Friday, May 9, 2025
5/9/2025
Identification of diagnostic biomarkers for flea-borne typhus - Abstract Typhus group rickettsioses (TGRs) include epidemic typhus (ET) and murine typhus (MT), caused by Rickettsia prowazekii and R. typhi, respectively. MT continues to cause serious infectious in otherwise healthy individuals and results in increased health-care cost worldwide. ET is a bioterrorism and potential threat to public health in situations with poor hygiene. Due to unspecific symptoms and lack of a reliable laboratory test at the early stage of disease, diagnosis of TGRs has been problematic and accounts for the significant morbidity and disease burden. Although often under-recognized, MT is the second most frequently reported rickettsial infection in the US. Therefore, a novel antigen-based diagnostic assay for TGRs will be an important resource that will ensure the Nation’s capability to recognize and treat these diseases. Our objectives in this research are to identify the diagnostic biomarkers for TGRs and to develop a proof-of-concept immunoassay that can be further advanced to an acute diagnostic assay for these infections. Our pilot studies have identified two rickettsial proteins as the potential diagnostic targets by proteomic analysis using in vitro and in vivo experimental models of MT. These two molecules have both shown a greater than 95% identity based on their amino acid sequences in R. typhi compared to those in R. prowazekii. Thus, our central hypothesis is that immuno-detection of diagnostic biomarkers will provide an antigen-based assay for early diagnosis of MT. We propose that this diagnostic assay will also be applicable to ET. This project will test this hypothesis utilizing two linked and complementary specific aims. Aim 1 will define the diagnostic biomarker(s) for TGRs. We will validate and quantify two identified rickettsial proteins as potential biomarkers through proteomic analysis, as described in our recently published studies. Aim 2 will develop an immunoassay for detecting the diagnostic target(s) for TGRs. We will identify the potential diagnostic biomarkers in patients with confirmed MT during the acute phase of infection using SID-PRM-MS assay. These diagnostic biomarkers will then be detected using a sensitive chemiluminescent sandwich ELISA using a panel of specific monoclonal antibodies. The immunoassay's application for diagnosing ET will be evaluated using R. prowazekii-infected guinea pig models. Completion of these two aims is expected to yield a proof-of-concept immunoassay, which can be further developed into an acute laboratory diagnostic assay for both MT and ET. This advancement will facilitate timely treatment, favorable outcomes, and reduced healthcare expenditures.
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