Tick extracellular vesicles in host skin immunity and pathogen transmission

Abstract

Ticks can transmit a variety of human pathogens, including intracellular and extracellular bacteria, viruses, and protozoan parasites. Historically, their saliva has been of immense interest due to its anticoagulant, anti-inflammatory, and anesthetic properties. Only recently, it was discovered that tick saliva contains extracellular vesicles (EVs). Briefly, it has been observed that proteins associated with EVs are important for multiple tick-borne intracellular microbial lifestyles. The impact of tick EVs on viral and intracellular bacterial pathogen transmission from the tick to the mammalian host has been shown experimentally. Additionally, tick EVs interact with the mammalian skin immune system at the bite site. The interplay between tick EVs, the transmission of pathogens, and the host skin immune system affords opportunities for future research.

Keywords: exosomes; microbial transmission; microvesicles; skin immunity; tick-borne disease.

Figure 1.. Tick bite and transmission dynamics.

(A) When a tick bites, they shred the skin and begin to feed. During the blood meal, ticks inject their saliva, EVs, immunomodulatory compounds, and any pathogens they may be carrying into the wound. The damaged keratinocytes produce chemokines and cytokines that activates skin immune cells and begin a local immune response that cascades into a systematic immune response. Some immune cells that are important during a tick bite include γδ T cells, Langerhans cells, and DETCs. The epidermis and the dermis are not drawn to scale, as we focused our discussion primarily on the skin epidermis. Additionally, Langerhans and tissue resident memory T cells are not depicted in the epidermis for illustrative purposes. (B) When I. scapularis EVs are injected into mice with A. phagocytophilum, a non-lethal pathogen, the infection is promoted. Contrarily, when EVs from D. andersoni are injected into mice in with F. tularensis, a lethal pathogen, the EVs reduced morbidity and mortality in mice. These results indicate that tick EVs may impact disease outcome, depending on the pathogenic potential of a microbe. Yet, other differences between these two pathogens cannot be overlooked.

Figure 2.. Tick salivary glands, EVs, and key players.

Tick salivary glands are necessary for successful tick feeding. Their saliva contains multiple immunomodulatory compounds, anti-coagulants, and analgesics that allow successful long-term feeding. Their saliva also contains EVs that are known to carry miRNAs, non-coding RNAs, heat shock proteins, vitellogenin proteins, ferritin, and some host proteins such as serotransferrins, fibrinogen, and serum albumin. Intracellular bacteria in other systems are known to manipulate EV cargo, but it is unknown if tick-borne bacteria do so. Most tick-borne pathogens are transmitted to the vertebrate host through tick saliva. Proteins associated with EV biogenesis, such as ESCRT and Rab proteins, are expressed in the tick salivary glands. Moreover, the importance of these proteins for tick-borne bacterial life cycles in mammalian cells has been reported. However, the impact of microbes on their expression or their importance within the tick for tick-borne microbial survival or transmission is unknown.

Figure 3, Key Figure.. Biological circuit of vector transmission.

Vectors, their hosts, and any microbes shared between them are in an intricate relationship. When a tick feeds on a mouse, the tick impacts the host’s physiology and molecular responses and vice versa. Similarly, when microbes are included in this relationship, they impact the tick and host responses. These relationships quickly become even more complex when considering the role of tick EVs, EV cargo, and any other players such as the tick immune system or mouse immune system. These associations contribute to the difficulty in dissecting the role that each party plays in the development of tick-borne disease and even more so when attempting to determine the specific roles of proteins or cells. Thus, the importance of tick EVs within these dynamics cannot be understated, and they should be a focal point of future research.