Infection and Immunity, Apr. 2025. Ixodes scapularis ticks are an important vector for at least seven tick-borne human pathogens, including a North American Lyme disease spirochete, Borrelia burgdorferi. The ability for these ticks to survive in nature is credited, in part, to their ability to feed on a variety of hosts without triggering an immune response capable of preventing tick feeding. While the ability of nymphal ticks to feed on a variety of hosts has been well documented, the host-parasite interactions between larval I. scapularis and different vertebrate hosts are relatively unexplored. Here we report on the changes in the vertebrate host transcriptome present at the larval tick bite site using the natural I. scapularis host Peromyscus leucopus, a non-natural rodent host, Mus musculus (BALB/c), and humans. We note substantially less evidence of activation of canonical proinflammatory pathways in P. leucopus compared to BALB/c mice and pronounced evidence of inflammation in humans. Pathway enrichment analyses revealed a particularly strong signature of interferon gamma, tumor necrosis factor, and interleukin 1 signaling at the BALB/c and human tick bite sites. We also note that bite sites on BALB/c mice and humans, but not deer mice, show activation of wound-healing pathways. These data provide molecular evidence of the coevolution between larval I. scapularis and P. leucopus and, in addition, expand our overall understanding of I. scapularis feeding.

Plos Pathogens, Dec. 2025. Lyme disease is caused by the host-adapted spirochete Borrelia burgdorferi. With a genome of only 1.5 mbp, B. burgdorferi is dependent on metabolites scavenged from their vertebrate and invertebrate hosts for growth. These scavenged nutrients include several lipid precursors: the spirochete is auxotrophic for fatty acids and cholesterol, and also accumulates environmental phospholipids. Comprehensive lipidomic analysis of B. burgdorferi by LC MS/MS was used to identify previously undescribed membrane components. These include some likely scavenged from the culture medium and some which may be synthesized de novo via unknown pathways. Changes in fatty acid composition as cells enter stationary phase suggest that scavenging of environmental lipids is preferential to de novo synthesis, while transcriptomics suggests that this may be due to the energetic cost of synthesizing glycerol phosphate precursors. In media supplemented with excess phospholipids, scavenged lipids can be found at high concentrations in cells, suggesting that the membranes of infecting bacteria are likely to be partly shaped by the host environment. Transcriptomic analysis also show a link between environmental lipids and the expression of virulence-associated surface lipoproteins including reciprocal regulation of ospA and ospC. Given that borrelial membrane lipids are known to be antigenic during infection, these findings identify potential new targets for the development of diagnostic tests or vaccines.

Frontiers in Immunology, Nov 2025. Introduction: Clinical presentation of Lyme disease is largely due to host immune response to infection. Previously, we identified a variant (1805GG) in the TLR1 gene, a key immune sensor for Borrelia burgdorferi, which was associated with excessive inflammation and severe disease. Herein we examined the mechanism by which this variant leads to dysregulated immunity.

Methods: We found that patients with post-infectious Lyme arthritis, a condition characterized by marked persistent synovitis in joints, have a higher frequency of TLR1-1805GG compared to those whose arthritis resolves with antibiotics. To explore the possibility that this genotype-phenotype association was due to excessive inflammation, we then tested the functional impact of TLR1-1805GG on inflammatory responses and immune tolerance in PBMCs with or without this SNP and in THP-1 cell lines lacking TLR1.

Results: In response to B. burgdorferi stimulation, PBMCs with TLR1-1805GG had greater transcriptional upregulation of ~1200 immune-related genes and significantly higher cytokine levels in supernatants compared to cells without this variant. Moreover, repeat B. burgdorferi stimulation, which mimics tolerogenic conditions during the infection, failed to induce innate immune tolerance in PBMCs with TLR1-1805GG, or in THP-1 cells lacking TLR1, resulting in seemingly unabated immune activation consistent with marked inflammation in Lyme arthritis joints.

Conclusions: These results suggest that excessive inflammation in patients with TLR1-1805GG variant appears to be due to immune dysregulation and inability to induce immune tolerance. The findings help explain how early events during the infection may contribute to sustained immune activation after antibiotics and point to the role of TLR1 signaling in immune regulation.

Ticks and Tick-borne Diseases, Nov 2025. Tolerance and resistance are two host eco-immunological strategies in response to microparasite invasion. In the strategy of “resistance”, host responses are induced to decrease microparasite replication while the “tolerance” strategy allows hosts coexistence with microparasites by minimizing responses to avoid immune-mediated damage. The causative agent of Lyme disease is a group of genotypically diverse bacterial species, Borrelia burgdorferi sensu lato (Bb), which is transmitted by Ixodes ticks and persists in different reservoir animals. In North America, eastern fence lizards (Sceloporus undulatus) can be fed on by Ixodes ticks but are incompetent to one genotype of Bb (i.e., ospC type A). However, field-collected lizards showed evidence of previous infection by Bb strains with undefined genotypes. Supporting this evidence, we introduced three genotypically different Bb strains individually to eastern fence lizards and found a Bb genotype-dependent manner of infectivity. We compared liver transcriptomics and observed elevated immune responses triggered by a lizard-incompetent Bb strain (strain B31). We showed two lizard-competent strains with one having no immunomodulation (strain B379) but the other developing upregulated immune responses (strain 297). These results suggest that genetic variation in microparasites both induces different host strategies for dealing with infection and determines microparasite fitness in the hosts. These findings demonstrate that Bb and eastern fence lizards can serve as a model to investigate the mechanisms underlying eco-immunological strategies of tolerance vs. resistance during host-microparasite interaction.

Clinical Infectious Diseases, Dec 2025. Description: Babesiosis is a tick-borne disease that is endemic in the United States (US). The major species, Babesia microti, is readily transmissible via blood transfusion. Since 2019, blood donors in 14 US states and Washington DC have been routinely screened for Babesia infection using highly sensitive and specific nucleic acid testing (NAT). Currently, there are no recommendations regarding the management of asymptomatic blood donors who test positive for Babesia.

Methods: A multidisciplinary expert panel was convened to develop guidance for the management of asymptomatic Babesia-infected blood donors. A survey was distributed through the Infectious Diseases Society of America (IDSA) Emerging Infections Network (EIN) to evaluate how a geographically diverse group of infectious diseases specialists would approach this problem.

Results: The expert panel recommends that all Babesia NAT positive blood donors should be referred for clinical evaluation and retested using peripheral blood smear (PBS) and B. microti PCR within two months of blood donation screening. The panel also recommends observation rather than treatment for a reactive molecular test alone. Antimicrobial therapy should be considered for PBS positive cases. Donors should be counseled regarding the typically self-limiting nature of this infection and instructed to seek medical care if symptoms develop. The EIN survey results are consistent with these recommendations.

Conclusions: Several factors support these management recommendations. Blood donors typically comprise healthy, immunocompetent adults in whom most Babesia infections are self-limited based on studies showing that molecular evidence of infection clears in almost all asymptomatic blood donors without intervention.

Annals of Internal Medicine 2025. Lyme disease, caused by Borrelia burgdorferi, is the most common vector-borne disease in the United States, and the range of its tick vector continues to expand. Most Lyme disease cases are diagnosed with the onset of the erythema migrans rashes, which can be single or multiple and vary from a homogeneous erythema to bull’s-eye patterns. Serologic antibody testing is of low sensitivity at onset but becomes highly sensitive after a few weeks. Early dissemination may lead to neurologic and cardiac complications. Mono- or oligoarticular arthritis may develop in untreated patients. Antibiotic treatment is highly effective, but approximately 10% of treated patients experience persistent symptoms.

Science Translational Medicine March 2025. Ixodes scapularis is a primary vector of tick-borne pathogens in North America. Repeated exposure to these ticks can induce a humoral response to tick antigens and acquired tick resistance. However, identifying antigens contributing to this resistance is challenging because of the vast number of I. scapularis proteins secreted during feeding. To address this, we developed I. scapularis rapid extracellular antigen monitoring (IscREAM), a technique to detect antibody responses to more than 3000 tick antigens. We validated IscREAM with immunoglobulin G (IgG) from guinea pigs vaccinated with tick antigens, including a cement antigen cocktail that induced tick resistance. Furthermore, we explored the natural response to tick bites by profiling antigens recognized by IgG isolated from a tick-resistant individual, as well as from others with Lyme disease and tick-bitten guinea pigs and mice, to identify 199 recognized antigens. We observed that several antigens contained histamine-binding domains. This work enhances our understanding of the host immune response to I. scapularis and defines immunogen candidates for future antitick vaccines.

Journal of Infectious Diseases, 2026. Lyme disease spirochetes are maintained in natural reservoirs before spilling over into human populations. Targeting these reservoirs with vaccinations or antibiotics could impact the Borrelia burgdorferi enzootic cycle and reduce the risk of human Lyme disease. In this work we report that the narrow-spectrum antibiotic hygromycin A is sufficient to disrupt B burgdorferi transmission from the main eastern US reservoir, Peromyscus leucopus, to ticks. Additionally, hygromycin A-containing baits can clear B burgdorferi from P leucopus. These studies lay the foundation for the use of hygromycin A as a reservoir-targeted antibiotic to eradicate B burgdorferi in the wild.

Many of the diverse tick-borne diseases (TBD) in the US appear to be increasing in incidence, leading to concern that factors such as climate change may create challenging scenarios. The 18 TBD and 1 syndrome that cause illnesses in US residents present varying public health burdens (Table). For US clinicians, the most common TBD of concern is Lyme disease (estimated at about 476 000 cases each year1), with babesiosis, human granulocytic anaplasmosis (HGA), Rocky Mountain spotted fever, monocytic ehrlichiosis (HME), and alpha gal allergy (ie, red meat allergy) annually accounting for hundreds to thousands of cases. The remaining TBD are either rare (≤50 cases/y) or diagnosed sporadically every few years, although some of these carry severe morbidity or mortality. TBD cases have increased within the last decade, but the cause for this trend is multifactorial. Changes in case reporting and case definitions have contributed to the increase,2 as have improved diagnostic capacity, demographic shifts, urbanization, and an expansion in the range and local abundance of tick vectors.

Survivors of Powassan encephalitis often have persistent neurological disease. A new mouse model replicates some elements of the human disease and demonstrates the presence of viral RNA in the brain as well as myelitis more than 2 mo after the acute infection. The related tick-borne encephalitis and West Nile Neuroinvasive Disease (WNND) also have common neurological sequelae, and models for these better-studied diseases provide evidence for prolonged virus, RNA, and inflammation in some cases, in addition to damage from the acute encephalitic disease. A better understanding of the…