Induced Transient Immune Tolerance in Ticks and Vertebrate Host: A Keystone of Tick-Borne Diseases?

Abstract

Ticks and tick transmitted infectious agents are increasing global public health threats due to increasing abundance, expanding geographic ranges of vectors and pathogens, and emerging tick-borne infectious agents. Greater understanding of tick, host, and pathogen interactions will contribute to development of novel tick control and disease prevention strategies. Tick-borne pathogens adapt in multiple ways to very different tick and vertebrate host environments and defenses. Ticks effectively pharmacomodulate by its saliva host innate and adaptive immune defenses. In this review, we examine the idea that successful synergy between tick and tick-borne pathogen results in host immune tolerance that facilitates successful tick infection and feeding, creates a favorable site for pathogen introduction, modulates cutaneous and systemic immune defenses to establish infection, and contributes to successful long-term infection. Tick, host, and pathogen elements examined here include interaction of tick innate immunity and microbiome with tick-borne pathogens; tick modulation of host cutaneous defenses prior to pathogen transmission; how tick and pathogen target vertebrate host defenses that lead to different modes of interaction and host infection status (reservoir, incompetent, resistant, clinically ill); tick saliva bioactive molecules as important factors in determining those pathogens for which the tick is a competent vector; and, the need for translational studies to advance this field of study. Gaps in our understanding of these relationships are identified, that if successfully addressed, can advance the development of strategies to successfully disrupt both tick feeding and pathogen transmission.

Keywords: adaptive immunity; immune tolerance; innate immunity; skin immunity and microbiome; tick; tick-borne diseases.

Figure 1

Tick-borne diseases rely on interplays between the tick, the pathogen and the vertebrate host. To be a competent vector, the tick must control the pathogen population by its innate immunity and the tick microbiome seems to contribute to this control. During pathogen inoculation into the skin, tick saliva modulates the pharmacology and the immunology of the vertebrate host. Skin immunity plays a major role in tolerance of tick-borne pathogens. It is likely that the skin microbiome participates in this immunomodulation. Once inoculated, the infection outcome varies: (1) in animal reservoir like rodents, where no clinical manifestations develop and the pathogens survive for months allowing their persistence in the environment; (2) the vertebrate host has a sufficient immune system to neutralize the pathogens and antibody presence provides evidence of contact with the pathogens; and, (3) the vertebrate host does not trigger a sufficient and protective immune response and as a consequence develops clinical disease. Created with BioRender.com.

Figure 2

The skin is structured into three interconnected layers. The epidermis, the uppermost layer, mainly composed of keratinocytes accompanied by immune cells such as Langerhans cells and T cells. On its surface, the skin microbiome (bacteria, yeasts and virus) plays a key role in skin homeostasis. The dermis is responsible for resistance and elasticity of the skin. Dermal resident cells are fibroblasts secreting extracellular matrix with numerous immune cells such as dendritic cells, T cells, mast cells, Innate Lymphoid cells (ILCs) and others. Different appendages are present: hair follicles surrounded by dermal adipocytes, sweat glands, microcirculation blood vessels, nerves and sebaceous glands. Then beneath the dermis is the hypodermis that contains numerous adipocytes. During the process of an ixodid, hard tick bite, a feeding pool develops around the tick mouthparts. Saliva is introduced into the bite site and modulates the local host immune response with the goal of avoiding tick rejection. The tick microbiome can be secreted into the skin as exosomes. Likely, transkingdom miRNAs participate in the regulation of the infection. The role of skin immunity and skin and tick microbiomes deserves to be better investigated during the process of pathogen inoculation, multiplication and persistence. Some immune privileged sites like the hair follicle and the adipocytes might help pathogens to better survive within the skin. Recently, the potential role of nerves in the skin immune regulation has been evoked. Created with BioRender.com.