, we will use our unique biorepository of over 3,000 SFI patients, allocated between derivation and validation sets. This large repository includes approximately 200 SFGR cases enrolled in cohorts from SRI lanka, tanzania, and the US. The validation set will also include prospective SFI enrollment and SFGR case accrual in north carolina, a highly endemic region for SFGR in the US. Collectively, this project is well-positioned to make important discoveries regarding the human immune response to rickettsioses. These discoveries will support the development of host response-based diagnostic biomarkers to address key gaps in the timely recognition and management of this neglected serious bacterial infection.