Publications by authors named "Joao H F Pedra"

46 Publications

Tick extracellular vesicles enable arthropod feeding and promote distinct outcomes of bacterial infection.

Nat Commun 2021 06 17;12(1):3696. Epub 2021 Jun 17.

Department of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA.

Extracellular vesicles are thought to facilitate pathogen transmission from arthropods to humans and other animals. Here, we reveal that pathogen spreading from arthropods to the mammalian host is multifaceted. Extracellular vesicles from Ixodes scapularis enable tick feeding and promote infection of the mildly virulent rickettsial agent Anaplasma phagocytophilum through the SNARE proteins Vamp33 and Synaptobrevin 2 and dendritic epidermal T cells. However, extracellular vesicles from the tick Dermacentor andersoni mitigate microbial spreading caused by the lethal pathogen Francisella tularensis. Collectively, we establish that tick extracellular vesicles foster distinct outcomes of bacterial infection and assist in vector feeding by acting on skin immunity. Thus, the biology of arthropods should be taken into consideration when developing strategies to control vector-borne diseases.
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http://dx.doi.org/10.1038/s41467-021-23900-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211691PMC
June 2021

Grappling with the tick microbiome.

Trends Parasitol 2021 08 4;37(8):722-733. Epub 2021 May 4.

Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06420, USA.

Ixodes scapularis and Ixodes pacificus are the predominant vectors of multiple human pathogens, including Borrelia burgdorferi, one of the causative agents of Lyme disease in North America. Differences in the habitats and host preferences of these closely related tick species present an opportunity to examine key aspects of the tick microbiome. While advances in sequencing technologies have accelerated a descriptive understanding of the tick microbiome, molecular and mechanistic insights into the tick microbiome are only beginning to emerge. Progress is stymied by technical difficulties in manipulating the microbiome and by biological variables related to the life cycle of Ixodid ticks. This review highlights these challenges and examines avenues to understand the significance of the tick microbiome in tick biology.
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http://dx.doi.org/10.1016/j.pt.2021.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282638PMC
August 2021

The genus Anaplasma: drawing back the curtain on tick-pathogen interactions.

Pathog Dis 2021 Apr;79(5)

Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA.

Tick-borne illnesses pose a serious concern to human and veterinary health and their prevalence is on the rise. The interactions between ticks and the pathogens they carry are largely undefined. However, the genus Anaplasma, a group of tick-borne bacteria, has been instrumental in uncovering novel paradigms in tick biology. The emergence of sophisticated technologies and the convergence of entomology with microbiology, immunology, metabolism and systems biology has brought tick-Anaplasma interactions to the forefront of vector biology with broader implications for the infectious disease community. Here, we discuss the use of Anaplasma as an instrument for the elucidation of novel principles in arthropod-microbe interactions. We offer an outlook of the primary areas of study, outstanding questions and future research directions.
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http://dx.doi.org/10.1093/femspd/ftab022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062235PMC
April 2021

Ticks Resist Skin Commensals with Immune Factor of Bacterial Origin.

Cell 2020 12;183(6):1562-1571.e12

Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA; Chan Zuckerberg Biohub, San Francisco, CA. Electronic address:

Ticks transmit a diverse array of microbes to vertebrate hosts, including human pathogens, which has led to a human-centric focus in this vector system. Far less is known about pathogens of ticks themselves. Here, we discover that a toxin in blacklegged ticks (Ixodes scapularis) horizontally acquired from bacteria-called domesticated amidase effector 2 (dae2)-has evolved to kill mammalian skin microbes with remarkable efficiency. Secreted into the saliva and gut of ticks, Dae2 limits skin-associated staphylococci in ticks while feeding. In contrast, Dae2 has no intrinsic ability to kill Borrelia burgdorferi, the tick-borne Lyme disease bacterial pathogen. These findings suggest ticks resist their own pathogens while tolerating symbionts. Thus, just as tick symbionts can be pathogenic to humans, mammalian commensals can be harmful to ticks. Our study underscores how virulence is context-dependent and bolsters the idea that "pathogen" is a status and not an identity.
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http://dx.doi.org/10.1016/j.cell.2020.10.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034492PMC
December 2020

Epigenetic Regulation of Tick Biology and Vectorial Capacity.

Trends Genet 2021 01 2;37(1):8-11. Epub 2020 Oct 2.

Department of Veterinary Medicine, University of Maryland, College Park, MD, USA; Virginia-Maryland College of Veterinary Medicine, College Park, MD, USA. Electronic address:

Ticks exist across diverse environments and transmit numerous pathogens. Due to their long and unique life cycles, these arthropods likely evolved robust epigenetic mechanisms that provide sustainable responses and buffers against extreme environmental conditions. Herein, we highlight how the study of the epigenetic basis of tick biology and vectorial capacity will enrich our knowledge of tick-borne infections.
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http://dx.doi.org/10.1016/j.tig.2020.09.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008791PMC
January 2021

Immunometabolism in Arthropod Vectors: Redefining Interspecies Relationships.

Trends Parasitol 2020 10 18;36(10):807-815. Epub 2020 Aug 18.

Department of Microbiology and Immunology, School of Medicine, University of Maryland, Baltimore, MD, USA. Electronic address:

Metabolism influences biochemical networks, and arthropod vectors are endowed with an immune system that affects microbial acquisition, persistence, and transmission to humans and other animals. Here, we aim to persuade the scientific community to expand their interests in immunometabolism beyond mammalian hosts and towards arthropod vectors. Immunometabolism investigates the interplay of metabolism and immunology. We provide a conceptual framework for investigators from diverse disciplines and indicate that relationships between microbes, mammalian hosts and their hematophagous arthropods may result in cost-effective (mutualism) or energetically expensive (parasitism) interactions. We argue that disparate resource allocations between species may partially explain why some microbes act as pathogens when infecting humans and behave as mutualistic or commensal organisms when colonizing arthropod vectors.
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http://dx.doi.org/10.1016/j.pt.2020.07.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897511PMC
October 2020

Interactions between Borrelia burgdorferi and ticks.

Nat Rev Microbiol 2020 10 10;18(10):587-600. Epub 2020 Jul 10.

Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.

Borrelia burgdorferi is the causative agent of Lyme disease and is transmitted to vertebrate hosts by Ixodes spp. ticks. The spirochaete relies heavily on its arthropod host for basic metabolic functions and has developed complex interactions with ticks to successfully colonize, persist and, at the optimal time, exit the tick. For example, proteins shield spirochaetes from immune factors in the bloodmeal and facilitate the transition between vertebrate and arthropod environments. On infection, B. burgdorferi induces selected tick proteins that modulate the vector gut microbiota towards an environment that favours colonization by the spirochaete. Additionally, the recent sequencing of the Ixodes scapularis genome and characterization of tick immune defence pathways, such as the JAK-STAT, immune deficiency and cross-species interferon-γ pathways, have advanced our understanding of factors that are important for B. burgdorferi persistence in the tick. In this Review, we summarize interactions between B. burgdorferi and I. scapularis during infection, as well as interactions with tick gut and salivary gland proteins important for establishing infection and transmission to the vertebrate host.
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http://dx.doi.org/10.1038/s41579-020-0400-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351536PMC
October 2020

Protective Immunity and New Vaccines for Lyme Disease.

Clin Infect Dis 2020 04;70(8):1768-1773

Department of Medicine, Rutgers New Jersey Medical School, Newark, New Jersey, USA.

Lyme disease, caused by some Borrelia burgdorferi sensu lato, is the most common tick-borne illness in the Northern Hemisphere and the number of cases, and geographic spread, continue to grow. Previously identified B. burgdorferi proteins, lipid immunogens, and live mutants lead the design of canonical vaccines aimed at disrupting infection in the host. Discovery of the mechanism of action of the first vaccine catalyzed the development of new strategies to control Lyme disease that bypassed direct vaccination of the human host. Thus, novel prevention concepts center on proteins produced by B. burgdorferi during tick transit and on tick proteins that mediate feeding and pathogen transmission. A burgeoning area of research is tick immunity as it can unlock mechanistic pathways that could be targeted for disruption. Studies that shed light on the mammalian immune pathways engaged during tick-transmitted B. burgdorferi infection would further development of vaccination strategies against Lyme disease.
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http://dx.doi.org/10.1093/cid/ciz872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7155782PMC
April 2020

Message in a vesicle - trans-kingdom intercommunication at the vector-host interface.

J Cell Sci 2019 03 18;132(6). Epub 2019 Mar 18.

Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA

Vector-borne diseases cause over 700,000 deaths annually and represent 17% of all infectious illnesses worldwide. This public health menace highlights the importance of understanding how arthropod vectors, microbes and their mammalian hosts interact. Currently, an emphasis of the scientific enterprise is at the vector-host interface where human pathogens are acquired and transmitted. At this spatial junction, arthropod effector molecules are secreted, enabling microbial pathogenesis and disease. Extracellular vesicles manipulate signaling networks by carrying proteins, lipids, carbohydrates and regulatory nucleic acids. Therefore, they are well positioned to aid in cell-to-cell communication and mediate molecular interactions. This Review briefly discusses exosome and microvesicle biogenesis, their cargo, and the role that nanovesicles play during pathogen spread, host colonization and disease pathogenesis. We then focus on the role of extracellular vesicles in dictating microbial pathogenesis and host immunity during transmission of vector-borne pathogens.
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http://dx.doi.org/10.1242/jcs.224212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451414PMC
March 2019

p47 licenses activation of the immune deficiency pathway in the tick .

Proc Natl Acad Sci U S A 2019 01 17;116(1):205-210. Epub 2018 Dec 17.

Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201

The E3 ubiquitin ligase X-linked inhibitor of apoptosis (XIAP) acts as a molecular rheostat for the immune deficiency (IMD) pathway of the tick How XIAP activates the IMD pathway in response to microbial infection remains ill defined. Here, we identified the XIAP enzymatic substrate p47 as a positive regulator of the IMD network. XIAP polyubiquitylates p47 in a lysine 63-dependent manner and interacts with the p47 ubiquitin-like (UBX) module. p47 also binds to Kenny (IKKγ/NEMO), the regulatory subunit of the inhibitor of nuclear factor (NF)- κB kinase complex. Replacement of the amino acid lysine to arginine within the p47 linker region completely abrogated molecular interactions with Kenny. Furthermore, mitigation of transcription levels through RNA interference in limited Kenny accumulation, reduced phosphorylation of IKKβ (IRD5), and impaired cleavage of the NF-κB molecule Relish. Accordingly, disruption of expression increased microbial colonization by the Lyme disease spirochete and the rickettsial agent Collectively, we highlight the importance of ticks for the elucidation of paradigms in arthropod immunology. Manipulating immune signaling cascades within may lead to innovative approaches to reducing the burden of tick-borne diseases.
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http://dx.doi.org/10.1073/pnas.1808905116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320499PMC
January 2019

Vector Immunity and Evolutionary Ecology: The Harmonious Dissonance.

Trends Immunol 2018 11 6;39(11):862-873. Epub 2018 Oct 6.

Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA. Electronic address:

Recent scientific breakthroughs have significantly expanded our understanding of arthropod vector immunity. Insights in the laboratory have demonstrated how the immune system provides resistance to infection, and in what manner innate defenses protect against a microbial assault. Less understood, however, is the effect of biotic and abiotic factors on microbial-vector interactions and the impact of the immune system on arthropod populations in nature. Furthermore, the influence of genetic plasticity on the immune response against vector-borne pathogens remains mostly elusive. Herein, we discuss evolutionary forces that shape arthropod vector immunity. We focus on resistance, pathogenicity and tolerance to infection. We posit that novel scientific paradigms should emerge when molecular immunologists and evolutionary ecologists work together.
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http://dx.doi.org/10.1016/j.it.2018.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218297PMC
November 2018

Deviant Behavior: Tick-Borne Pathogens and Inflammasome Signaling.

Vet Sci 2016 Sep 28;3(4). Epub 2016 Sep 28.

Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.

In the face of an assault, host cells mount an immediate response orchestrated by innate immunity. Two of the best described innate immune signaling networks are the Toll- and the Nod-like receptor pathways. Extensive work has been done characterizing both signaling cascades with several recent advances on the forefront of inflammasome biology. In this review, we will discuss how more commonly-studied pathogens differ from tick-transmitted microbes in the context of Nod-like receptor signaling and inflammasome formation. Because pathogens transmitted by ticks have unique characteristics, we offer the opinion that these microbes can be used to uncover novel principles of Nod-like receptor biology.
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http://dx.doi.org/10.3390/vetsci3040027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5606592PMC
September 2016

Engineering of obligate intracellular bacteria: progress, challenges and paradigms.

Nat Rev Microbiol 2017 Sep 19;15(9):544-558. Epub 2017 Jun 19.

Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.

It is estimated that approximately one billion people are at risk of infection with obligate intracellular bacteria, but little is known about the underlying mechanisms that govern their life cycles. The difficulty in studying Chlamydia spp., Coxiella spp., Rickettsia spp., Anaplasma spp., Ehrlichia spp. and Orientia spp. is, in part, due to their genetic intractability. Recently, genetic tools have been developed; however, optimizing the genomic manipulation of obligate intracellular bacteria remains challenging. In this Review, we describe the progress in, as well as the constraints that hinder, the systematic development of a genetic toolbox for obligate intracellular bacteria. We highlight how the use of genetically manipulated pathogens has facilitated a better understanding of microbial pathogenesis and immunity, and how the engineering of obligate intracellular bacteria could enable the discovery of novel signalling circuits in host-pathogen interactions.
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http://dx.doi.org/10.1038/nrmicro.2017.59DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5557331PMC
September 2017

Tick Humoral Responses: Marching to the Beat of a Different Drummer.

Front Microbiol 2017 14;8:223. Epub 2017 Feb 14.

Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore MD, USA.

Ticks transmit a variety of human pathogens, including , the etiological agent of Lyme disease. Multiple pathogens that are transmitted simultaneously, termed "coinfections," are of increasing importance and can affect disease outcome in a host. Arthropod immunity is central to pathogen acquisition and transmission by the tick. Pattern recognition receptors recognize pathogen-associated molecular patterns and induce humoral responses through the Toll and Immune Deficiency (IMD) pathways. Comparative analyses between insects and ticks reveal that while the Toll pathway is conserved, the IMD network exhibits a high degree of variability. This indicates that major differences in humoral immunity exist between insects and ticks. While many variables can affect immunity, one of the major forces that shape immune outcomes is the microbiota. In light of this, we discuss how the presence of commensal bacteria, symbionts and/or coinfections can lead to altered immune responses in the tick that impact pathogen persistence and subsequent transmission. By investigating non-insect arthropod immunity, we will not only better comprehend tick biology, but also unravel the intricate effects that pathogen coinfections have on vector competence and tick-borne disease transmission.
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http://dx.doi.org/10.3389/fmicb.2017.00223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5306392PMC
February 2017

Infection-derived lipids elicit an immune deficiency circuit in arthropods.

Nat Commun 2017 02 14;8:14401. Epub 2017 Feb 14.

Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.

The insect immune deficiency (IMD) pathway resembles the tumour necrosis factor receptor network in mammals and senses diaminopimelic-type peptidoglycans present in Gram-negative bacteria. Whether unidentified chemical moieties activate the IMD signalling cascade remains unknown. Here, we show that infection-derived lipids 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (POPG) and 1-palmitoyl-2-oleoyl diacylglycerol (PODAG) stimulate the IMD pathway of ticks. The tick IMD network protects against colonization by three distinct bacteria, that is the Lyme disease spirochete Borrelia burgdorferi and the rickettsial agents Anaplasma phagocytophilum and A. marginale. Cell signalling ensues in the absence of transmembrane peptidoglycan recognition proteins and the adaptor molecules Fas-associated protein with a death domain (FADD) and IMD. Conversely, biochemical interactions occur between x-linked inhibitor of apoptosis protein (XIAP), an E3 ubiquitin ligase, and the E2 conjugating enzyme Bendless. We propose the existence of two functionally distinct IMD networks, one in insects and another in ticks.
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http://dx.doi.org/10.1038/ncomms14401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5316886PMC
February 2017

For Whom the Bell Tolls (and Nods): Spit-acular Saliva.

Curr Trop Med Rep 2016 Jun 5;3(2):40-50. Epub 2016 Apr 5.

Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA. .

Having emerged during the early part of the Cretaceous period, ticks are an ancient group of hematophagous ectoparasites with significant veterinary and public health importance worldwide. The success of their life strategy can be attributed, in part, to saliva. As we enter into a scientific era where the collection of massive data sets and structures for biological application is possible, we suggest that understanding the molecular mechanisms that govern the life cycle of ticks is within grasp. With this in mind, we discuss what is currently known regarding the manipulation of Toll-like (TLR) and Nod-like (NLR) receptor signaling pathways by tick salivary proteins, and how these molecules impact pathogen transmission.
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http://dx.doi.org/10.1007/s40475-016-0072-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4987094PMC
June 2016

The Prostaglandin E2-EP3 Receptor Axis Regulates Anaplasma phagocytophilum-Mediated NLRC4 Inflammasome Activation.

PLoS Pathog 2016 08 2;12(8):e1005803. Epub 2016 Aug 2.

Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.

Rickettsial agents are sensed by pattern recognition receptors but lack pathogen-associated molecular patterns commonly observed in facultative intracellular bacteria. Due to these molecular features, the order Rickettsiales can be used to uncover broader principles of bacterial immunity. Here, we used the bacterium Anaplasma phagocytophilum, the agent of human granulocytic anaplasmosis, to reveal a novel microbial surveillance system. Mechanistically, we discovered that upon A. phagocytophilum infection, cytosolic phospholipase A2 cleaves arachidonic acid from phospholipids, which is converted to the eicosanoid prostaglandin E2 (PGE2) via cyclooxygenase 2 (COX2) and the membrane associated prostaglandin E synthase-1 (mPGES-1). PGE2-EP3 receptor signaling leads to activation of the NLRC4 inflammasome and secretion of interleukin (IL)-1β and IL-18. Importantly, the receptor-interacting serine/threonine-protein kinase 2 (RIPK2) was identified as a major regulator of the immune response against A. phagocytophilum. Accordingly, mice lacking COX2 were more susceptible to A. phagocytophilum, had a defect in IL-18 secretion and exhibited splenomegaly and damage to the splenic architecture. Remarkably, Salmonella-induced NLRC4 inflammasome activation was not affected by either chemical inhibition or genetic ablation of genes associated with PGE2 biosynthesis and signaling. This divergence in immune circuitry was due to reduced levels of the PGE2-EP3 receptor during Salmonella infection when compared to A. phagocytophilum. Collectively, we reveal the existence of a functionally distinct NLRC4 inflammasome illustrated by the rickettsial agent A. phagocytophilum.
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http://dx.doi.org/10.1371/journal.ppat.1005803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970705PMC
August 2016

The Tick Protein Sialostatin L2 Binds to Annexin A2 and Inhibits NLRC4-Mediated Inflammasome Activation.

Infect Immun 2016 06 24;84(6):1796-1805. Epub 2016 May 24.

Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA

Tick saliva contains a number of effector molecules that inhibit host immunity and facilitate pathogen transmission. How tick proteins regulate immune signaling, however, is incompletely understood. Here, we describe that loop 2 of sialostatin L2, an anti-inflammatory tick protein, binds to annexin A2 and impairs the formation of the NLRC4 inflammasome during infection with the rickettsial agent Anaplasma phagocytophilum Macrophages deficient in annexin A2 secreted significantly smaller amounts of interleukin-1β (IL-1β) and IL-18 and had a defect in NLRC4 inflammasome oligomerization and caspase-1 activation. Accordingly, Annexin a2-deficient mice were more susceptible to A. phagocytophilum infection and showed splenomegaly, thrombocytopenia, and monocytopenia. Providing translational support to our findings, better binding of annexin A2 to sialostatin L2 in sera from 21 out of 23 infected patients than in sera from control individuals was also demonstrated. Overall, we establish a unique mode of inflammasome evasion by a pathogen, centered on a blood-feeding arthropod.
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http://dx.doi.org/10.1128/IAI.01526-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4907130PMC
June 2016

Genomic insights into the Ixodes scapularis tick vector of Lyme disease.

Nat Commun 2016 Feb 9;7:10507. Epub 2016 Feb 9.

Department of Medicine, Division of Infectious Diseases, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.

Ticks transmit more pathogens to humans and animals than any other arthropod. We describe the 2.1 Gbp nuclear genome of the tick, Ixodes scapularis (Say), which vectors pathogens that cause Lyme disease, human granulocytic anaplasmosis, babesiosis and other diseases. The large genome reflects accumulation of repetitive DNA, new lineages of retro-transposons, and gene architecture patterns resembling ancient metazoans rather than pancrustaceans. Annotation of scaffolds representing ∼57% of the genome, reveals 20,486 protein-coding genes and expansions of gene families associated with tick-host interactions. We report insights from genome analyses into parasitic processes unique to ticks, including host 'questing', prolonged feeding, cuticle synthesis, blood meal concentration, novel methods of haemoglobin digestion, haem detoxification, vitellogenesis and prolonged off-host survival. We identify proteins associated with the agent of human granulocytic anaplasmosis, an emerging disease, and the encephalitis-causing Langat virus, and a population structure correlated to life-history traits and transmission of the Lyme disease agent.
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http://dx.doi.org/10.1038/ncomms10507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4748124PMC
February 2016

All For One and One For All on the Tick-Host Battlefield.

Trends Parasitol 2016 05 30;32(5):368-377. Epub 2016 Jan 30.

Institute of Parasitology, Biology Center, Czech Academy of Sciences, Budweis, Czech Republic. Electronic address:

The saliva of ixodid ticks contains a mixture of bioactive molecules that target a wide spectrum of host defense mechanisms to allow ticks to feed on the vertebrate host for several days. Tick salivary proteins cluster in multigenic protein families, and individual family members display redundancy and pluripotency in their action to ameliorate or evade host immune responses. It is now clear that members of different protein families can target the same cellular or molecular pathway of the host physiological response to tick feeding. We present and discuss our hypothesis that redundancy and pluripotency evolved in tick salivary immunomodulators to evade immune recognition by the host while retaining the immunomodulatory potential of their saliva.
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http://dx.doi.org/10.1016/j.pt.2016.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4851932PMC
May 2016

Sialomes and Mialomes: A Systems-Biology View of Tick Tissues and Tick-Host Interactions.

Trends Parasitol 2016 Mar 28;32(3):242-254. Epub 2015 Oct 28.

Institute of Parasitology, Biology Center, Czech Academy of Sciences, Budweis, Czech Republic. Electronic address:

Tick saliva facilitates tick feeding and infection of the host. Gene expression analysis of tick salivary glands and other tissues involved in host-pathogen interactions has revealed a wide range of bioactive tick proteins. Transcriptomic analysis has been a milestone in the field and has recently been enhanced by next-generation sequencing (NGS). Furthermore, the application of quantitative proteomics to ticks with unknown genomes has provided deeper insights into the molecular mechanisms underlying tick hematophagy, pathogen transmission, and tick-host-pathogen interactions. We review current knowledge on the transcriptomics and proteomics of tick tissues from a systems-biology perspective and discuss future challenges in the field.
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http://dx.doi.org/10.1016/j.pt.2015.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767689PMC
March 2016

Modulation of host immunity by tick saliva.

J Proteomics 2015 Oct 17;128:58-68. Epub 2015 Jul 17.

Faculty of Science, University of South Bohemia in České Budějovice, Budweis, Czech Republic; Department of Clinical Pathobiochemistry, Technische Universität Dresden, Dresden, Germany.

Unlabelled: Next generation sequencing and proteomics have helped to comprehensively characterize gene expression in tick salivary glands at both the transcriptome and the proteome level. Functional data are, however, lacking. Given that tick salivary secretions are critical to the success of the tick transmission lifecycle and, as a consequence, for host colonization by the pathogens they spread, we thoroughly review here the literature on the known interactions between tick saliva (or tick salivary gland extracts) and the innate and adaptive vertebrate immune system. The information is intended to serve as a reference for functional characterization of the numerous genes and proteins expressed in tick salivary glands with an ultimate goal to develop novel vector and pathogen control strategies.

Significance: We overview all the known interactions of tick saliva with the vertebrate immune system. The provided information is important, given the recent developments in high-throughput transcriptomic and proteomic analysis of gene expression in tick salivary glands, since it may serve as a guideline for the functional characterization of the numerous newly-discovered genes expressed in tick salivary glands.
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http://dx.doi.org/10.1016/j.jprot.2015.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4619117PMC
October 2015

Deep Sequencing Analysis of the Ixodes ricinus Haemocytome.

PLoS Negl Trop Dis 2015 May 13;9(5):e0003754. Epub 2015 May 13.

Vector Biology Section, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America.

Background: Ixodes ricinus is the main tick vector of the microbes that cause Lyme disease and tick-borne encephalitis in Europe. Pathogens transmitted by ticks have to overcome innate immunity barriers present in tick tissues, including midgut, salivary glands epithelia and the hemocoel. Molecularly, invertebrate immunity is initiated when pathogen recognition molecules trigger serum or cellular signalling cascades leading to the production of antimicrobials, pathogen opsonization and phagocytosis. We presently aimed at identifying hemocyte transcripts from semi-engorged female I. ricinus ticks by mass sequencing a hemocyte cDNA library and annotating immune-related transcripts based on their hemocyte abundance as well as their ubiquitous distribution.

Methodology/principal Findings: De novo assembly of 926,596 pyrosequence reads plus 49,328,982 Illumina reads (148 nt length) from a hemocyte library, together with over 189 million Illumina reads from salivary gland and midgut libraries, generated 15,716 extracted coding sequences (CDS); these are displayed in an annotated hyperlinked spreadsheet format. Read mapping allowed the identification and annotation of tissue-enriched transcripts. A total of 327 transcripts were found significantly over expressed in the hemocyte libraries, including those coding for scavenger receptors, antimicrobial peptides, pathogen recognition proteins, proteases and protease inhibitors. Vitellogenin and lipid metabolism transcription enrichment suggests fat body components. We additionally annotated ubiquitously distributed transcripts associated with immune function, including immune-associated signal transduction proteins and transcription factors, including the STAT transcription factor.

Conclusions/significance: This is the first systems biology approach to describe the genes expressed in the haemocytes of this neglected disease vector. A total of 2,860 coding sequences were deposited to GenBank, increasing to 27,547 the number so far deposited by our previous transcriptome studies that serves as a discovery platform for studies with I. ricinus biochemistry and physiology.
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http://dx.doi.org/10.1371/journal.pntd.0003754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4430169PMC
May 2015

The tick salivary protein sialostatin L2 inhibits caspase-1-mediated inflammation during Anaplasma phagocytophilum infection.

Infect Immun 2014 Jun 31;82(6):2553-64. Epub 2014 Mar 31.

Center for Disease Vector Research and Department of Entomology, University of California, Riverside, California, USA.

Saliva from arthropod vectors facilitates blood feeding by altering host inflammation. Whether arthropod saliva counters inflammasome signaling, a protein scaffold that regulates the activity of caspase-1 and cleavage of interleukin-1β (IL-1β) and IL-18 into mature molecules, remains elusive. In this study, we provide evidence that a tick salivary protein, sialostatin L2, inhibits inflammasome formation during pathogen infection. We show that sialostatin L2 targets caspase-1 activity during host stimulation with the rickettsial agent Anaplasma phagocytophilum. A. phagocytophilum causes macrophage activation and hemophagocytic syndrome features. The effect of sialostatin L2 in macrophages was not due to direct caspase-1 enzymatic inhibition, and it did not rely on nuclear factor κB or cathepsin L signaling. Reactive oxygen species from NADPH oxidase and the Loop2 domain of sialostatin L2 were important for the regulatory process. Altogether, our data expand the knowledge of immunoregulatory pathways of tick salivary proteins and unveil an important finding in inflammasome biology.
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http://dx.doi.org/10.1128/IAI.01679-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4019176PMC
June 2014

Decoding the ubiquitin-mediated pathway of arthropod disease vectors.

PLoS One 2013 21;8(10):e78077. Epub 2013 Oct 21.

Institute for Integrative Genome Biology, Center for Disease Vector Research and Department of Entomology, University of California Riverside, Riverside, California, United States of America.

Protein regulation by ubiquitin has been extensively described in model organisms. However, characterization of the ubiquitin machinery in disease vectors remains mostly unknown. This fundamental gap in knowledge presents a concern because new therapeutics are needed to control vector-borne diseases, and targeting the ubiquitin machinery as a means for disease intervention has been already adopted in the clinic. In this study, we employed a bioinformatics approach to uncover the ubiquitin-mediated pathway in the genomes of Anopheles gambiae, Aedes aegypti, Culex quinquefasciatus, Ixodes scapularis, Pediculus humanus and Rhodnius prolixus. We observed that (1) disease vectors encode a lower percentage of ubiquitin-related genes when compared to Drosophila melanogaster, Mus musculus and Homo sapiens but not Saccharomyces cerevisiae; (2) overall, there are more proteins categorized as E3 ubiquitin ligases when compared to E2-conjugating or E1-activating enzymes; (3) the ubiquitin machinery within the three mosquito genomes is highly similar; (4) ubiquitin genes are more than doubled in the Chagas disease vector (R. prolixus) when compared to other arthropod vectors; (5) the deer tick I. scapularis and the body louse (P. humanus) genomes carry low numbers of E1-activating enzymes and HECT-type E3 ubiquitin ligases; (6) R. prolixus have low numbers of RING-type E3 ubiquitin ligases; and (7) C. quinquefasciatus present elevated numbers of predicted F-box E3 ubiquitin ligases, JAB and UCH deubiquitinases. Taken together, these findings provide novel opportunities to study the interaction between a pathogen and an arthropod vector.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0078077PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3804464PMC
September 2014

A Nod to disease vectors: mitigation of pathogen sensing by arthropod saliva.

Front Microbiol 2013 21;4:308. Epub 2013 Oct 21.

Department of Microbiology and Immunology, University of Maryland School of Medicine Baltimore, MD, USA.

Arthropod saliva possesses anti-hemostatic, anesthetic, and anti-inflammatory properties that facilitate feeding and, inadvertently, dissemination of pathogens. Vector-borne diseases caused by these pathogens affect millions of people each year. Many studies address the impact of arthropod salivary proteins on various immunological components. However, whether and how arthropod saliva counters Nod-like (NLR) sensing remains elusive. NLRs are innate immune pattern recognition molecules involved in detecting microbial molecules and danger signals. Nod1/2 signaling results in activation of the nuclear factor-κB and the mitogen-activated protein kinase pathways. Caspase-1 NLRs regulate the inflammasome~- a protein scaffold that governs the maturation of interleukin (IL)-1β and IL-18. Recently, several vector-borne pathogens have been shown to induce NLR activation in immune cells. Here, we provide a brief overview of NLR signaling and discuss clinically relevant vector-borne pathogens recognized by NLR pathways. We also elaborate on possible anti-inflammatory effects of arthropod saliva on NLR signaling and microbial pathogenesis for the purpose of exchanging research perspectives.
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http://dx.doi.org/10.3389/fmicb.2013.00308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3801108PMC
December 2013

NSD1 mitigates caspase-1 activation by listeriolysin O in macrophages.

PLoS One 2013 18;8(9):e75911. Epub 2013 Sep 18.

Division of Biomedical Sciences, University of California Riverside, Riverside, California, United States of America.

Mammals and plants share pathogen-sensing systems named nod-like receptors (NLRs). Some NLRs form the inflammasome, a protein scaffold that regulates the secretion of interleukin (IL)-1β and IL-18 by cleaving catalytically inactive substrates into mature cytokines. Here, we show an immune conservation between plant and mammalian NLRs and demonstrate that the murine nuclear receptor binding SET domain protein 1 (NSD1), a protein that bears similarity to the NLR regulator enhanced downy mildew 2 (EDM2) in Arabidopsis, diminishes caspase-1 activity during extracellular stimulation with Listeria monocytogenes listeriolysin O (LLO). EDM2 is known to regulate plant developmental processes, whereas NSD1 is associated with developmental disorders. We observed that NSD1 neither affects nuclear factor (NF)-κB signaling nor regulates NLRP3 inflammasome gene expression at the chromatin, transcriptional or translational level during LLO stimulation of macrophages. Silencing of Nsd1 followed by LLO stimulation led to increased caspase-1 activation, enhanced post-translational maturation of IL-1β and IL-18 and elevated pyroptosis, a form of cell death associated with inflammation. Furthermore, treatment of macrophages with LLO(W492A), which lacks hemolytic activity due to a tryptophan to alanine substitution in the undecapeptide motif, indicates the importance of functional LLO for NSD1 regulation of the NLRP3 inflammasome. Taken together, our results indicate that NLR signaling in plants may be used for gene discovery in mammals.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0075911PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3776765PMC
September 2014

The E3 ubiquitin ligase XIAP restricts Anaplasma phagocytophilum colonization of Ixodes scapularis ticks.

J Infect Dis 2013 Dec 29;208(11):1830-40. Epub 2013 Jul 29.

Center for Disease Vector Research and Department of Entomology.

Ubiquitination is a posttranslational modification that regulates protein degradation and signaling in eukaryotes. Although it is acknowledged that pathogens exploit ubiquitination to infect mammalian cells, it remains unknown how microbes interact with the ubiquitination machinery in medically relevant arthropods. Here, we show that the ubiquitination machinery is present in the tick Ixodes scapularis and demonstrate that the E3 ubiquitin ligase named x-linked inhibitor of apoptosis protein (XIAP) restricts bacterial colonization of this arthropod vector. We provide evidence that xiap silencing significantly increases tick colonization by the bacterium Anaplasma phagocytophilum, the causative agent of human granulocytic anaplasmosis. We also demonstrate that (i) XIAP polyubiquitination is dependent on the really interesting new gene (RING) catalytic domain, (ii) XIAP polyubiquitination occurs via lysine (K)-63 but not K-48 residues, and (iii) XIAP-dependent K-63 polyubiquitination requires zinc for catalysis. Taken together, our data define a role for ubiquitination during bacterial colonization of disease vectors.
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http://dx.doi.org/10.1093/infdis/jit380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3814841PMC
December 2013

Sterol regulatory element binding protein 2 activation of NLRP3 inflammasome in endothelium mediates hemodynamic-induced atherosclerosis susceptibility.

Circulation 2013 Aug 9;128(6):632-42. Epub 2013 Jul 9.

Division of Biomedical Sciences, University of California, Riverside, USA.

Background: The molecular basis for the focal nature of atherosclerotic lesions is poorly understood. Here, we explored whether disturbed flow patterns activate an innate immune response to form the NLRP3 inflammasome scaffold in vascular endothelial cells via sterol regulatory element binding protein 2 (SREBP2).

Methods And Results: Oscillatory flow activates SREBP2 and induces NLRP3 inflammasome in endothelial cells. The underlying mechanisms involve SREBP2 transactivating NADPH oxidase 2 and NLRP3. Consistently, SREBP2, NADPH oxidase 2, and NLRP3 levels were elevated in atheroprone areas of mouse aortas, suggesting that the SREBP2-activated NLRP3 inflammasome causes functionally disturbed endothelium with increased inflammation. Mimicking the effect of atheroprone flow, endothelial cell-specific overexpression of the activated form of SREBP2 synergized with hyperlipidemia to increase atherosclerosis in the atheroresistant areas of mouse aortas.

Conclusions: Atheroprone flow induces NLRP3 inflammasome in endothelium through SREBP2 activation. This increased innate immunity in endothelium synergizes with hyperlipidemia to cause topographical distribution of atherosclerotic lesions.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.113.002714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3798034PMC
August 2013
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