RESUMO
Repeated exposure of animals to Ixodes scapularis ticks can result in acquired tick resistance (ATR). The first manifestation of ATR is erythema at the tick bite site, however, the specific peptide targets and mechanisms associated with this early aspect of ATR are not understood. In this study, we immunized guinea pigs with a lipid nanoparticle containing the mRNA encoding 25 amino acids in the carboxyl terminus of Salp14 (Salp14-C mRNA-LNP), an I. scapularis salivary protein. The animals produced high titers of IgG directed at the carboxyl terminus of Salp14. Guinea pigs immunized with Salp14-C mRNA-LNP and then exposed to I. scapularis, developed erythema at the tick bite site. Transcriptomics of the skin of guinea pigs at the I. scapularis bite sites elucidated selected pathways, including histamine activation, that are associated with the development of erythema. The study demonstrates that an mRNA vaccine encoding a small peptide can induce the initial phase of ATR in guinea pigs.
Assuntos
Ixodes , Picadas de Carrapatos , Animais , Cobaias , Picadas de Carrapatos/imunologia , Ixodes/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Vacinação/métodos , Proteínas e Peptídeos Salivares/imunologia , Proteínas e Peptídeos Salivares/genética , Epitopos/imunologia , Feminino , RNA Mensageiro/imunologia , RNA Mensageiro/genética , Nanopartículas/química , Eritema/imunologia , Eritema/etiologia , Vacinas de mRNA , LipossomosRESUMO
Powassan virus (POWV) is an emergent tick-borne flavivirus that causes fatal encephalitis in the elderly and long-term neurologic sequelae in survivors. How age contributes to severe POWV encephalitis remains an enigma, and no animal models have assessed age-dependent POWV neuropathology. Inoculating C57BL/6 mice with a POWV strain (LI9) currently circulating in Ixodes ticks resulted in age-dependent POWV lethality 10-20 dpi. POWV infection of 50-week-old mice was 82% fatal with lethality sequentially reduced by age to 7.1% in 10-week-old mice. POWV LI9 was neuroinvasive in mice of all ages, causing acute spongiform CNS pathology and reactive gliosis 5-15 dpi that persisted in survivors 30 dpi. High CNS viral loads were found in all mice 10 dpi. However, by 15 dpi, viral loads decreased by 2-4 logs in 10- to 40-week-old mice, while remaining at high levels in 50-week-old mice. Age-dependent differences in CNS viral loads 15 dpi occurred concomitantly with striking changes in CNS cytokine responses. In the CNS of 50-week-old mice, POWV induced Th1-type cytokines (IFNγ, IL-2, IL-12, IL-4, TNFα, IL-6), suggesting a neurodegenerative pro-inflammatory M1 microglial program. By contrast, in 10-week-old mice, POWV-induced Th2-type cytokines (IL-10, TGFß, IL-4) were consistent with a neuroprotective M2 microglial phenotype. These findings correlate age-dependent CNS cytokine responses and viral loads with POWV lethality and suggest potential neuroinflammatory therapeutic targets. Our results establish the age-dependent lethality of POWV in a murine model that mirrors human POWV severity and long-term CNS pathology in the elderly. IMPORTANCE: Powassan virus is an emerging tick-borne flavivirus causing lethal encephalitis in aged individuals. We reveal an age-dependent POWV murine model that mirrors human POWV encephalitis and long-term CNS damage in the elderly. We found that POWV is neuroinvasive and directs reactive gliosis in all age mice, but at acute stages selectively induces pro-inflammatory Th1 cytokine responses in 50-week-old mice and neuroprotective Th2 cytokine responses in 10-week-old mice. Our findings associate CNS viral loads and divergent cytokine responses with age-dependent POWV lethality and survival outcomes. Responses of young mice suggest potential therapeutic targets and approaches for preventing severe POWV encephalitis that may be broadly applicable to other neurodegenerative diseases. Our age-dependent murine POWV model permits analysis of vaccines that prevent POWV lethality, and therapeutics that resolve severe POWV encephalitis.
Assuntos
Citocinas , Modelos Animais de Doenças , Vírus da Encefalite Transmitidos por Carrapatos , Encefalite Transmitida por Carrapatos , Camundongos Endogâmicos C57BL , Neuroglia , Carga Viral , Animais , Camundongos , Vírus da Encefalite Transmitidos por Carrapatos/imunologia , Encefalite Transmitida por Carrapatos/imunologia , Encefalite Transmitida por Carrapatos/virologia , Encefalite Transmitida por Carrapatos/mortalidade , Encefalite Transmitida por Carrapatos/patologia , Citocinas/metabolismo , Citocinas/imunologia , Neuroglia/virologia , Neuroglia/imunologia , Neuroglia/patologia , Feminino , Fatores Etários , Ixodes/virologia , Ixodes/imunologia , Sistema Nervoso Central/virologia , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/patologia , Encéfalo/virologia , Encéfalo/patologia , Encéfalo/imunologiaRESUMO
Ticks are obligate hematophagous arthropods that transmit a wide range of pathogens to humans as well as wild and domestic animals. They also harbor a non-pathogenic microbiota, although our previous study has shown that the diverse bacterial microbiome in the midgut of Ixodes ricinus is quantitatively poor and lacks a core. In artificial infections by capillary feeding of ticks with two model bacteria (Gram-positive Micrococcus luteus and Gram-negative Pantoea sp.), rapid clearance of these microbes from the midgut was observed, indicating the presence of active immune mechanisms in this organ. In the current study, RNA-seq analysis was performed on the midgut of I. ricinus females inoculated with either M. luteus or Pantoea sp. or with sterile water as a control. While no immune-related transcripts were upregulated by microbial inoculation compared to that of the sterile control, capillary feeding itself triggered dramatic transcriptional changes in the tick midgut. Manual curation of the transcriptome from the midgut of unfed I. ricinus females, complemented by the proteomic analysis, revealed the presence of several constitutively expressed putative antimicrobial peptides (AMPs) that are independent of microbial stimulation and are referred to here as 'guard' AMPs. These included two types of midgut-specific defensins, two different domesticated amidase effector 2 (Dae2), microplusin/ricinusin-related molecules, two lysozymes, and two gamma interferon-inducible lysosomal thiol reductases (GILTs). The in vitro antimicrobial activity assays of two synthetic mature defensins, defensin 1 and defensin 8, confirmed their specificity against Gram-positive bacteria showing exceptional potency to inhibit the growth of M. luteus at nanomolar concentrations. The antimicrobial activity of midgut defensins is likely part of a multicomponent system responsible for the rapid clearance of bacteria in the tick midgut. Further studies are needed to evaluate the role of other identified 'guard' AMPs in controlling microorganisms entering the tick midgut.
Assuntos
Ixodes , Animais , Ixodes/microbiologia , Ixodes/imunologia , Feminino , Micrococcus luteus/imunologia , Peptídeos Antimicrobianos/metabolismo , Transcriptoma , Trato Gastrointestinal/microbiologia , Trato Gastrointestinal/imunologia , Perfilação da Expressão Gênica , ProteômicaRESUMO
The immune system of ticks, along with that of other invertebrates, is comparatively simpler than that of vertebrates, relying solely on innate immune responses. Direct antimicrobial defence is provided by the synthesis of antimicrobial peptides (AMPs), including defensins. The aim of this study was to investigate the differences in defensin genes expression between questing and engorged Ixodes ricinus (def1 and def2) and Dermacentor reticulatus (defDr) ticks, in the presence of selected pathogens: Borrelia spp., Rickettsia spp., Babesia spp., Anaplasma phagocytophilum, and Neoehrlichia mikurensis in the natural environment. After pathogen screening by PCR/qPCR, the expression of defensin genes in pathogen positive ticks and ticks without any of the tested pathogens, was analysed by reverse transcription qPCR. The results showed an increased expression of defensin genes in I. ricinus ticks after blood feeding and I. ricinus and D. reticulatus ticks during in cases of co-infection. In particular, the expression of defensins genes was higher in questing D. reticulatus than in questing and engorged I. ricinus ticks, when borreliae were detected. This study contributes to uncovering the expression patterns of defensin genes in the presence of several known tick pathogens, the occurrence of these pathogens and possible regulatory mechanisms of defensins in tick vector competence.
Assuntos
Defensinas , Dermacentor , Ixodes , Animais , Ixodes/microbiologia , Ixodes/genética , Ixodes/imunologia , Dermacentor/microbiologia , Dermacentor/genética , Dermacentor/imunologia , Defensinas/genética , Defensinas/metabolismo , Imunidade Inata/genética , Doenças Transmitidas por Carrapatos/imunologia , Borrelia/imunologia , Babesia/imunologia , Anaplasma phagocytophilum/imunologia , Rickettsia/imunologia , Rickettsia/fisiologia , Proteínas de Artrópodes/genética , Proteínas de Artrópodes/metabolismoRESUMO
Ancestral signaling pathways serve critical roles in metazoan development, physiology, and immunity. We report an evolutionary interspecies communication pathway involving a central Ixodes scapularis tick receptor termed Dome1, which acquired a mammalian cytokine receptor motif exhibiting high affinity for interferon-gamma (IFN-γ). Host-derived IFN-γ facilitates Dome1-mediated activation of the Ixodes JAK-STAT pathway. This accelerates tick blood meal acquisition and development while upregulating antimicrobial components. The Dome1-JAK-STAT pathway, which exists in most Ixodid tick genomes, regulates the regeneration and proliferation of gut cells-including stem cells-and dictates metamorphosis through the Hedgehog and Notch-Delta networks, ultimately affecting Ixodes vectorial competence. We highlight the evolutionary dependence of I. scapularis on mammalian hosts through cross-species signaling mechanisms that dually influence arthropod immunity and development.
Assuntos
Vetores Aracnídeos , Interações Hospedeiro-Parasita , Ixodes , Janus Quinases , Receptores de Citocinas , Fatores de Transcrição STAT , Animais , Interferon gama/metabolismo , Ixodes/genética , Ixodes/imunologia , Janus Quinases/genética , Janus Quinases/metabolismo , Transdução de Sinais , Fatores de Transcrição STAT/genética , Fatores de Transcrição STAT/metabolismo , Interações Hospedeiro-Parasita/imunologia , Receptores de Citocinas/metabolismo , Vetores Aracnídeos/imunologiaAssuntos
Vetores Aracnídeos/imunologia , Ixodes/imunologia , Vacinas contra Doença de Lyme , Doença de Lyme/prevenção & controle , Picadas de Carrapatos/imunologia , Vacinas Sintéticas , Animais , Vetores Aracnídeos/fisiologia , Humanos , Ixodes/fisiologia , Doença de Lyme/transmissão , Vacinas de mRNARESUMO
In Europe, Ixodes ricinus is the most important vector of human infectious diseases, most notably Lyme borreliosis and tick-borne encephalitis virus. Multiple non-natural hosts of I. ricinus have shown to develop immunity after repeated tick bites. Tick immunity has also been shown to impair B. burgdorferi transmission. Most interestingly, multiple tick bites reduced the likelihood of contracting Lyme borreliosis in humans. A vaccine that mimics tick immunity could therefore potentially prevent Lyme borreliosis in humans. A yeast surface display library (YSD) of nymphal I. ricinus salivary gland genes expressed at 24, 48 and 72 h into tick feeding was constructed and probed with antibodies from humans repeatedly bitten by ticks, identifying twelve immunoreactive tick salivary gland proteins (TSGPs). From these, three proteins were selected for vaccination studies. An exploratory vaccination study in cattle showed an anti-tick effect when all three antigens were combined. However, immunization of rabbits did not provide equivalent levels of protection. Our results show that YSD is a powerful tool to identify immunodominant antigens in humans exposed to tick bites, yet vaccination with the three selected TSGPs did not provide protection in the present form. Future efforts will focus on exploring the biological functions of these proteins, consider alternative systems for recombinant protein generation and vaccination platforms and assess the potential of the other identified immunogenic TSGPs.
Assuntos
Antígenos/isolamento & purificação , Ixodes/imunologia , Doença de Lyme/transmissão , Glândulas Salivares/imunologia , Proteínas e Peptídeos Salivares/imunologia , Picadas de Carrapatos/imunologia , Infestações por Carrapato/imunologia , Animais , Antígenos/sangue , Antígenos/imunologia , Borrelia burgdorferi/isolamento & purificação , Bovinos , Técnicas de Visualização da Superfície Celular/métodos , Feminino , Humanos , Imunização , Doença de Lyme/sangue , Doença de Lyme/parasitologia , Masculino , Fragmentos de Peptídeos/imunologia , Biblioteca de Peptídeos , Coelhos , Saccharomyces cerevisiae , Infestações por Carrapato/parasitologiaRESUMO
The lack of tools for the precise manipulation of the tick microbiome is currently a major limitation to achieve mechanistic insights into the tick microbiome. Anti-tick microbiota vaccines targeting keystone bacteria of the tick microbiota alter tick feeding, but their impact on the taxonomic and functional profiles of the tick microbiome has not been tested. In this study, we immunized a vertebrate host model (Mus musculus) with live bacteria vaccines targeting keystone (i.e., Escherichia-Shigella) or non-keystone (i.e., Leuconostoc) taxa of tick microbiota and tested the impact of bacterial-specific antibodies (Abs) on the structure and function of tick microbiota. We also investigated the effect of these anti-microbiota vaccines on mice gut microbiota composition. Our results showed that the tick microbiota of ticks fed on Escherichia coli-immunized mice had reduced Escherichia-Shigella abundance and lower species diversity compared to ticks fed on control mice immunized with a mock vaccine. Immunization against keystone bacteria restructured the hierarchy of nodes in co-occurrence networks and reduced the resistance of the bacterial network to taxa removal. High levels of E. coli-specific IgM and IgG were negatively correlated with the abundance of Escherichia-Shigella in tick microbiota. These effects were not observed when Leuconostoc was targeted with vaccination against Leuconostoc mesenteroides. Prediction of functional pathways in the tick microbiome using PICRUSt2 revealed that E. coli vaccination reduced the abundance of lysine degradation pathway in tick microbiome, a result validated by qPCR. In contrast, the gut microbiome of immunized mice showed no significant alterations in the diversity, composition and abundance of bacterial taxa. Our results demonstrated that anti-tick microbiota vaccines are a safe, specific and an easy-to-use tool for manipulation of vector microbiome. These results guide interventions for the control of tick infestations and pathogen infection/transmission.
Assuntos
Anticorpos Antibacterianos/imunologia , Bactérias , Vacinas Bacterianas , Microbioma Gastrointestinal/imunologia , Ixodes , Animais , Bactérias/classificação , Bactérias/imunologia , Vacinas Bacterianas/imunologia , Vacinas Bacterianas/farmacologia , Ixodes/imunologia , Ixodes/microbiologia , CamundongosRESUMO
BACKGROUND: An epitope, Galα1-3Galß1-4GlcNAc-R, termed α-gal, is present in glycoconjugates of New World monkeys (platyrrhines) and other mammals but not in hominoids and Old World monkeys (catarrhines). The difference is due to the inactivation of α1-3 galactosyl transferase (α1-3 GT) genes in catarrhines. Natural antibodies to α-gal are therefore developed in catarrhines but not platyrrhines and other mammals. Hypersensitivity reactions are commonly elicited by mosquito and tick vector bites. IgE antibodies against α-gal cause food allergy to red meat in persons who have been exposed to tick bites. Three enzymes synthesising the terminal α1-3-linked galactose in α-gal, that are homologous to mammalian α and ß1-4 GTs but not mammalian α1-3 GTs, were recently identified in the tick vector Ixodes scapularis. IgG and IgM antibodies to α-gal are reported to protect against malaria because mosquito-derived sporozoites of malaria parasites express α-gal on their surface. This article explores the possibility that the α-gal in sporozoites are acquired from glycoconjugates synthesised by mosquitoes rather than through de novo synthesis by sporozoites. METHODS: The presence of proteins homologous to the three identified tick α1-3 GTs and mammalian α1-3 GTs in two important mosquito vectors, Aedes aegypti and Anopheles gambiae, as well as Plasmodium malaria parasites, was investigated by BLASTp analysis to help clarify the source of the α-gal on sporozoite surfaces. RESULTS: Anopheles gambiae and Ae. aegypti possessed several different proteins homologous to the three I. scapularis proteins with α1-3 GT activity, but not mammalian α1-3 GTs. The putative mosquito α1-3 GTs possessed conserved protein domains characteristic of glycosyl transferases. However, the genus Plasmodium lacked proteins homologous to the three I. scapularis proteins with α1-3 GT activity and mammalian α1-3 GTs. CONCLUSIONS: The putative α1-3 GTs identified in the two mosquito vectors may synthesise glycoconjugates containing α-gal that can be transferred to sporozoite surfaces before they are inoculated into skin during blood feeding. The findings merit further investigation because of their implications for immunity against malaria, hypersensitivity to mosquito bites, primate evolution, and proposals for immunisation against α-gal.
Assuntos
Galactosiltransferases/genética , Hipersensibilidade , Proteínas de Insetos/imunologia , Ixodes/química , Malária/imunologia , Mosquitos Vetores/química , Picadas de Carrapatos/imunologia , Alérgenos/imunologia , Animais , Vetores de Doenças , Galactosiltransferases/imunologia , Humanos , Hipersensibilidade/prevenção & controle , Imunoglobulina E/imunologia , Proteínas de Insetos/genética , Ixodes/enzimologia , Ixodes/genética , Ixodes/imunologia , Malária/prevenção & controle , Mosquitos Vetores/enzimologia , Mosquitos Vetores/genéticaRESUMO
Ixodes scapularis ticks feed on humans and other vertebrate hosts and transmit several pathogens of public health concern. Tick saliva is a complex mixture of bioactive proteins, lipids and immunomodulators, such as I. scapularis sphingomyelinase (IsSMase)-like protein, an ortholog of dermonecrotoxin SMase D found in the venom of Loxosceles spp. of spiders. IsSMase modulates the host immune response towards Th2, which suppresses Th1-mediated cytokines to facilitate pathogen transmission. Arboviruses utilize exosomes for their transmission from tick to the vertebrate host, and exosomes derived from tick saliva/salivary glands suppress C-X-C motif chemokine ligand 12 and interleukin-8 immune response(s) in human skin to delay wound healing and repair processes. IsSMase affects also viral replication and exosome biogenesis, thereby inhibiting tick-to-vertebrate host transmission of pathogenic exosomes. In this review, we elaborate on exosomes and their biogenesis as potential candidates for developing novel control measure(s) to combat tick-borne diseases. Such targets could help with the development of an efficient anti-tick vaccine for preventing the transmission of tick-borne pathogens.
Assuntos
Infecções por Arbovirus , Arbovírus/imunologia , Proteínas de Artrópodes/imunologia , Fatores Imunológicos/imunologia , Ixodes , Esfingomielina Fosfodiesterase/imunologia , Animais , Infecções por Arbovirus/imunologia , Infecções por Arbovirus/prevenção & controle , Infecções por Arbovirus/transmissão , Humanos , Ixodes/imunologia , Ixodes/virologia , Glândulas Salivares/imunologia , Glândulas Salivares/virologia , Células Th1/imunologia , Células Th2/imunologiaRESUMO
Introduction: Borrelia burgdorferi sensu lato (sl) is the causative agent of Lyme borreliosis. Currently there is no human vaccine against Lyme borreliosis, and most research focuses on recombinant protein vaccines. DNA tattoo vaccination with B. afzelii strain PKo OspC in mice has proven to be fully protective against B. afzelii syringe challenge and induces a favorable humoral immunity compared to recombinant protein vaccination. Alternatively, several recombinant protein vaccines based on tick proteins have shown promising effect in tick-bite infection models. In this study, we evaluated the efficacy of DNA vaccines against Borrelia OspC or tick antigens in a tick-bite infection model. Method: We vaccinated C3H/HeN mice with OspC using a codon-optimized DNA vaccine or with recombinant protein. We challenged these mice with B. burgdorferi sensu stricto (ss)-infected Ixodes scapularis nymphs. Subsequently, we vaccinated C3H/HeN mice with DNA vaccines coding for tick proteins for which recombinant protein vaccines have previously resulted in interference with tick feeding and/or Borrelia transmission: Salp15, tHRF, TSLPI, and Tix-5. These mice were also challenged with B. burgdorferi ss infected Ixodes scapularis nymphs. Results: DNA tattoo and recombinant OspC vaccination both induced total IgG responses. Borrelia cultures and DNA loads of skin and bladder remained negative in the mice vaccinated with OspC DNA vaccination, except for one culture. DNA vaccines against tick antigens Salp15 and Tix-5 induced IgG responses, while those against tHRF and TSLPI barely induced any IgG response. In addition, Borrelia cultures, and DNA loads from mice tattooed with DNA vaccines against tick proteins TSLPI, Salp15, tHRF, and Tix-5 were all positive. Conclusion: A DNA tattoo vaccine against OspC induced high specific IgG titers and provided near total protection against B. burgdorferi ss infection by tick challenge. In contrast, DNA tattoo vaccines against tick proteins TSLPI, Salp15, tHRF, and Tix-5 induced low to moderate IgG titers and did not provide protection. Therefore, DNA tattoo vaccination does not seem a suitable vaccine strategy to identify, or screen for, tick antigens for anti-tick vaccines. However, DNA tattoo vaccination is a straightforward and effective vaccination platform to assess novel B. burgdorferi sl antigen candidates in a relevant tick challenge model.
Assuntos
Antígenos de Bactérias/imunologia , Proteínas de Artrópodes/imunologia , Proteínas da Membrana Bacteriana Externa/imunologia , Borrelia burgdorferi/imunologia , Ixodes/imunologia , Vacinas contra Doença de Lyme/imunologia , Doença de Lyme/prevenção & controle , Vacinas de DNA/imunologia , Animais , Anticorpos Antibacterianos/sangue , Anticorpos Antibacterianos/imunologia , Antígenos de Bactérias/genética , Proteínas da Membrana Bacteriana Externa/genética , Borrelia burgdorferi/genética , Feminino , Imunização , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Doença de Lyme/transmissão , CamundongosRESUMO
Ixodes scapularis ticks transmit multiple pathogens, including Borrelia burgdorferi sensu stricto, and encode many proteins harboring epidermal growth factor (EGF)-like domains. We show that I. scapularis produces multiple orthologs for Bm86, a widely studied tick gut protein considered as a target of an anti-tick vaccine, herein termed as Is86. We show that Is86 antigens feature at least three identifiable regions harboring EGF-like domains (termed as EGF-1, EGF-2, and EGF-3) and are differentially upregulated during B. burgdorferi infection. Although the RNA interference-mediated knockdown of Is86 genes did not show any influences on tick engorgement or B. burgdorferi sensu stricto persistence, the immunization of murine hosts with specific recombinant EGF antigens marginally reduced spirochete loads in the skin, in addition to affecting tick blood meal engorgement and molting. However, given the borderline impact of EGF immunization on tick engorgement and pathogen survival in the vector, it is unlikely that these antigens, at least in their current forms, could be developed as potential vaccines. Further investigations of the biological significance of Is86 (and other tick antigens) would enrich our knowledge of the intricate biology of ticks, including their interactions with resident pathogens, and contribute to the development of anti-tick measures to combat tick-borne illnesses.
Assuntos
Anticorpos/imunologia , Proteínas de Artrópodes/imunologia , Borrelia burgdorferi/imunologia , Comportamento Alimentar , Ixodes/imunologia , Doença de Lyme/imunologia , Animais , CamundongosRESUMO
In many regions where ticks negatively impact public health or economic production, multiple medically important tick species may have overlapping geographic distribution, and in North America, this includes members of Ixodes, Dermacentor, and Amblyomma genera. Acquired tick resistance is the process by which some animals develop an immune response against feeding ticks after one or more exposures. This form of immunity can restrict the ability of ticks to feed and may inhibit transmission of pathogens. Likewise, many proteins present in tick saliva are conserved among tick species, and prior studies have reported cross-protective host immunity against certain combinations of ticks. In this study, we used a guinea pig model to assess whether host resistance against Ixodes scapularis could confer protection against two other medically important tick vectors, Dermacentor variabilis and Amblyomma americanum. Tick challenges using nymphs were used to induce host resistance against a primary species, followed by additional challenge using a secondary tick species. Tick attachment to hosts and engorgement weights were reduced significantly for D. variabilis and A. americanum feeding on I. scapularis-sensitized hosts. Reciprocally, I. scapularis engorgement weights were reduced to a lesser extent, and attachment was unaffected when feeding on hosts sensitized with either D. variabilis or A. americanum. These results indicate that immunity against I. scapularis could potentially be exploited for use in an anti-tick vaccine targeting multiple tick species and their associated pathogens.
Assuntos
Vetores Aracnídeos/imunologia , Suscetibilidade a Doenças/imunologia , Cobaias , Ixodes/imunologia , Doenças dos Roedores/parasitologia , Infestações por Carrapato/veterinária , Animais , Ciência dos Animais de Laboratório , Doenças dos Roedores/imunologia , Infestações por Carrapato/imunologiaRESUMO
The bacterial pathogen Borrelia burgdorferi is the causative agent of Lyme disease and is transmitted to humans through an Ixodes tick vector. B. burgdorferi is able to survive in both mammalian and tick hosts through careful modulation of its gene expression. This allows B. burgdorferi to adapt to the environmental and nutritional changes that occur when it is transmitted between the two hosts. Distinct interactions between the spirochete and its host occur at every step of the enzootic cycle and dictate the ability of the spirochete to survive until the next stage of the cycle. Studying the interface between B. burgdorferi, the Ixodes tick vector and the natural mammalian reservoirs has been made significantly more feasible through the complete genome sequences of the organisms and the advent of high throughput screening technologies. Ultimately, a thorough investigation of the interplay between the two domains (and two phyla within one domain) is necessary in order to completely understand how the pathogen is transmitted.
Assuntos
Vetores Aracnídeos/microbiologia , Borrelia burgdorferi/fisiologia , Interações entre Hospedeiro e Microrganismos/fisiologia , Ixodes/microbiologia , Doença de Lyme/microbiologia , Mamíferos/microbiologia , Animais , Vetores Aracnídeos/imunologia , Borrelia burgdorferi/genética , Expressão Gênica , Humanos , Ixodes/imunologia , Doença de Lyme/epidemiologia , Doença de Lyme/transmissão , Mamíferos/sangue , Mamíferos/parasitologia , Microbiota , Ninfa/microbiologia , Glândulas Salivares/microbiologiaRESUMO
The complement system is an ancient arm of the innate immune system that plays important roles in pathogen recognition and elimination. Upon activation by microbes, complement opsonizes bacterial surfaces, recruits professional phagocytes, and causes bacteriolysis. Borreliella species are spirochetal bacteria that are transmitted to vertebrate hosts via infected Ixodes ticks and are the etiologic agents of Lyme disease. Pathogens that traffic in blood and other body fluids, like Borreliella, have evolved means to evade complement. Lyme disease spirochetes interfere with complement by producing a small arsenal of outer-surface lipoproteins that bind host complement components and manipulate their native activities. Here we review the current landscape of complement evasion by Lyme disease spirochetes and provide an update on recent discoveries.
Assuntos
Borrelia burgdorferi/imunologia , Proteínas do Sistema Complemento/imunologia , Evasão da Resposta Imune , Doença de Lyme/imunologia , Doença de Lyme/microbiologia , Animais , Borrelia burgdorferi/genética , Borrelia burgdorferi/fisiologia , Humanos , Imunidade Inata , Ixodes/imunologia , Ixodes/microbiologia , Ixodes/fisiologia , Doença de Lyme/transmissãoRESUMO
Lyme disease (LD) is an infectious disease caused by the spirochetes of genus borrelia, which are transmitted by the ticks of the genus ixodes. LD is transmitted by the spirochete B. burgdorferi sensu lato. Once in contact with the host through a tick bite, the pathogen comes into contact with the host defense, and must escape this machinery to establish LD, thus using a large number of mechanisms involving the vector of the pathogen, the pathogen itself and also the host. The initial diagnosis of the disease can be made based on the clinical symptoms of LD and the disease can be treated and cured with antibiotics if the diagnosis is made early in the beginning of the disease. Contrariwise, if LD is left untreated, the pathogen disseminates throughout the tissues and organs of the body, where it establishes different types of disease manifestations. In the nervous system, the inflammation caused by B. burgdorferi is known as Lyme neuroborreliosis (LNB). LNB is one of the principal manifestations of LD. In this review, we systematically describe the different molecular interactions among B. burgdorferi, the vector (tick) and the mammalian host.
Assuntos
Vetores Aracnídeos/microbiologia , Proteínas de Bactérias/genética , Borrelia burgdorferi/patogenicidade , Interações Hospedeiro-Patógeno/genética , Ixodes/microbiologia , Doença de Lyme/genética , Proteínas de Membrana/genética , Receptores de Superfície Celular/genética , Animais , Vetores Aracnídeos/imunologia , Proteínas de Bactérias/imunologia , Borrelia burgdorferi/imunologia , Citocinas/genética , Citocinas/imunologia , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/imunologia , Humanos , Ixodes/imunologia , Doença de Lyme/imunologia , Doença de Lyme/microbiologia , Doença de Lyme/patologia , Proteínas de Membrana/imunologia , Sistema Nervoso/imunologia , Sistema Nervoso/microbiologia , Sistema Nervoso/patologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , Receptores de Superfície Celular/imunologia , Saliva/microbiologia , Transdução de SinaisAssuntos
Desenvolvimento de Medicamentos , Vacinas contra Doença de Lyme/normas , Vacinas contra Doença de Lyme/uso terapêutico , Doença de Lyme/prevenção & controle , Animais , Atitude Frente a Saúde , Borrelia burgdorferi/imunologia , Aprovação de Drogas , Humanos , Ixodes/imunologia , Ixodes/microbiologia , Doença de Lyme/transmissão , Vacinas contra Doença de Lyme/efeitos adversos , Vacinas contra Doença de Lyme/imunologia , Picadas de Carrapatos/prevenção & controleRESUMO
Tick innate immunity involves humoral and cellular responses. Among the humoral effector molecules in ticks are the defensins which are a family of small peptides with a conserved γ-core motif that is crucial for their antimicrobial activity. Defensin families have been identified in several hard and soft tick species. However, little is known about the presence and antimicrobial activity of defensins from the Australian paralysis tick Ixodes holocyclus. In this study the I. holocyclus transcriptome was searched for the presence of defensins. Unique and non-redundant defensin sequences were identified and designated as holosins 1 - 5. The antimicrobial activity of holosins 2 and 3 and of the predicted γ-cores of holosins 1-4 (HoloTickCores 1-4), was assessed using Gram-negative and Gram-positive bacteria as well as the fungus Fusarium graminearum and the yeast Candida albicans. All holosins had molecular features that are conserved in other tick defensins. Furthermore holosins 2 and 3 were very active against the Gram-positive bacteria Staphylococcus aureus and Listeria grayi. Holosins 2 and 3 were also active against F. graminearum and C. albicans and 5 µM of peptide abrogate the growth of these microorganisms. The activity of the synthetic γ-cores was lower than that of the mature defensins apart from HoloTickCore 2 which had activity comparable to mature holosin 2 against the Gram-negative bacterium Escherichia coli. This study reveals the presence of a multigene defensin family in I. holocyclus with wide antimicrobial activity.
Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Defensinas/genética , Defensinas/imunologia , Ixodes/genética , Ixodes/imunologia , Sequência de Aminoácidos , Animais , Antibacterianos/química , Antifúngicos/química , Proteínas de Artrópodes/química , Proteínas de Artrópodes/genética , Proteínas de Artrópodes/imunologia , Austrália , Candida albicans/efeitos dos fármacos , Defensinas/química , Fusarium/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Filogenia , Alinhamento de Sequência , TranscriptomaRESUMO
The E3 ubiquitin ligase X-linked inhibitor of apoptosis (XIAP) acts as a molecular rheostat for the immune deficiency (IMD) pathway of the tick Ixodes scapularis 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 I. scapularis 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 p47 transcription levels through RNA interference in I. scapularis limited Kenny accumulation, reduced phosphorylation of IKKß (IRD5), and impaired cleavage of the NF-κB molecule Relish. Accordingly, disruption of p47 expression increased microbial colonization by the Lyme disease spirochete Borrelia burgdorferi and the rickettsial agent Anaplasma phagocytophilum Collectively, we highlight the importance of ticks for the elucidation of paradigms in arthropod immunology. Manipulating immune signaling cascades within I. scapularis may lead to innovative approaches to reducing the burden of tick-borne diseases.