Trends in Immunology
Volume 42, Issue 7, July 2021, Pages 554-574
Journal home page for Trends in Immunology

Feature Review
Tick host immunity: vector immunomodulation and acquired tick resistance

https://doi.org/10.1016/j.it.2021.05.005Get rights and content

Highlights

  • Ticks can repeatedly parasitize their permissive reservoir hosts. Recent studies suggest that the tick bite sites reflect a broad sessile lesion without signs of pain or itchiness, despite intense inflammation. These observations reinforce the 'immune evasion theory', where the tick sialome can efficiently engage and evade immune responses in permissive hosts.

  • Many non-natural or incidental hosts, potentially including humans, can develop acquired tick resistance against repeated tick bites. New research has uncovered key factors that drive these tick rejections in resistant hosts, suggesting diversity in the architectural, sensory, and neurological aspects of tick bite lesions and the types of host responses.

  • Although research has yet to identify the precise tick proteins that trigger the host responses associated with tick rejection in incidental hosts, new studies suggest that repeated host exposure to tick saliva, specifically its glycoproteins or particular saliva fractions, can independently drive partial immunity against tick bites.

Ticks have an unparalleled ability to parasitize diverse land vertebrates. Their natural persistence and vector competence are supported by the evolution of sophisticated hematophagy and remarkable host immune-evasion activities. We analyze the immunomodulatory roles of tick saliva which facilitates their acquisition of a blood meal from natural hosts and allows pathogen transmission. We also discuss the contrasting immunological events of tick–host associations in non-reservoir or incidental hosts, in which the development of acquired tick resistance can deter tick attachment. A critical appraisal of the intricate immunobiology of tick–host associations can plant new seeds of innovative research and contribute to the development of novel preventive strategies against ticks and tick-transmitted infections.

Section snippets

Evolution of sophisticated hematophagy in ticks and the perplexing immunobiology of tick–host associations

Ticks comprise a diverse group of highly adapted and obligate blood-feeding ectoparasites classified into the Ixodidae (hard tick, see Glossary) and Argasidae (soft tick) families, encompassing 692 and 186 species, respectively [1]. A third ancestral family, the Nuttalliellidae, is represented by a single surviving species that exists only in South Africa [2]. Although there is uncertainty about the precise location or timeline of the origin of ticks, it is likely that they evolved and

Tick immunomodulation of natural hosts

Because ticks (particularly hard tick species) engorge for a prolonged time on permissive vertebrates, including natural or reservoir hosts, they must counteract or circumvent the complex defense mechanisms of the host that have evolved to prevent blood loss and infection. We focus here on the cytological events at the tick bite site and the multidimensional roles of tick saliva proteins, especially their influences on major host defenses, which allow the vectors to successfully secure a blood

Saliva-assisted pathogen transmission

With the exception of a defined set of transovarially transmitted pathogens, most tick-borne diseases are passively transmitted to the host dermis via tick saliva [26,74]. Ticks such as I. scapularis produce multiple SG proteins with anti-hemostatic, anti-inflammatory, and (as shown in many experimental studies) immunosuppressive properties, which can support the transmission of tick-borne pathogens (Table 1) [15,29]. For example, as highlighted in Table 1, transmission of B. burgdorferi,

Acquired tick resistance

Although some tick species such as I. scapularis can feed repeatedly without apparent resistance on their natural or reservoir hosts, for example the white-footed mouse (P. leucopus), some non-natural or incidental hosts can quickly develop strong resistance against tick bites [25]. William Trager first reported this spectacular immunological event in 1939 when guinea pigs were shown to develop robust resistance against multiple infestations by the American dog tick, D. variabilis [17]. This

Contrasting and overlapping immune responses: the possible outcomes of tick–host associations

We discuss here the major hypothesis that the immune responses of natural reservoir hosts versus non-natural incidental hosts might dictate the differing outcomes of tick feeding events. We also present a comparison of these types of host responses.

Concluding remarks: gaps, challenges, and future directions

Ticks, which originated before the first dinosaurs, have evolved a remarkable hematophagy over millions of years of parasitism. Given the monophyletic nature of tick evolution and the unique hematophagy of hard ticks, their vector–host associations are likely to be fundamentally different from those of other blood-feeding arthropods [143,144]. Recent studies involving repeated engorgements of Ixodes tick on mice and guinea pigs have unearthed new paradigms for the concepts of tick immune

Acknowledgments

The authors are thankful to Kathryn Nassar for assistance with the preparation of this manuscript. This study was supported by the National Institute of Allergy and Infectious Diseases, award numbers R01AI080615, AI116620, and P01AI138949 to U.P.

Declaration of interests

The authors declare no conflicts of interest.

Glossary

Acquired tick resistance (ATR)
an immunological mechanism that allows specific hosts to develop immunity against repeated infestations by ticks. It develops after multiple successive tick infestations in a non-natural host, leading to tick detachment or death.
Apyrase
an ATP-diphosphohydrolase that catalyzes the sequential hydrolysis of ATP to ADP and ADP to AMP, releasing inorganic phosphate. In ticks, apyrase can impair platelet aggregation by breaking down ADP released by activated platelets

References (170)

  • I.M. Francischetti

    Cloning of a salivary gland metalloprotease and characterization of gelatinase and fibrin(ogen)lytic activities in the saliva of the Lyme disease tick vector Ixodes scapularis

    Biochem. Biophys. Res. Commun.

    (2003)
  • I.M. Francischetti

    Ixolaris, a novel recombinant tissue factor pathway inhibitor (TFPI) from the salivary gland of the tick, Ixodes scapularis: identification of factor X and factor Xa as scaffolds for the inhibition of factor VIIa/tissue factor complex

    Blood

    (2002)
  • V. Hajnicka

    Ixodid tick salivary gland products target host wound healing growth factors

    Int. J. Parasitol.

    (2011)
  • S. Fukumoto

    Tick troponin I-like molecule is a potent inhibitor for angiogenesis

    Microvasc. Res.

    (2006)
  • C. Kramer

    Dermacentor variabilis: regulation of fibroblast migration by tick salivary gland extract and saliva

    Exp. Parasitol.

    (2008)
  • J.G. Valenzuela

    Purification, cloning, and expression of a novel salivary anticomplement protein from the tick, Ixodes scapularis

    J. Biol. Chem.

    (2000)
  • T.K. Kim

    Amblyomma americanum serpin 41 (AAS41) inhibits inflammation by targeting chymase and chymotrypsin

    Int. J. Biol. Macromol.

    (2020)
  • J.M. Ribeiro et al.

    Ixodes scapularis: salivary kininase activity is a metallo dipeptidyl carboxypeptidase

    Exp. Parasitol.

    (1998)
  • G.C. Paesen

    Tick histamine-binding proteins: isolation, cloning, and three-dimensional structure

    Mol. Cell

    (1999)
  • J.M. Ribeiro

    An annotated catalog of salivary gland transcripts from Ixodes scapularis ticks

    Insect Biochem. Mol. Biol.

    (2006)
  • J. Anguita

    Salp15, an Ixodes scapularis saliva protein, inhibits CD4+ T cell activation

    Immunity

    (2002)
  • G. Leboulle

    Characterization of a novel salivary immunosuppressive protein from Ixodes ricinus ticks

    J. Biol. Chem.

    (2002)
  • D. Yu

    A tick B-cell inhibitory protein from salivary glands of the hard tick, Hyalomma asiaticum

    Biochem. Biophys. Res. Commun.

    (2006)
  • C. Menten-Dedoyart

    Kinetic study of the antibody response during the blood meal of Ixodes ricinus: implication on plasma cell maturation in vivo and for anti-Ixodes vaccination

    Vaccine

    (2011)
  • T.J. Schuijt

    A tick mannose-binding lectin inhibitor interferes with the vertebrate complement cascade to enhance transmission of the lyme disease agent

    Cell Host Microbe

    (2011)
  • S. Narasimhan

    A tick antioxidant facilitates the Lyme disease agent's successful migration from the mammalian host to the arthropod vector

    Cell Host Microbe

    (2007)
  • K.E. Murfin

    Borrelia burgdorferi chemotaxis toward tick protein Salp12 contributes to acquisition

    Ticks Tick Borne Dis.

    (2019)
  • W.C. Brown

    Adaptive immunity to Anaplasma pathogens and immune dysregulation: implications for bacterial persistence

    Comp. Immunol. Microbiol. Infect. Dis.

    (2012)
  • J.R. Allen

    Tick resistance: basophils in skin reactions of resistant guinea pigs

    Int. J. Parasitol.

    (1973)
  • S.J. Brown

    Bovine resistance to Amblyomma americanum ticks: an acquired immune response characterized by cutaneous basophil infiltrates

    Vet. Parasitol.

    (1984)
  • E.K. Piper

    Tick-susceptible Bos taurus cattle display an increased cellular response at the site of larval Rhipicephalus (Boophilus) microplus attachment, compared with tick-resistant Bos indicus cattle

    Int. J. Parasitol.

    (2010)
  • S. Nava

    An overview of systematics and evolution of ticks

    Front. Biosci.

    (2009)
  • B.J. Mans

    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)
  • P. Parola et al.

    Ticks and tickborne bacterial diseases in humans: an emerging infectious threat

    Clin. Infect. Dis.

    (2001)
  • J. de la Fuente

    The fossil record and the origin of ticks (Acari: Parasitiformes: Ixodida)

    Exp. Appl. Acarol.

    (2003)
  • B.J. Mans

    Evolution of hematophagy in ticks: common origins for blood coagulation and platelet aggregation inhibitors from soft ticks of the genus Ornithodoros

    Mol. Biol. Evol.

    (2002)
  • D.E. Sonenshine

    Biology of Ticks

    (1993)
  • D.E. Sonenshine

    Range expansion of tick disease vectors in north america: implications for spread of tick-borne disease

    Int. J. Environ. Res. Public Health

    (2018)
  • C.D. Paddock

    Changing Paradigms for Tick-Borne Diseases in the Americas

    (2016)
  • J. de la Fuente

    Tick–pathogen interactions and vector competence: identification of molecular drivers for tick-borne diseases

    Front. Cell. Infect. Microbiol.

    (2017)
  • J.H. Oliver

    Biology and systematics of ticks (Acari:Ixodida)

    Annu. Rev. Ecol. Syst.

    (1989)
  • V. Honig

    Broad-range survey of vector-borne pathogens and tick host identification of Ixodes ricinus from Southern Czech Republic

    FEMS Microbiol. Ecol.

    (2017)
  • J. Perner

    RNA-seq analyses of the midgut from blood- and serum-fed Ixodes ricinus ticks

    Sci. Rep.

    (2016)
  • J. de la Fuente

    Tick–host–pathogen interactions: conflict and cooperation

    PLoS Pathog.

    (2016)
  • C. Kurokawa

    Interactions between Borrelia burgdorferi and ticks

    Nat. Rev. Microbiol.

    (2020)
  • S. Wikel

    Immunobiology of tick–host–pathogen interactions

    Parasite Immunol.

    (2021)
  • W. Trager

    Acquired immunity to ticks

    J. Parasitol.

    (1939)
  • H. Karasuyama

    Immunobiology of acquired resistance to ticks

    Front. Immunol.

    (2020)
  • S. Nazario

    Prevention of Borrelia burgdorferi transmission in guinea pigs by tick immunity

    Am. J. Trop. Med. Hyg.

    (1998)
  • S.K. Wikel

    Infestation with pathogen-free nymphs of the tick Ixodes scapularis induces host resistance to transmission of Borrelia burgdorferi by ticks

    Infect. Immun.

    (1997)
  • Cited by (0)

    View full text