Biology subjects

Chou, S.

Publications and source records attributed to Chou, S..

At least 19 recordsLinked to original sources

bioRxiv2025

Therapeutic Inhibition of Metalloproteases by Tetracyclines during Infection by Multi-Drug Resistant Pseudomonas

IntroductionBoth host and microbial proteases contribute to the destruction of tissue during Pseudomonas aeruginosa pulmonary infections. We previously reported that beneficial therapeutic effects of metalloprotease inhibitors in Pseudomonas aeruginosa pulmonary infections are not only from targeting the host matrix metalloproteases, the intended target, but also from cross-inhibition of the secreted bacterial metalloprotease LasB. MethodsWe used computation modeling and biochemical assays to investigate whether doxycycline and other structurally-related antibiotics of the tetracycline family inhibit the Pseudomonas protease, LasB. Modeling infection in vitro with human neutrophils and in vivo with a murine model of pulmonary infection, we investigate the effect of on tetracyclines inhibit LasB activity, bacterial survival, and inflammation. ResultsTetracycline, doxycycline, minocycline, and sanocycline all inhibit proteolysis by Pseudomonas LasB. At sub-antimicrobial concentrations, this sensitizes the bacterium killing by neutrophils. During pulmonary infection, tetracyclines significantly reduce pathological inflammation in the lung. ConclusionsOur study shows that tetracycline-family antibiotics, known inhibitors of mammalian matrix metalloproteinases, also inhibit LasB and have beneficial anti-inflammatory activity during infections by extensively drug-resistant P. aeruginosa. By controlling pathological host inflammation, inhibiting bacterial virulence factors, and directly killing bacteria, tetracyclines can have tripartite therapeutic benefits.

microbiology↗

bioRxiv2025

Butyrolactol A is a phospholipid flippase inhibitor that potentiates the bioactivity of caspofungin against resistant fungi

Fungal infections cause millions of deaths annually and are challenging to treat due to limited therapeutic options and rising resistance. Cryptococci are intrinsically resistant to the latest generation of antifungals, echinocandins, while Candida auris, a notorious global threat, is also increasingly resistant. We performed a natural product extract screen to rescue caspofungin fungicidal activity against Cryptococcus neoformans H99 and identified butyrolactol A, which restores echinocandin efficacy against resistant fungal pathogens, including multidrug-resistant C. auris. Mode of action studies revealed that butyrolactol A inhibits the phospholipid flippase Apt1-Cdc50, blocking phospholipid transport. Cryo-electron microscopy analysis of the Apt1*butyrolactol A complex revealed that the flippase is trapped in a dead-end state. Apt1 inhibition disrupts membrane asymmetry, vesicular trafficking, and cytoskeletal organization, thereby enhancing echinocandin uptake and potency. This study identifies lipid flippases as promising antifungal targets and demonstrates the potential of revisiting natural products to expand the antifungal arsenal and combat resistance.

biochemistry↗

bioRxiv2024

Nebulized 2-deoxylated glucose analogues inhibit respiratory viral infection in advanced in vitro airway models

Respiratory viral infections caused by rhinoviruses (RVs), influenza A virus (IAV) and endemic corona viruses (HCoV) result in a serious strain on healthcare systems and public health, underscoring an urgent need for inhaled broad-spectrum antiviral therapies. However, their development is challenging, as no standardized in vitro methodologies that can fully replicate the in vivo environment have been established. In this work, we aimed to investigate the antiviral and anti-inflammatory effect of three 2-deoxylated glucose analogues (2-DGA): 2-deoxy-D-glucose, 2-fluoro-2-dexoy-D-glucose and 2-fluoro-2-dexoy-D-mannose (2-FDM), by utilizing advanced in vitro air-liquid interface (ALI) airway models. We demonstrated that commonly used ALI models have variable susceptibility to RV, IAV and HCoV infection. Further, we showed that 2-DGA have an anti-inflammatory effect and suppress respiratory viral replication in models mimicking the upper and lower respiratory airways. Moreover, we confirmed that 2-DGA can be delivered via nebulization in vitro, highlighting their potential to be used as broad-spectrum inhaled antivirals. Finally, our results demonstrate the importance of incorporating complex in vitro methodologies, such as primary cell ALI cultures and aerosol exposure, at an early stage of drug development.

microbiology↗

bioRxiv2024

P66 is a bacterial mimic of CD47 that binds the anti-phagocytic receptor SIRPα and facilitates macrophage evasion by Borrelia burgdorferi

Summary ParagraphInnate immunity, the first line of defense against pathogens, relies on efficient elimination of invading agents by phagocytes. In the co-evolution of host and pathogen, pathogens developed mechanisms to dampen and evade phagocytic clearance. Here, we report that bacterial pathogens can evade clearance by macrophages through mimicry at the mammalian anti-phagocytic "dont eat me" signaling axis between CD47 (ligand) and SIRP (receptor). We identified a protein, P66, on the surface of Borrelia burgdorferi that, like CD47, is necessary and sufficient to bind the macrophage receptor SIRP. Expression of the gene encoding the protein is required for bacteria to bind SIRP or a high-affinity CD47 reagent. Genetic deletion of p66 increases phagocytosis by macrophages. Blockade of P66 during infection promotes clearance of the bacteria. This study demonstrates that mimicry of the mammalian anti-phagocytic protein CD47 by B. burgdorferi inhibits macrophage-mediated bacterial clearance. Such a mechanism has broad implications for understanding of host-pathogen interactions and expands the function of the established innate immune checkpoint receptor SIRP. Moreover, this report reveals P66 as a novel therapeutic target in the treatment of Lyme Disease.

immunology↗

bioRxiv2023

Tropomyosin 1 deficiency facilitates cell state transitions and enhances hemogenic endothelial cell specification during hematopoiesis

Tropomyosins coat actin filaments and impact actin-related signaling and cell morphogenesis. Genome-wide association studies have linked Tropomyosin 1 (TPM1) with human blood trait variation. Prior work suggested that TPM1 regulated blood cell formation in vitro, but it was unclear how or when TPM1 affected hematopoiesis. Using gene-edited induced pluripotent stem cell (iPSC) model systems, TPM1 knockout was found to augment developmental cell state transitions, as well as TNF and GTPase signaling pathways, to promote hemogenic endothelial (HE) cell specification and hematopoietic progenitor cell (HPC) production. Single-cell analyses showed decreased TPM1 expression during human HE specification, suggesting that TPM1 regulated in vivo hematopoiesis via similar mechanisms. Indeed, analyses of a TPM1 gene trap mouse model showed that TPM1 deficiency enhanced the formation of HE during embryogenesis. These findings illuminate novel effects of TPM1 on developmental hematopoiesis.

cell biology↗

bioRxiv2023

Terminal type-specific cannabinoid CB1 receptor alterations in patients with schizophrenia: a pilot study

BackgroundIndividuals with schizophrenia are at elevated genetic risks for comorbid cannabis use, and often experience exacerbations of cognitive and psychotic symptoms when exposed to cannabis. These findings have led a number of investigators to examine cannabinoid CB1 receptor (CB1R) alterations in schizophrenia, though with conflicting results. We recently demonstrated the presence of CB1R in both excitatory and inhibitory boutons in the human prefrontal cortex, with differential levels of the receptor between bouton types. We hypothesized that the differential enrichment of CB1R between bouton types - a factor previously unaccounted for when examining CB1R changes in schizophrenia - may resolve prior discrepant reports and increase our insight into the effects of CB1R alterations on the pathophysiology of schizophrenia. MethodsUsing co-labeling immunohistochemistry and fluorescent microscopy, we examined total CB1R levels and CB1R levels within excitatory (vGlut1-positive) and inhibitory (vGAT-positive) boutons of prefrontal cortex samples from ten pairs of individuals diagnosed with schizophrenia and non-psychiatric comparisons. ResultsSignificantly higher total CB1R levels were found within samples from individuals with schizophrenia. Terminal type-specific analyses identified significantly higher CB1R levels within excitatory boutons in samples from individuals with schizophrenia relative to comparisons. In contrast, CB1R levels within the subset of inhibitory boutons that normally express high CB1R levels (presumptive cholecystokinin neuron boutons) were lower in samples from individuals with schizophrenia relative to comparison samples. ConclusionGiven CB1Rs role in suppressing neurotransmission upon activation, these results suggest an overall shift in excitatory and inhibitory balance regulation toward a net reduction of excitatory activity in schizophrenia.

neuroscience↗

bioRxiv2023

Lipopolysaccharide integrity primes bacterial sensitivity to a cell wall-degrading intermicrobial toxin

Gram-negative bacteria can antagonize neighboring microbes using a type VI secretion system (T6SS) to deliver toxins that target different essential cellular features. Despite the conserved nature of these targets, T6SS potency can vary across recipient species. To understand the molecular basis of intrinsic T6SS susceptibility, we screened for essential Escherichia coli genes that affect its survival when antagonized by a cell wall-degrading T6SS toxin from Pseudomonas aeruginosa, Tae1. We revealed genes associated with both the cell wall and a separate layer of the cell envelope, surface lipopolysaccharide, that modulate Tae1 toxicity in vivo. Disruption of lipopolysaccharide synthesis provided Escherichia coli (Eco) with novel resistance to Tae1, despite significant cell wall degradation. These data suggest that Tae1 toxicity is determined not only by direct substrate damage, but also by indirect cell envelope homeostasis activities. We also found that Tae1-resistant Eco exhibited reduced cell wall synthesis and overall slowed growth, suggesting that reactive cell envelope maintenance pathways could promote, not prevent, self-lysis. Together, our study highlights the consequences of co-regulating essential pathways on recipient fitness during interbacterial competition, and how antibacterial toxins leverage cellular vulnerabilities that are both direct and indirect to their specific targets in vivo.

microbiology↗

bioRxiv2022

Longitudinal map of transcriptome changes in the Lyme pathogen Borrelia burgdorferi during tick-borne transmission

Borrelia burgdorferi (Bb), the causative agent of Lyme disease, adapts to vastly different environments as it cycles between tick vector and vertebrate host. During a tick bloodmeal, Bb alters its gene expression to prepare for vertebrate infection; however, the full range of transcriptional changes that occur over several days inside of the tick are technically challenging to capture. We developed an experimental approach to enrich Bb cells to longitudinally define their global transcriptomic landscape inside nymphal Ixodes scapularis ticks during a transmitting bloodmeal. We identified 192 Bb genes that substantially change expression over the course of the bloodmeal from one to four days after host attachment. The majority of upregulated genes encode proteins found at the cell envelope or proteins of unknown function, including 45 outer surface lipoproteins embedded in the unusual protein-rich coat of Bb. As these proteins may facilitate Bb interactions with the host, we utilized mass spectrometry to identify candidate tick proteins that physically associate with Bb. The Bb enrichment methodology along with the ex vivo Bb transcriptomes and candidate tick interacting proteins presented here provide a resource to facilitate investigations into key determinants of Bb priming and transmission during the tick stage of its unique transmission cycle.

microbiology↗

bioRxiv2022

mNGS Investigation of Single Ixodes pacificus Ticks Reveals Diverse Microbes, Viruses, and a Novel mRNA-like Endogenous Viral Elements

Ticks are increasingly important vectors of human and agricultural diseases. While many studies have focused on tick-borne bacteria, far less is known about tick-associated viruses and their roles in public health or tick physiology. To address this, we investigated patterns of bacterial and viral communities across two field populations of western black-legged ticks (Ixodes pacificus). Through metatranscriptomic analysis of 100 individual ticks, we quantified taxon prevalence, abundance, and co-occurrence with other members of the tick microbiome. Our analysis revealed 11 novel RNA viruses from Rhabdoviridae, Chuviridae, Picornaviridae, Phenuiviridae, Reoviridae, Solemovidiae, Narnaviridae, and 2 highly divergent RNA viruses lacking sequence similarity to known viral families. The majority of these viruses were also detectable in lab-raised ticks at all developmental life stages, localize to tick salivary glands, and show evidence of circulation in mice fed on by ticks. These data suggest that viruses are stable, heritable, and transmissible members of the tick microbiota. We also unexpectedly identified numerous virus-like transcripts that are associated with tick genomic DNA, most of which are distinct from known endogenous viral element-mediated immunity pathways in invertebrates. Together, our work reveals that in addition to potentially serving as vectors for potential viral pathogens, I. pacificus ticks may also have symbiotic partnerships with their own vertically-transmitted viruses or with ancient viruses through evolutionarily acquired virus-like transcripts. Our findings highlight how pervasive and intimate tick-virus interactions are, with major implications for both the fundamental physiology and vector biology of I. pacificus ticks.

microbiology↗

bioRxiv2022

Host-directed therapy with 2-Deoxy-D-glucose inhibits human rhinoviruses, endemic coronaviruses, and SARS-CoV-2

Rhinoviruses (RVs) and coronaviruses (CoVs) upregulate host cell metabolic pathways such as glycolysis to meet their bioenergetic demands for rapid multiplication. Using the glycolysis inhibitor 2-deoxy-D-glucose (2-DG), we assessed the dose-dependent inhibition of viral replication of minor- and major-receptor group RVs in epithelial cells. 2-DG disrupted RV infection cycle by inhibiting template negative-strand as well as genomic positive-strand RNA synthesis, resulting in less progeny virus and RV-mediated cell death. Assessment of 2-DGs intracellular kinetics revealed that after a short-exposure to 2-DG, the active intermediate, 2-DG6P, is stored intracellularly for several hours. Finally, we confirmed the antiviral effect of 2-DG on pandemic SARS-CoV-2 and showed for the first time that 2-DG also reduces replication of endemic human coronaviruses (HCoVs). These results provide further evidence that 2-DG could be utilized as a broad-spectrum antiviral. HIGHLIGHTSO_LI2-DG inhibits replication of minor- and major-group rhinoviruses in epithelial cells including human nasal epithelial cell. C_LIO_LI2-DG disrupts rhinovirus infection cycle and reduces rhinovirus-mediated cell death in vitro. C_LIO_LI2-DG treatment attenuates viral load of endemic coronaviruses in vitro. C_LI

microbiology↗

bioRxiv2022

Label-free three-photon imaging of intact human cerebral organoids: tracking early events in brain development and deficits in Rett Syndrome

Human cerebral organoids are unique in their development of progenitor-rich zones akin to ventricular zones from which neuronal progenitors differentiate and migrate radially. Analyses of cerebral organoids thus far have been performed in sectioned tissue or in superficial layers due to their high scattering properties. Here, we demonstrate label-free three-photon imaging of whole, uncleared intact organoids ([~]2 mm depth) to assess early events of early human brain development. Optimizing a custom-made three-photon microscope to image intact cerebral organoids generated from Rett Syndrome patients, we show defects in the ventricular zone volumetric structure of mutant organoids compared to isogenic control organoids. Long-term imaging live organoids reveals that shorter migration distances and slower migration speeds of mutant radially migrating neurons are associated with more tortuous trajectories. Our label-free imaging system constitutes a particularly useful platform for tracking normal and abnormal development in individual organoids, as well as for screening therapeutic molecules via intact organoid imaging.

neuroscience↗

bioRxiv2022

Substrate topology and cognate immunity modulate antibacterial toxicity of Tae cell wall hydrolases

Members of the bacterial T6SS amidase effector (Tae) superfamily of toxins are delivered between competing bacteria to degrade cell wall peptidoglycan. Although Taes share a common substrate, they exhibit distinct antimicrobial potency across different competitor species. To investigate the molecular basis governing these differences, we quantitatively defined the functional determinants of Tae1 from Pseudomonas aeruginosa PAO1 using a combination of nuclear magnetic resonance (NMR) and a high-throughput in vivo genetic approach called deep mutational scanning (DMS). As expected, combined analyses confirmed the role of critical residues near the Tae1 catalytic center. Unexpectedly, DMS revealed substantial contributions to enzymatic activity from a much larger, ring-like functional hot spot extending around the entire circumference of the enzyme. Comparative DMS across distinct growth conditions highlighted how functional contribution of different surfaces is highly context-dependent, varying alongside composition of targeted cell walls. These observations suggest that Tae1 engages with the intact cell wall network through a more distributed three-dimensional interaction interface than previously appreciated, providing an explanation for observed differences in antimicrobial potency across divergent Gram-negative competitors. Further binding studies of several Tae1 variants with their cognate immunity protein demonstrate that requirements to maintain protection from Tae activity may be a significant constraint on the mutational landscape of tae1 toxicity in the wild. In total, our work reveals that Tae diversification has likely been shaped by multiple independent pressures to maintain interactions with binding partners that vary across bacterial species and conditions.

biochemistry↗

bioRxiv2021

Structural and molecular rationale for the diversification of resistance mediated by the Antibiotic_NAT family

The environmental microbiome harbors a vast repertoire of antibiotic resistance genes (ARGs) which can serve as evolutionary predecessors for ARGs found in pathogenic bacteria, or can be directly mobilized to pathogens in the presence of selection pressures. Thus, ARGs from benign environmental bacteria are an important resource for understanding clinically relevant resistance. Here, we conduct a comprehensive functional analysis of the Antibiotic_NAT family of aminoglycoside acetyltransferases. We determined a pan-family antibiogram of 21 Antibiotic_NAT enzymes, including 8 derived from clinical isolates and 13 from environmental metagenomic samples. We find that environment-derived representatives confer high-level, broad-spectrum resistance, including against the atypical aminoglycoside apramycin, and that a metagenome-derived gene likely is ancestral to an AAC(3) gene found in clinical isolates. Through crystallographic analysis, we rationalize the molecular basis for diversification of substrate specificity across the family. This work provides critical data on the molecular mechanism underpinning resistance to established and emergent aminoglycoside antibiotics and broadens our understanding of ARGs in the environment.

microbiology↗

bioRxiv2021

Hematopoiesis at single cell resolution spanning human development and maturation

Hematopoiesis is a process of constitutive regeneration whereby hematopoietic stem and progenitor cells (HSPCs) replenish mature blood cells. During maturation and aging, HSPCs shift their output to support the demands of prenatal development and postnatal maturation both at homeostasis and in response to stress. How HSPC ontogeny changes throughout life is unknown; studies to date have largely focused on specific individual ages, particularly at single cell resolution. Here, we performed single cell RNA-seq of human HSPCs from early prenatal development into mature adulthood. We observed shifts in HSPC transcriptional states and differentiation trajectories over time. We identified age-specific gene expression patterns throughout human maturation and developed methods for identifying, prospectively purifying, and functionally validating age-specific HSC states. Together, our findings define the temporal maturation of human HSPCs and uncover principles applicable to age-biased blood diseases. SummarySingle cell RNA sequencing reveals that the mechanisms of human hematopoietic stem and progenitor cell (HSPC) fate commitment change over a lifetime from gestation to mature adulthood.

developmental biology↗

bioRxiv2021

The STING ligand 2'3'-cGAMP induces an NF-κB-dependent anti-bacterial innate immune response in the starlet sea anemone Nematostella vectensis

In mammals, cyclic dinucleotides (CDNs) bind and activate STING to initiate an anti-viral type I interferon response. CDNs and STING originated in bacteria and are present in most animals. By contrast, interferons are believed to have emerged in vertebrates; thus, the function of CDN signaling in invertebrates is unclear. Here, we use a CDN, 23-cGAMP, to activate immune responses in a model cnidarian invertebrate, the starlet sea anemone Nematostella vectensis. Using RNA-Seq, we found that 23-cGAMP induces robust transcription of both anti-viral and anti-bacterial genes in N. vectensis. Many of the anti-viral genes induced by 23-cGAMP are homologs of vertebrate interferon stimulated genes, implying that the interferon response predates the evolution of interferons. Knockdown experiments identified a role for NF-{kappa}B in specifically inducing anti-bacterial genes downstream of 23-cGAMP. Some of these putative anti-bacterial genes were also found to be induced during Pseudomonas aeruginosa infection. We characterized the protein product of one of the putative anti-bacterial genes, the N. vectensis homolog of Dae4, and found that it has conserved anti-bacterial activity. This work suggests that a broad anti-bacterial and anti-viral transcriptional response is an evolutionarily ancestral output of 23-cGAMP signaling in animals. Significance statementCyclic dinucleotides are signaling molecules that originated in bacteria and were subsequently acquired and co-opted by animals for immune signaling. The major cyclic dinucleotide signaling pathway in mammals results in the production of anti-viral molecules called interferons. Invertebrates such as sea anemones lack interferons, and thus it was unclear whether cyclic dinucleotide signaling would play a role in immunity in these animals. Here we report that in the anemone Nematostella vectensis, cyclic dinucleotides activate both anti-viral and anti-bacterial immune responses, and do so through a conserved pathway. These results provide insights into the evolutionary origins of innate immunity, and suggest a broader ancestral role for cyclic dinucleotide signaling that evolved toward more specialized anti-viral functions in mammals.

immunology↗

bioRxiv2021

Lizard feeding enhances Ixodes pacificus vector competency

A vectors susceptibility and ability to transmit a pathogen-- termed vector competency--determines disease outcomes, yet the ecological factors influencing tick vector competency remain largely unknown. Ixodes pacificus, the vector of Borrelia burgdorferi (Bb) in the western U.S., feeds on rodents, birds, and lizards. While rodents and birds are reservoirs for Bb and infect juvenile ticks, lizards are Bb-refractory. Despite I. pacificus feeding on a range of hosts, it is undetermined how larval host bloodmeal identity affects future nymphal vector competency. We experimentally evaluate the influence of larval host bloodmeal on Bb acquisition by nymphal I. pacificus. Larval I. pacificus were fed on either lizards or mice and after molting, nymphs were fed on Bb-infected mice. We found that lizard-fed larvae were significantly more likely to become infected with Bb during their next bloodmeal than mouse-fed larvae. We also conducted the first RNA-seq analysis on whole-bodied I. pacificus and found significant upregulation of antioxidants and antimicrobial peptides in the lizard-fed group. Our results indicate that the lizard bloodmeal significantly alters vector competency and gene regulation in ticks, highlighting the importance of host bloodmeal identity in disease transmission and upends prior notions about the role of lizards in Lyme disease transmission.

ecology↗

bioRxiv2020

Ceragenins and antimicrobial peptides kill bacteria through distinct mechanisms

Ceragenins are a family of synthetic amphipathic molecules designed to mimic the properties of naturally-occurring cationic antimicrobial peptides (CAMPs). Although ceragenins have potent antimicrobial activity, whether their mode of action is similar to that of CAMPs has remained elusive. Here we report the results of a comparative study of the bacterial responses to two well-studied CAMPs, LL37 and colistin, and two ceragenins with related structures, CSA13 and CSA131. Using transcriptomic and proteomic analyses, we found that Escherichia coli responds similarly to both CAMPs and ceragenins by inducing a Cpx envelope stress response. However, whereas E. coli exposed to CAMPs increased expression of genes involved in colanic acid biosynthesis, bacteria exposed to ceragenins specifically modulated functions related to phosphate transport, indicating distinct mechanisms of action between these two classes of molecules. Although traditional genetic approaches failed to identify genes that confer high-level resistance to ceragenins, using a Clustered Regularly Interspaced Short Palindromic Repeats interference (CRISPRi) approach we identified E. coli essential genes that when knocked down modify sensitivity to these molecules. Comparison of the essential gene-antibiotic interactions for each of the CAMPs and ceragenins identified both overlapping and distinct dependencies for their antimicrobial activities. Overall, this study indicates that while some bacterial responses to ceragenins overlap with those induced by naturally-occurring CAMPs, these synthetic molecules target the bacterial envelope using a distinctive mode of action. IMPORTANCEThe development of novel antibiotics is essential since the current arsenal of antimicrobials will soon be ineffective due to the widespread occurrence of antibiotic resistance. Development of naturally-occurring cationic antimicrobial peptides (CAMPs) for therapeutics to combat antibiotic resistance has been hampered by high production costs and protease sensitivity, among other factors. The ceragenins are a family of synthetic CAMP mimics that kill a broad spectrum of bacterial species but are less expensive to produce, resistant to proteolytic degradation and have been associated with low levels of resistance. Determining how ceragenins function may identify new essential biological pathways of bacteria that are less prone to development of resistance and will further our understanding of the design principles for maximizing the effects of synthetic CAMPs.

microbiology↗

bioRxiv2020

Immune factor of bacterial origin protects ticks against host microbial commensals

Hard ticks are blood-feeding arthropods that carry and transmit microbes to their vertebrate hosts1. Tick-borne disease cases have been on the rise over the last several decades, drawing much-needed attention to the molecular interplay between transmitted pathogens and their human hosts. However, far less is known about how ticks control their own microbes, which is critical for understanding how zoonotic transmission cycles persist. We previously found that ticks horizontally acquired an antimicrobial toxin gene from bacteria known as domesticated amidase effector 2 (dae2)2. Here we show that this effector from the tick vector Ixodes scapularis (Dae2Is) has structurally and biochemically diverged from ancestral bacterial representatives, expanding its antibacterial targeting range to include host skin microbes. Disruption of dae2Is increases the burden of skin-associated staphylococci within I. scapularis and adversely affects tick fitness, suggesting resistance of host microbes may be important for the parasitic blood-feeding lifestyle. In contrast, Dae2Is has no intrinsic ability to kill Borrelia burgdorferi, the tick-borne bacterium of Lyme disease. Our observations suggest that ticks have evolved to tolerate their own symbionts while resisting host skin commensals, which we discover are natural opportunistic pathogens of ticks. This work moves our understanding of vector biology beyond a human-centric view: just as tick commensals are pathogenic to humans, so too do our commensals pose a threat to ticks. These observations illuminate how a complex and mirrored set of interkingdom interactions between blood-feeding vectors, their hosts, and associated microbes can ultimately lead to disease.

evolutionary biology↗