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Current knowledge on immune cell interactions with Borrelia burgdorferi (Bb) derives mostly from studies done in vitro and ex vivo, which cannot assess host immunity to natural tick-delivered Bb within the complex architecture of host tissues. We report the first in vivo study on local and systemic immune responses to Bb during tick feeding on a surrogate reservoir host, in comparison with uninfected-tick and subcutaneously delivered Bb. We show that uninfected-tick and tick-transmitted Bb engaged mixed type-1/type-2/type-17 immune responses in the presence of anti-inflammatory IL-10, in contrast to a type-1 response induced by subcutaneously delivered Bb. Analyses of immune responses to tick-transmitted Bb in a reservoir host can enlighten immunity mechanisms that mediate persistence of Bb.

The lytic cycle of Toxoplasma gondii is critical for parasite dissemination and disease progression in the host. Calcium signaling plays a crucial role in driving these processes; however, the molecules that control calcium storage and release remain poorly understood. The endoplasmic reticulum, likely the largest calcium reservoir in T. gondii , has been understudied in the context of calcium signaling. Here, we uncover a direct link between ER redox regulation and calcium homeostasis, showing that ER redox activity can influence calcium signaling events that govern microneme protein maturation and secretion, parasite invasion, and replication. Our findings indicate that redox-dependent calcium regulation in the ER contributes to control of the parasite lytic cycle and reveals a previously unrecognized mechanism that may influence parasite virulence.

Effective control of tick-borne disease begins by first understanding how ticks acquire, harbor, and transmit pathogens. Over their lifetime, ticks encounter many sources of oxidative stress-inducing stimuli. Here, we explore the factors contributing to oxidative stress in ticks-including blood digestion, pesticide exposure, and pathogen infection-and then discuss how ticks counter this stress by employing antioxidant defenses. We highlight how non-tick-borne pathogens manipulate the host antioxidant response for survival and speculate that tick-borne pathogens may be acting similarly in the arthropod. We conclude by conjecturing that the robust antioxidant defenses that ticks have evolved to withstand the stress associated with hematophagy may also be inadvertently supporting the pathogens they carry.

Borrelia burgdorferi , the tick-borne agent of Lyme disease, is the causative agent of one of the most prevalent vector-borne infections in many regions worldwide. Despite extensive study, the biological functions of many of its protein and small RNA (sRNA) products remain poorly defined. Here, we confirm and extend the regulatory roles of the linear plasmid ( lp )17-encoded protein BBD18 and the sRNA SR0736 ( ittA ) in spirochete infectivity. Importantly, we identify a previously unrecognized regulatory function for an adjacent sRNA, SR0735 , underscoring lp17 as a key regulatory region in B. burgdorferi . Together, our findings highlight the bbd18 locus and its surrounding sRNA elements as an independent, multilayered regulatory module that controls gene products, including those required for mammalian infection. Defining how these three regulators shape gene expression and virulence will reveal new mechanisms underlying Lyme disease pathogenesis and may inform the development of new strategies to prevent this widespread illness.

Understanding how pre-existing human immunity shapes susceptibility to emerging influenza viruses is central to pandemic preparedness. Here, we determined that human sera contain widespread, functional antibodies targeting H5N1 neuraminidase, which correlate with virus neutralization, whereas HA-directed responses are limited. We further show that acquisition of an NA glycosylation site reduces antibody inhibition, highlighting a potential pathway for immune evasion. These results identify neuraminidase-specific immunity as a major immunological barrier to severe H5N1 disease in humans and emphasize the need to incorporate NA antigenicity into influenza surveillance, risk assessment, and next-generation vaccine design.

Spore resistance and exit from dormancy during germination are central to the transmission and pathogenesis of endospore-forming pathogens like Bacillus anthracis . Our understanding of the molecular mechanisms underlying these processes has principally been informed by studies in the non-pathogenic model Bacillus subtilis . Here, we identify and characterize a membrane complex in B. anthracis that is critical for spore resistance and spore germination that is absent from B. subtilis . We show that this complex is required for the accumulation of dipicolinic acid in the spore core during sporulation and functions in its release from the core during germination. A deeper understanding of the molecular mechanisms of B. anthracis sporulation and germination will facilitate the development of strategies for more effective disease prevention and treatment.

Rickettsial pathogens are strictly dependent on the cellular biology of their hosts for survival and replication. Predominantly transmitted by blood-feeding arthropods, these vector-borne pathogens are forced to adapt between the disparate environments of their mammalian host and arthropod vector. To achieve this, the Rickettsial bacteria undergo extensive transcriptional reprogramming, with over 41% of its genes differentially transcribed between mammals and ticks. How the bacterium orchestrates this dramatic transcriptional reprogramming is not understood. The gene encodes a Helix-Turn-Helix DNA-binding protein that is exclusively expressed during tick infection. Herein, we show that is essential for survival in ticks and regulates the transcription of other genes necessary to adapt to the arthropod vector. We demonstrate that Tr1 is a DNA-binding protein that recognizes promoters of tick-specific genes in , including secreted effector , alternate components of the type IV secretion system (T4SS), and membrane proteins. Our findings demonstrate that Tr1 is a master regulator of genes critical for adaptation to the tick.IMPORTANCETick-borne pathogens are a persistent threat to human and animal health worldwide. These pathogens must be capable of surviving in both the arthropod vector and the mammalian hosts to successfully complete their lifecycle. To achieve this, these pathogens reciprocally regulate genes that are specific for either mammalian or tick infection. The mechanism orchestrating this switch remains undefined. In this study, we identify a transcriptional regulator controlling how the tick-borne agent for granulocytic anaplasmosis, , adapts to life in the tick. Disabling this transcriptional switch and the genes it controls renders the bacteria unable to survive in the arthropod vector. Understanding how this central regulator and the genes under its control impact tick infection could lead to interventions that disrupt the cycle of transmission, thereby preventing disease.

The phosphatidylinositol derivative PI3P is a key second messenger that regulates multiple cellular processes, particularly membrane trafficking and autophagy. We report here that PikA, a T4SS substrate of R. rickettsii , functions as a PI-3 kinase that catalyzes the production of PI3P to promote autophagy influx. PikA achieves this by recruiting Beclin 1 through direct protein-protein interactions. The expression of the dual-specific PI phosphatase Myotubularin counteracted the effects of PikA and inhibited intracellular R . rickettsii replication. Our results reveal that the modulation of PI metabolism by a bacterial PI-3 kinase is critical for R . rickettsii virulence, and this pathway may provide potential target for the development of therapeutics against infections caused by this pathogen.

Leptospirosis is a globally significant severe infectious disease that affects a range of mammals. To understand its complex aetiopathogenesis, spp. are classified as pathogenic or saprophytic, with serum resistance a key differentiator of virulence. LIC13259 is a leptospiral surface lipoprotein that binds C8 of the host complement system; however, the molecular basis of this interaction has remained unclear. AlphaFold2 structural predictions, together with protein engineering, biochemical, and immunological validations, revealed that LIC13259 binds specifically to the C8γ subunit via thiol-disulfide exchange. Binding assays confirmed that LIC13259 from pathogenic, but not saprophytic, adheres to C8γ, preventing C8α binding, and enabling membrane attack complex evasion. Substitution of cysteine-133 with an alanine abolished both C8γ binding and complement inhibition. Removal (alanine substitution) of the target cysteine from C8γ prevented pathogenic LIC13259 binding, whereas removing LIC13259 cysteine-108, which forms a predicted intramolecular disulfide bond with cysteine-133, enhanced C8γ binding. These results identify an unprecedented cross-kingdom intermolecular disulfide bond mediating complement evasion and highlight the value of AlphaFold structural modeling, combined with targeted mutagenesis and biochemical validation, for discovering host-pathogen protein-protein interactions. The discovery of this novel immune evasion mechanism may allow recognition of this unique host-pathogen interaction in a range of diseases, while therapeutics and vaccines targeting such cross-kingdom disulfide-mediated mimicry may enable future infectious disease control. Leptospirosis is a globally important zoonotic disease of humans and animals, caused by the bacteria Leptospira. A central determinant of virulence is the ability for these bacteria to evade complement, a host defense system that assembles the membrane attack complex to eliminate pathogens. Here, we elucidate a novel immune evasion mechanism in which the leptospiral surface protein LIC13259 forms a disulfide bond with complement component C8γ, preventing binding of C8α. This interaction disrupts the membrane attack complex assembly and promotes bacterial survival. To our knowledge, this represents the first example of a cross-kingdom disulfide bond mediating bacterial pathogenesis. These findings provide novel insights into leptospiral immune modulation and demonstrate the power of AlphaFold-based structural predictions to reveal unique host-pathogen interactions.

A/H5N1 influenza A viruses continue to pose a pandemic threat to humans. Recent infection of dairy cattle and poultry with A/H5N1 in the USA has magnified that concern. We determined the level of antibodies that recognize A/H5N1 hemagglutinin (HA) and neuraminidase (NA) proteins in a population in Baltimore, MD. We show that while low levels of H5 HA-binding and A/H5N1-neutralizing antibodies are present, there is a significantly stronger recognition of bovine N1 NA. Vaccines that target the N1 NA protein may induce protective antibody responses in humans due to the presence of cross-reactive human N1 NA antibodies.