Hard ticks (family Ixodidae) are significant vectors of pathogens affecting humans and animals. This review explores the composition of tick saliva, focusing on proteases and protease inhibitors, their biological roles, and their potential in vaccines and therapies. Tick saliva contains various proteases, mostly metalloproteases, serpins, cystatins, and Kunitz-type inhibitors, which modulate host hemostatic, immune, and wound healing responses to facilitate blood feeding and pathogen transmission. Proteases inhibit blood clotting, degrade extracellular matrix components, and modulate immune responses. Serpins, cystatins, and Kunitz-type inhibitors further inhibit key proteases involved in coagulation and inflammation, making them promising candidates for anticoagulant, anti-inflammatory, and immunomodulatory therapies. Several tick proteases and protease inhibitors have shown potential as vaccine targets, reducing tick feeding success and pathogen transmission. Future research should focus on comprehensive proteomic and genomic analyses, detailed structural and functional studies, and vaccine trials. Advanced omics approaches and bioinformatics tools will be crucial in uncovering the complex interactions between ticks, hosts, and pathogens, improving tick control strategies and public health outcomes.

Centre for Infectious Animal Diseases Faculty of Tropical AgriSciences Czech University of Life Sciences Prague Prague Suchdol Czechia

Section of Infectious Diseases Department of Internal Medicine Yale School of Medicine New Haven CT United States; Laboratory of Host Pathogen Dynamics National Heart Lung and Blood Institute National Institutes of Health Bethesda MD United States; Molecular and Cellular Immunology Section Laboratory of Immunogenetics National Institute of Allergy and Infectious Diseases National Institutes of Health Rockville MD United States

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Amblyostatin-1, the first salivary cystatin with host immunomodulatory and anti-inflammatory properties from the Neotropical tick Amblyomma sculptum, vector of Brazilian spotted fever