Borrelia burgdorferi conserved gene products BB0406 and BB0405, members of a common B. burgdorferi paralogous gene family, share 59% similarity. Although both gene products can function as potential porins, only BB0405 is essential for infection. Here we show that, despite sequence homology and coexpression from the same operon, both proteins differ in their membrane localization attributes, antibody accessibility, and immunogenicity in mice. BB0406 is required for spirochete survival in mammalian hosts, particularly for the disseminated infection in distant organs. We identified that BB0406 interacts with laminin, one of the major constituents of the vascular basement membrane, and facilitates spirochete transmigration across host endothelial cell barriers. A better understanding of how B. burgdorferi transmigrates through dermal and tissue vascular barriers and establishes disseminated infections will contribute to the development of novel therapeutics to combat early infection.

Ixodes scapularis ticks transmit multiple pathogens, including Borrelia burgdorferi sensu stricto, and encode many proteins harboring epidermal growth factor (EGF)-like domains. We show that I. scapularis produces multiple orthologs for Bm86, a widely studied tick gut protein considered as a target of an anti-tick vaccine, herein termed as Is86. We show that Is86 antigens feature at least three identifiable regions harboring EGF-like domains (termed as EGF-1, EGF-2, and EGF-3) and are differentially upregulated during B. burgdorferi infection. Although the RNA interference-mediated knockdown of Is86 genes did not show any influences on tick engorgement or B. burgdorferi sensu stricto persistence, the immunization of murine hosts with specific recombinant EGF antigens marginally reduced spirochete loads in the skin, in addition to affecting tick blood meal engorgement and molting. However, given the borderline impact of EGF immunization on tick engorgement and pathogen survival in the vector, it is unlikely that these antigens, at least in their current forms, could be developed as potential vaccines. Further investigations of the biological significance of Is86 (and other tick antigens) would enrich our knowledge of the intricate biology of ticks, including their interactions with resident pathogens, and contribute to the development of anti-tick measures to combat tick-borne illnesses.

The Borrelia burgdorferi BB0323 protein undergoes a complex yet poorly defined proteolytic maturation event that generates N-terminal and C-terminal proteins with essential functions in cell growth and infection. Here, we report that a borrelial protease, B. burgdorferi high temperature requirement A protease (BbHtrA), cleaves BB0323 between asparagine (N) and leucine (L) at positions 236 and 237, while the replacement of these residues with alanine in the mutant protein prevents its cleavage, despite preserving its normal secondary structure.

Ticks represent a major group of arthropod vectors that are present worldwide and transmit a number of serious infections (Parola & Raoult, 2001). They exhibit a high degree of heterogeneity in terms of their habitat, biology, and genome, which possibly dictates their remarkable vectorial competence, as evidenced by their ability to harbor a diverse range of pathogenic agents, including viruses, bacteria, protozoa, and nematodes (Jia et al., 2020). The hematophagous and ectoparasitic behavior of ticks facilitates the acquisition and transmission of certain pathogens between reservoir hosts and ticks, as well as frequent transmission from ticks to incidental hosts. Many human and animal diseases are caused by tick-borne pathogens. For example, tick-borne encephalitis (TBE) (Beaute et al., 2018) is elicited by a virus of the family Flaviviridae, the TBE virus (Mansfield et al., 2009), which occurs in many European countries, northern China, Mongolia, and the Russian Federation, while Lyme disease, or Lyme borreliosis, is caused by the bacteria Borrelia burgdorferi sensu lato, which is prevalent in North America and Eurasia (Radolf et al., 2012). The latest estimate from the United States Center for Disease Control and Prevention (CDC) suggests that, in recent years, there were likely over 400,000 new cases of Lyme disease annually in the United States alone (Kugeler et al., 2021). This infection is predominantly transmitted by Ixodes scapularis ticks, in addition to closely related species, such as I. pacificus, I. ricinus, and I. persulcatus, that are found across specific geographical regions of North America, Eurasia, and Asia. While many distinct tick species transmit various human diseases, Ixodes ticks are considered as one of the most prolific vectors; besides Lyme disease and TBE, they also transmit numerous other human infections, such as anaplasmosis,