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

Sonenshine DE, Roe RM. Biology of ticks volume 1. 2nd ed. New York: Oxford University Press; 2014. p. 560. Sonenshine DE, Roe RM. Biology of ticks volume 2. 2nd ed. New York: Oxford University Press; 2014. p. 560. Mans BJ, de Klerk D, Pienaar R, Latif AA. Nuttalliella namaqua: a living fossil and closest relative to the ancestral tick lineage: implications for the evolution of blood-feeding in ticks. PLoS ONE. 2011;6, e23675. Baneth G. Tick-borne infections of animals and humans: a common ground. Int J Parasitol. 2014;44:591–6. Kotál J, Langhansová H, Lieskovská J, Andersen JF, Francischetti IMB, Chavakis T, et al. Modulation of host immunity by tick saliva. J Proteomics. 2015;128:58–68. A comprehensive review covering what is known about the effect of tick saliva on hemostasis, cellular, humoral, and innate immunity. Brubaker SW, Bonham KS, Zanoni I, Kagan JC. Innate immune pattern recognition: a cell biological perspective. Annu Rev Immunol. 2015;33:257–90. An excellent review discussing pattern recognition receptor signaling in the context of receptor location and compartmentalization. Kawai T, Akira S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity. 2011;34:637–50. Lemaitre B, Nicolas E, Michaut L, Reichhart J-M, Hoffmann JA. The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell. 1996;86:973–83. Iwasaki A, Medzhitov R. Control of adaptive immunity by the innate immune system. Nat Immunol. 2015;16:343–53. Bortoluci KR, Medzhitov R. Control of infection by pyroptosis and autophagy: role of TLR and NLR. Cell Mol Life Sci. 2010;67:1643–51. Caruso R, Warner N, Inohara N, Núñez G. NOD1 and NOD2: signaling, host defense, and inflammatory disease. Immunity. 2014;41:898–908. This article reviews what is currently known about recognition, activation, and regulation of NOD1 and NOD2 signaling and the implications this has for both microbial and sterile inflammatory diseases. Motta V, Soares F, Sun T, Philpott DJ. NOD-like receptors: versatile cytosolic sentinels. Physiol Rev. 2015;95:149–78. This is an in-depth review discussing the diversity of NLRs, the distribution in the animal kingdom, the involvement in both immunity and other biological functions, and the molecular mechanisms underlying these processes. Inohara N, Ogura Y, Chen FF, Muto A, Nuñez G. Human Nod1 confers responsiveness to bacterial lipopolysaccharides. J Biol Chem. 2001;276:2551–4. Chamaillard M, Hashimoto M, Horie Y, Masumoto J, Qiu S, Saab L, et al. An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid. Nat Immunol. 2003;4:702–7. Hasegawa M, Yang K, Hashimoto M, Park J-H, Kim Y-G, Fujimoto Y, et al. Differential release and distribution of Nod1 and Nod2 immunostimulatory molecules among bacterial species and environments. J Biol Chem. 2006;281:29054–63. Girardin SE, Boneca IG, Carneiro LAM, Antignac A, Jéhanno M, Viala J, et al. Nod1 detects a unique muropeptide from Gram-negative bacterial peptidoglycan. Science. 2003;300:1584–7. Girardin SE, Boneca IG, Viala J, Chamaillard M, Labigne A, Thomas G, et al. Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem. 2003;278:8869–72. Kobayashi K, Inohara N, Hernandez LD, Galán JE, Núñez G, Janeway CA, et al. RICK/Rip2/CARDIAK mediates signalling for receptors of the innate and adaptive immune systems. Nature. 2002;416:194–9. Inohara N, Koseki T, del Peso L, Hu Y, Yee C, Chen S, et al. Nod1, an Apaf-1-like activator of caspase-9 and nuclear factor-κB. J Biol Chem. 1999;274:14560–7. Park J-H, Kim Y-G, Shaw M, Kanneganti T-D, Fujimoto Y, Fukase K, et al. Nod1/RICK and TLR signaling regulate chemokine and antimicrobial innate immune responses in mesothelial cells. J Immunol. 2007;179:514–21. Windheim M, Lang C, Peggie M, Plater LA, Cohen P. Molecular mechanisms involved in the regulation of cytokine production by muramyl dipeptide. Biochem J. 2007;404:179–90. Guo H, Callaway JB, Ting JP-Y. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med. 2015;21:677–87. This review focuses on the mechanisms underlying assembly of the best-characterized inflammasomes (NLRP3, NLRC4, and AIM2) and discusses these in the context of neurodegenerative diseases, sterile inflammatory diseases, and potential therapeutics targeting them. Lage SL, Longo C, Branco LM, da Costa TB, Buzzo C de L, Bortoluci KR. Emerging concepts about NAIP/NLRC4 inflammasomes. Front Immunol. 2014;5:309. Vance RE. The NAIP/NLRC4 inflammasomes. Curr Opin Immunol. 2015;32:84–9. An in-depth review of NLRC4 inflammasome assembly, the involvement of NAIPs, and how this benefits host defense against microbial infection versus inappropriate activation leading to an inflammatory disease. Chavarría-Smith J, Vance RE. The NLRP1 inflammasomes. Immunol Rev. 2015;265:22–34. von Moltke J, Ayres JS, Kofoed EM, Chavarría-Smith J, Vance RE. Recognition of bacteria by inflammasomes. Annu Rev Immunol. 2013;31:73–106. Steere AC, Coburn J, Glickstein L. The emergence of Lyme disease. J Clin Invest. 2004;113:1093–101. Fukunaga M, Takahashi Y, Tsuruta Y, Matsushita O, Ralph D, McClelland M, et al. Genetic and phenotypic analysis of Borrelia miyamotoi sp. nov., isolated from the ixodid tick Ixodes persulcatus, the vector for Lyme disease in Japan. Int J Syst Bacteriol. 1995;45:804–10. Scoles GA, Papero M, Beati L, Fish D. A relapsing fever group spirochete transmitted by Ixodes scapularis ticks. Vector-Borne Zoonotic Dis. 2001;1:21–34. Platonov AE, Karan LS, Kolyasnikova NM, Makhneva NA, Toporkova MG, Maleev VV, et al. Humans infected with relapsing fever spirochete Borrelia miyamotoi, Russia. Emerg Infect Dis. 2011;17:1816–23. Gugliotta JL, Goethert HK, Berardi VP, Telford SR. Meningoencephalitis from Borrelia miyamotoi in an immunocompromised patient. N Engl J Med. 2013;368:240–5. Krause PJ, Narasimhan S, Wormser GP, Rollend L, Fikrig E, Lepore T, et al. Human Borrelia miyamotoi infection in the United States. N Engl J Med. 2013;368:291–3. Krause PJ, Fish D, Narasimhan S, Barbour AG. Borrelia miyamotoi infection in nature and in humans. Clin Microbiol Infect. 2015;21:631–9. Schwan TG, Raffel SJ, Schrumpf ME, Porcella SF. Diversity and distribution of Borrelia hermsii. Emerg Infect Dis. 2007;13:436–42. Schwan TG, Policastro PF, Miller Z, Thompson RL, Damrow T, Keirans JE. Tick-borne relapsing fever caused by Borrelia hermsii. Emerg Infect Dis. 2003;9:1151–4. Schwan TG. Vector interactions and molecular adaptations of Lyme disease and relapsing fever spirochetes associated with transmission by ticks. Emerg Infect Dis. 2002;8:115–21. Dugat T, Lagrée A-C, Maillard R, Boulouis H-J, Haddad N. Opening the black box of Anaplasma phagocytophilum diversity: current situation and future perspectives. Front Cell Infect Microbiol. 2015;5:61. Lani R, Moghaddam E, Haghani A, Chang L-Y, AbuBakar S, Zandi K. Tick-borne viruses: a review from the perspective of therapeutic approaches. Ticks Tick-Borne Dis. 2014;5:457–65. Lin M, Rikihisa Y. Ehrlichia chaffeensis and Anaplasma phagocytophilum lack genes for lipid A biosynthesis and incorporate cholesterol for their survival. Infect Immun. 2003;71:5324–31. Takayama K, Rothenberg RJ, Barbour AG. Absence of lipopolysaccharide in the Lyme disease spirochete, Borrelia burgdorferi. Infect Immun. 1987;55:2311–3. Amano K, Tamura A, Ohashi N, Urakami H, Kaya S, Fukushi K. Deficiency of peptidoglycan and lipopolysaccharide components in Rickettsia tsutsugamushi. Infect Immun. 1987;55:2290–2. Min C-K, Yang J-S, Kim S, Choi M-S, Kim I-S, Cho N-H. Genome-based construction of the metabolic pathways of Orientia tsutsugamushi and comparative analysis within the Rickettsiales order. Comp Funct Genomics. 2008;623145. Gunn JS, Ernst RK. The structure and function of Francisella lipopolysaccharide. Ann N Y Acad Sci. 2007;1105:202–18. Girardin SE, Travassos LH, Hervé M, Blanot D, Boneca IG, Philpott DJ, et al. Peptidoglycan molecular requirements allowing detection by Nod1 and Nod2. J Biol Chem. 2003;278:41702–8. Center for Disease Control and Prevention (CDC). Reported cases of Lyme disease by year, United States. Division of Vector-Borne Infectious Diseases, Centers for Disease Control and Prevention. 1995-2009. Hirschfeld M, Kirschning CJ, Schwandner R, Wesche H, Weis JH, Wooten RM, et al. Cutting edge: inflammatory signaling by Borrelia burgdorferi lipoproteins is mediated by Toll-like receptor 2. J Immunol. 1999;163:2382–6. Wooten RM, Ma Y, Yoder RA, Brown JP, Weis JH, Zachary JF, et al. Toll-like receptor 2 is required for innate, but not acquired, host defense to Borrelia burgdorferi. J Immunol. 2002;168:348–55. Petzke MM, Brooks A, Krupna MA, Mordue D, Schwartz I. Recognition of Borrelia burgdorferi, the Lyme disease spirochete, by TLR7 and TLR9 induces a type I IFN response by human immune cells. J Immunol. 2009;183:5279–92. Cervantes JL, Dunham-Ems SM, La Vake CJ, Petzke MM, Sahay B, Sellati TJ, et al. Phagosomal signaling by Borrelia burgdorferi in human monocytes involves Toll-like receptor (TLR) 2 and TLR8 cooperativity and TLR8-mediated induction of IFN-β. Proc Natl Acad Sci U S A. 2011;108:3683–8. Salazar JC, Duhnam-Ems S, La Vake C, Cruz AR, Moore MW, Caimano MJ, et al. Activation of human monocytes by live Borrelia burgdorferi generates TLR2-dependent and -independent responses which include induction of IFN-β. PLoS Pathog. 2009;5, e1000444. Shin OS, Isberg RR, Akira S, Uematsu S, Behera AK, Hu LT. Distinct roles for MyD88 and Toll-like receptors 2, 5, and 9 in phagocytosis of Borrelia burgdorferi and cytokine induction. Infect Immun. 2008;76:2341–51. Petnicki-Ocwieja T, Chung E, Acosta DI, Ramos LT, Shin OS, Ghosh S, et al. TRIF mediates Toll-like receptor 2-dependent inflammatory responses to Borrelia burgdorferi. Infect Immun. 2013;81:402–10. Petnicki-Ocwieja T, Kern A, Killpack TL, Bunnell SC, Hu LT. Adaptor protein-3-mediated trafficking of TLR2 ligands controls specificity of inflammatory responses but not adaptor complex assembly. J Immunol. 2015;195:4331–40. This study highlights the immunoregulatory role of cellular compartmentalization by demonstrating that cytokine production differs depending on cellular localization of pattern recognition receptors. Pechová J, Stĕpánová G, Kovár L, Kopecký J. Tick salivary gland extract-activated transmission of Borrelia afzelii spirochaetes. Folia Parasitol (Praha). 2002;49:153–9. Zeidner NS, Schneider BS, Nuncio MS, Gern L, Piesman J. Coinoculation of Borrelia spp. with tick salivary gland lysate enhances spirochete load in mice and is tick species-specific. J Parasitol. 2002;88:1276–8. Horká H, Cerná-Kýcková K, Skallová A, Kopecký J. Tick saliva affects both proliferation and distribution of Borrelia burgdorferi spirochetes in mouse organs and increases transmission of spirochetes to ticks. Int J Med Microbiol IJMM. 2009;299:373–80. Montgomery RR, Lusitani D, de Boisfleury CA, Malawista SE. Tick saliva reduces adherence and area of human neutrophils. Infect Immun. 2004;72:2989–94. Ramamoorthi N, Narasimhan S, Pal U, Bao F, Yang XF, Fish D, et al. The Lyme disease agent exploits a tick protein to infect the mammalian host. Nature. 2005;436:573–7. Tyson K, Elkins C, Patterson H, Fikrig E, de Silva A. Biochemical and functional characterization of Salp20, an Ixodes scapularis tick salivary protein that inhibits the complement pathway. Insect Mol Biol. 2007;16:469–79. Schuijt TJ, Coumou J, Narasimhan S, Dai J, DePonte K, Wouters D, et al. A tick mannose-binding lectin inhibits the vertebrate complement cascade to enhance transmission of the Lyme disease agent. Cell Host Microbe. 2011;10:136–46. Páleníková J, Lieskovská J, Langhansová H, Kotsyfakis M, Chmelař J, Kopecký J. Ixodes ricinus salivary serpin IRS-2 affects Th17 differentiation via inhibition of the interleukin-6/STAT-3 signaling pathway. Infect Immun. 2015;83:1949–56. Kotsyfakis M, Horka H, Salat J, Andersen JF. The crystal structures of two salivary cystatins from the tick Ixodes scapularis and the effect of these inhibitors on the establishment of Borrelia burgdorferi infection in a murine model. Mol Microbiol. 2010;77:456–70. Bernard Q, Gallo RL, Jaulhac B, Nakatsuji T, Luft B, Yang X, et al. Ixodes tick saliva suppresses the keratinocyte cytokine response to TLR2/TLR3 ligands during early exposure to Lyme borreliosis. Exp Dermatol. 2015. An interesting study that address the additive effects of both PAMPs and DAMPs on the localized immune response that are both inevitably present at the site of a tick bite and the impact of tick saliva on this. Gavrilin MA, Wewers MD. Francisella recognition by inflammasomes: differences between mice and men. Front Microbio. 2011;2:11. doi:10.3389/fmicb.2011.00011. Jones CL, Weiss DS. TLR2 signaling contributes to rapid inflammasome activation during F. novicida infection. PLoS One. 2011;6, e20609. Meunier E, Wallet P, Dreier RF, Costanzo S, Anton L, Rühl S, et al. Guanylate-binding proteins promote activation of the AIM2 inflammasome during infection with Francisella novicida. Nat Immunol. 2015;16:476–84. Choi K-S, Scorpio DG, Dumler JS. Anaplasma phagocytophilum ligation to Toll-like receptor (TLR) 2, but not to TLR4, activates macrophages for nuclear factor-κB nuclear translocation. J Infect Dis. 2004;189:1921–5. Chen G, Severo MS, Sohail M, Sakhon OS, Wikel SK, Kotsyfakis M, et al. Ixodes scapularis saliva mitigates inflammatory cytokine secretion during Anaplasma phagocytophilum stimulation of immune cells. Parasit Vectors. 2012;5:229. Sukumaran B, Ogura Y, Pedra JHF, Kobayashi KS, Flavell RA, Fikrig E. Receptor interacting protein-2 contributes to host defense against Anaplasma phagocytophilum infection. FEMS Immunol Med Microbiol. 2012;66:211–9. Chen G, Wang X, Severo MS, Sakhon OS, Sohail M, Brown LJ, et al. The tick salivary protein sialostatin L2 inhibits caspase-1-mediated inflammation during Anaplasma phagocytophilum infection. Infect Immun. 2014;82:2553–64. Seminal work addressing the role of inflammasomes in Anaplasma phagocytophilum infection and the immunosuppressive effects of the tick saliva protein, SL2, in this context. Mansueto P, Vitale G, Cascio A, Seidita A, Pepe I, Carroccio A, et al. New insight into immunity and immunopathology of rickettsial diseases, new insight into immunity and immunopathology of rickettsial diseases. J Immunol Res J Immunol Res. 2012;2012, e967852. Chattoraj P, Yang Q, Khandai A, Al-Hendy O, Ismail N. TLR2 and Nod2 mediate resistance or susceptibility to fatal intracellular Ehrlichia infection in murine models of ehrlichiosis. PLoS ONE. 2013;8, e58514. This study demonstrates that while both TLR and inflammasome-associated genes are upregulated in response to Ehrlichia infection, Nod2 (and not TLR2) contributes to an inflammatory response that leads to Ehrlichia -induced toxic shock. Yang Q, Stevenson HL, Scott MJ, Ismail N. Type I interferon contributes to noncanonical inflammasome activation, mediates immunopathology, and impairs protective immunity during fatal infection with lipopolysaccharide-negative Ehrlichiae. Am J Pathol. 2015;185:446–61. Radulovic S, Price PW, Beier MS, Gaywee J, Macaluso JA, Azad A. Rickettsia-macrophage interactions: host cell responses to Rickettsia akari and Rickettsia typhi. Infect Immun. 2002;70:2576–82. Jordan JM, Woods ME, Soong L, Walker DH. Rickettsiae stimulate dendritic cells through toll-like receptor 4, leading to enhanced NK cell activation in vivo. J Infect Dis. 2009;199:236–42. Sahni SK, Narra HP, Sahni A, Walker DH. Recent molecular insights into rickettsial pathogenesis and immunity. Future Microbiol. 2013;8:1265–88. A comprehensive review discussing what is known regarding rickettsial disease and the recent advances in understanding rickettsial pathogenesis and associated immune responses. Milhano N, Saito TB, Bechelli J, Fang R, Vilhena M, De Sousa R, et al. The role of Rhipicephalus sanguineus sensu lato saliva in the dissemination of Rickettsia conorii in C3H/HeJ mice. Med Vet Entomol. 2015;29:225–9. Alexopoulou L, Thomas V, Schnare M, Lobet Y, Anguita J, Schoen RT, et al. Hyporesponsiveness to vaccination with Borrelia burgdorferi OspA in humans and in TLR1- and TLR2-deficient mice. Nat Med. 2002;8:878–84. Lieskovska J, Kopecky J. Effect of tick saliva on signalling pathways activated by TLR-2 ligand and Borrelia afzelii in dendritic cells. Parasite Immunol. 2012;34:421–9. Oliveira CJF, Sá-Nunes A, Francischetti IMB, Carregaro V, Anatriello E, Silva JS, et al. Deconstructing tick saliva non-protein molecules with potent immunomodulatory properties. J Biol Chem. 2011;286:10960–9. Lieskovská J, Páleníková J, Širmarová J, Elsterová J, Kotsyfakis M, Campos Chagas A, et al. Tick salivary cystatin sialostatin L2 suppresses IFN responses in mouse dendritic cells. Parasite Immunol. 2015;37:70–8. Klein M, Brühl T-J, Staudt V, Reuter S, Grebe N, Gerlitzki B, et al. Tick salivary sialostatin L represses the initiation of immune responses by targeting IRF4-dependent transcription in murine mast cells. J Immunol. 2015;195:621–31. This study demonstrates that the tick saliva protein, SL, suppresses inflammation at the RNA level by inhibiting the production of the transcription factor, IRF4. Carvalho-Costa TM, Mendes MT, da Silva MV, da Costa TA, Tiburcio MGS, Anhê ACBM, et al. Immunosuppressive effects of Amblyomma cajennense tick saliva on murine bone marrow-derived dendritic cells. Parasit Vectors. 2015;8:22. Radolf JD, Caimano MJ, Stevenson B, Hu LT. Of ticks, mice and men: understanding the dual-host lifestyle of Lyme disease spirochaetes. Nat Rev Microbiol. 2012;10:87–99. de Silva AM, Fikrig E. Arthropod- and host-specific gene expression by Borrelia burgdorferi. J Clin Invest. 1997;99:377–9. Dunham-Ems SM, Caimano MJ, Pal U, Wolgemuth CW, Eggers CH, Balic A, et al. Live imaging reveals a biphasic mode of dissemination of Borrelia burgdorferi within ticks. J Clin Invest. 2009;119:3652–65. Steere AC, Schoen RT, Taylor E. The clinical evolution of Lyme arthritis. Ann Intern Med. 1987;107:725–31. Steere AC, Levin RE, Molloy PJ, Kalish RA, Abraham JH, Liu NY, et al. Treatment of Lyme arthritis. Arthritis Rheum. 1994;37:878–88. Silva MJB, Carneiro MBH, dos Anjos PB, Pereira Silva D, de Lopes MME, dos Santos LM. The multifaceted role of commensal microbiota in homeostasis and gastrointestinal diseases. J Immunol Res. 2015;2015:321241. Frosali S, Pagliari D, Gambassi G, Landolfi R, Pandolfi F, Cianci R. How the intricate interaction among Toll-like receptors, microbiota, and intestinal immunity can influence gastrointestinal pathology. J Immunol Res. 2015;2015:489821. Sousa ACP, Szabó MPJ, Oliveira CJF, Silva MJB. Exploring the anti-tumoral effects of tick saliva and derived components. Toxicon. 2015;102:69–73. Horka H, Staudt V, Klein M, Taube C, Reuter S, Dehzad N, et al. The tick salivary protein sialostatin L inhibits the Th9-derived production of the asthma-promoting cytokine IL-9 and is effective in the prevention of experimental asthma. J Immunol. 2012;188:2669–76. Sun M, He C, Cong Y, Liu Z. Regulatory immune cells in regulation of intestinal inflammatory response to microbiota. Mucosal Immunol. 2015;8:969–78. Chen GY, Nuñez G. Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol. 2010;10:826–37. Chalouhi N, Ali MS, Jabbour PM, Tjoumakaris SI, Gonzalez LF, Rosenwasser RH, et al. Biology of intracranial aneurysms: role of inflammation. J Cereb Blood Flow Metab. 2012;32:1659–76. Sá-Nunes A, Bafica A, Antonelli LR, Choi EY, Francischetti IMB, Andersen JF, et al. The immunomodulatory action of sialostatin L on dendritic cells reveals its potential to interfere with autoimmunity. J Immunol. 2009;182:7422–9.