The present concept of the transmission of Lyme disease from Borrelia-infected Ixodes sp. ticks to the naïve host assumes that a low number of spirochetes that manage to penetrate the midgut epithelium migrate through the hemocoel to the salivary glands and subsequently infect the host with the aid of immunomodulatory compounds present in tick saliva. Therefore, humoral and/or cellular immune reactions within the tick hemocoel may play an important role in tick competence to act as a vector for borreliosis. To test this hypothesis we have examined complement-like reactions in the hemolymph of the hard tick Ixodes ricinus against Borrelia afzelii (the most common vector and causative agent of Lyme disease in Europe). We demonstrate that I. ricinus hemolymph does not exhibit borreliacidal effects comparable to complement-mediated lysis of bovine sera. However, after injection of B. afzelii into the tick hemocoel, the spirochetes were efficiently phagocytosed by tick hemocytes and this cellular defense was completely eliminated by pre-injection of latex beads. As tick thioester-containing proteins (T-TEPs) are components of the tick complement system, we performed RNAi-mediated silencing of all nine genes encoding individual T-TEPs followed by in vitro phagocytosis assays. Silencing of two molecules related to the C3 complement component (IrC3-2 and IrC3-3) significantly suppressed phagocytosis of B. afzelii, while knockdown of IrTep (insect type TEP) led to its stimulation. However, RNAi-mediated silencing of T-TEPs or elimination of phagocytosis by injection of latex beads in B. afzelii-infected I. ricinus nymphs had no obvious impact on the transmission of spirochetes to naïve mice, as determined by B. afzelii infection of murine tissues following tick infestation. This result supports the concept that Borrelia spirochetes are capable of avoiding complement-related reactions within the hemocoel of ticks competent to transmit Lyme disease.
- MeSH
- Arachnid Vectors immunology microbiology MeSH
- Borrelia burgdorferi Group immunology MeSH
- Phagocytosis * MeSH
- Hemocytes immunology MeSH
- Ixodes immunology microbiology MeSH
- Complement System Proteins metabolism MeSH
- Lyme Disease transmission MeSH
- Disease Models, Animal MeSH
- Mice MeSH
- Disease Transmission, Infectious MeSH
- Arthropod Proteins metabolism MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
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.
- MeSH
- Anaplasma phagocytophilum genetics immunology MeSH
- Annexin A2 chemistry genetics immunology MeSH
- Arachnid Vectors chemistry genetics immunology MeSH
- Cystatins chemistry genetics immunology MeSH
- Ehrlichiosis immunology microbiology pathology MeSH
- Escherichia coli genetics metabolism MeSH
- Immune Evasion * MeSH
- Inflammasomes genetics immunology MeSH
- Interleukin-18 genetics immunology MeSH
- Interleukin-1beta genetics immunology MeSH
- Caspase 1 genetics immunology MeSH
- Caspases genetics immunology MeSH
- Ixodes chemistry genetics immunology MeSH
- Humans MeSH
- Macrophages immunology microbiology MeSH
- Models, Molecular MeSH
- Mice MeSH
- Protein Isoforms chemistry genetics immunology MeSH
- Apoptosis Regulatory Proteins chemistry genetics immunology MeSH
- Calcium-Binding Proteins chemistry genetics immunology MeSH
- Gene Expression Regulation MeSH
- Recombinant Proteins chemistry genetics immunology MeSH
- Amino Acid Sequence MeSH
- Signal Transduction MeSH
- Protein Binding MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
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.
- MeSH
- Arachnid Vectors immunology parasitology MeSH
- Immune Evasion immunology MeSH
- Host-Parasite Interactions immunology MeSH
- Ixodidae immunology parasitology MeSH
- Humans MeSH
- Parasitic Diseases immunology transmission MeSH
- Arthropod Proteins immunology MeSH
- Salivary Proteins and Peptides immunology MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
- MeSH
- Antineoplastic Agents adverse effects therapeutic use MeSH
- Arachnid Vectors immunology MeSH
- Antibodies, Monoclonal, Humanized adverse effects therapeutic use MeSH
- Immunoglobulin E blood MeSH
- Tick Infestations immunology MeSH
- Ticks immunology MeSH
- Humans MeSH
- Neoplasms drug therapy immunology MeSH
- Tick-Borne Diseases immunology MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- United States MeSH
Ticks are hematophagous arachnids transmitting a wide variety of pathogens including viruses, bacteria, and protozoans to their vertebrate hosts. The tick vector competence has to be intimately linked to the ability of transmitted pathogens to evade tick defense mechanisms encountered on their route through the tick body comprising midgut, hemolymph, salivary glands or ovaries. Tick innate immunity is, like in other invertebrates, based on an orchestrated action of humoral and cellular immune responses. The direct antimicrobial defense in ticks is accomplished by a variety of small molecules such as defensins, lysozymes or by tick-specific antimicrobial compounds such as microplusin/hebraein or 5.3-kDa family proteins. Phagocytosis of the invading microbes by tick hemocytes is likely mediated by the primordial complement-like system composed of thioester-containing proteins, fibrinogen-related lectins and convertase-like factors. Moreover, an important role in survival of the ingested microbes seems to be played by host proteins and redox balance maintenance in the tick midgut. Here, we summarize recent knowledge about the major components of tick immune system and focus on their interaction with the relevant tick-transmitted pathogens, represented by spirochetes (Borrelia), rickettsiae (Anaplasma), and protozoans (Babesia). Availability of the tick genomic database and feasibility of functional genomics based on RNA interference greatly contribute to the understanding of molecular and cellular interplay at the tick-pathogen interface and may provide new targets for blocking the transmission of tick pathogens.
- MeSH
- Anaplasma immunology pathogenicity MeSH
- Arachnid Vectors immunology microbiology parasitology MeSH
- Babesia immunology pathogenicity MeSH
- Borrelia immunology pathogenicity MeSH
- Host-Pathogen Interactions * MeSH
- Ticks immunology microbiology parasitology MeSH
- Immunity, Innate * MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
