Ixodes scapularis is a primary vector of several important tick-borne pathogens including Borrelia burgdorferi sensu lato, the causative bacterial genospecies complex of Lyme disease, Babesia microti, Anaplasma phagocytophilum, Borrelia miyamotoi, Ehrlichia muris eauclarensis, and Powassan virus. Salivary compounds secreted by I. scapularis during blood feeding are immunogenic and can elicit robust antibody responses in humans which can potentially be leveraged as surrogate markers of prior tick bite exposure. In this study, we investigate the potential of a tick secreted salivary serine protease inhibitor, IxsS7, as a novel antigenic biomarker of I. scapularis exposure in humans. We demonstrate that the IxsS7 protein-coding sequence is highly conserved (>90 % identity) among other important Ixodes species (e.g., Ixodes ricinus, Ixodes persulcatus, and Ixodes pacificus) and poorly conserved (<50 % identity) with homologs from other tick genera, such as Amblyomma spp., Dermacentor spp., Rhipicephalus spp., and Haemaphysalis spp. Antibodies in sera from rabbits immunized with recombinant IxsS7 (rIxsS7) strongly recognize native IxsS7 when challenged with salivary gland homogenate (SGH) from blood-fed I. scapularis females, while showing minimal cross-reactivity with SGH from other hard tick (Ixodidae) genera. Western blot and ELISA analyses revealed that human subjects who reported recent prior exposure to ticks possessed IgG antibodies that recognized rIxsS7, highlighting its potential as a biomarker of exposure specifically against I. scapularis. Further development of serological tools that can measure human antibody responses to Ixodes-specific salivary antigens is essential to better quantify individual- and population-level risk of important tick-borne diseases such as Lyme disease.

Global Vaccines Medical Affairs Pfizer Research and Development Cambridge MS USA

Global Vaccines Medical Affairs Pfizer Research and Development NY NY USA

Global Vaccines Medical Affairs Pfizer Research and Development NY NY USA; Tick Pathogen Transmission Unit Laboratory of Bacteriology Rocky Mountain Laboratories Division of Intramural Research National Institute of Allergy and Infectious Diseases Hamilton MT USA

Global Vaccines Medical Affairs Pfizer Research and Development NY NY USA; Vector Molecular Biology Section Laboratory of Malaria and Vector Research Division of Intramural Research National Institute of Allergy and Infectious Diseases Rockville MD USA

Johns Hopkins University Baltimore MD USA

Lyme Disease Studies Unit Laboratory of Clinical Immunology and Microbiology Division of Intramural Research National Institute of Allergy and Infectious Diseases Bethesda MD USA

Tick Pathogen Transmission Unit Laboratory of Bacteriology Rocky Mountain Laboratories Division of Intramural Research National Institute of Allergy and Infectious Diseases Hamilton MT USA

Tick Pathogen Transmission Unit Laboratory of Bacteriology Rocky Mountain Laboratories Division of Intramural Research National Institute of Allergy and Infectious Diseases Hamilton MT USA; Centro de Pesquisa Experimental Hospital de Clínicas de Porto Alegre Porto Alegre RS Brazil

Tick Pathogen Transmission Unit Laboratory of Bacteriology Rocky Mountain Laboratories Division of Intramural Research National Institute of Allergy and Infectious Diseases Hamilton MT USA; Department of Biochemistry and Molecular Biology University of Nevada Reno NV USA

Tick Pathogen Transmission Unit Laboratory of Bacteriology Rocky Mountain Laboratories Division of Intramural Research National Institute of Allergy and Infectious Diseases Hamilton MT USA; Department of Medical Biology Faculty of Science University of South Bohemia in České Budějovice Budweis Czech Republic

Vector Molecular Biology Section Laboratory of Malaria and Vector Research Division of Intramural Research National Institute of Allergy and Infectious Diseases Rockville MD USA

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