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is one of the few extracellular pathogens capable of establishing persistent infection in mammals. The mechanisms that sustain long-term survival of this bacterium are largely unknown. Here we report a unique innate immune evasion strategy of , orchestrated by a surface protein annotated as BBA57, through its modulation of multiple spirochete virulent determinants. BBA57 function is critical for early infection but largely redundant for later stages of spirochetal persistence, either in mammals or in ticks. The protein influences host IFN responses as well as suppresses multiple host microbicidal activities involving serum complement, neutrophils, and antimicrobial peptides. We also discovered a remarkable plasticity in BBA57-mediated spirochete immune evasion strategy because its loss, although resulting in near clearance of pathogens at the inoculum site, triggers nonheritable adaptive changes that exclude detectable nucleotide alterations in the genome but incorporate transcriptional reprograming events. Understanding the malleability in spirochetal immune evasion mechanisms that ensures their host persistence is critical for the development of novel therapeutic and preventive approaches to combat long-term infections like Lyme borreliosis.

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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,