Lizards and the enzootic cycle of Borrelia burgdorferi sensu lato

Abstract

Emerging and re-emerging pathogens often stem from zoonotic origins, cycling between humans and animals, and are frequently vectored and maintained by hematophagous arthropod vectors. The efficiency by which these disease agents are successfully transmitted between vertebrate hosts is influenced by many factors, including the host on which a vector feeds. The Lyme disease bacterium Borrelia burgdorferi sensu lato has adapted to survive in complex host environments, vectored by Ixodes ticks, and maintained in multiple vertebrate hosts. The versatility of Lyme borreliae in disparate host milieus is a compelling platform to investigate mechanisms dictating pathogen transmission through complex networks of vertebrates and ticks. Squamata, one of the most diverse clade of extant reptiles, is comprised primarily of lizards, many of which are readily fed upon by Ixodes ticks. Yet, lizards are one of the least studied taxa at risk of contributing to the transmission and life cycle maintenance of Lyme borreliae. In this review, we summarize the current evidence, spanning from field surveillance to laboratory infection studies, supporting their contributions to Lyme borreliae circulation. We also summarize the current understanding of divergent lizard immune responses that may explain the underlying molecular mechanisms to confer Lyme spirochete survival in vertebrate hosts. This review offers a critical perspective on potential enzootic cycles existing between lizard-tick-Borrelia interactions and highlights the importance of an eco-immunology lens for zoonotic pathogen transmission studies.

Keywords: Borrelia; Lyme disease; lizards; reptiles; spirochetes.

Figure 1.. Host dilution and amplification effects on B. burgdorferi s.l. prevalence.

The prevalence of ticks carrying B. burgdorferi s.l. is directly related to the availability of pathogen-competent and incompetent hosts within tick questing range. (A) The dilution hypothesis supports ticks’ feeding efforts would be diverted to the incompetent hosts in the environment with highly diverse host species, including competent and incompetent hosts. Such dilution effects predict the occurance of lower B. burgdorferi s.l. prevalence in questing ticks. (B) In the habitats with lower diversity of host species, specifically enriched in the competent hosts, B. burgdorferi s.l. can be constantly acquired and transmitted by those hosts, resulting in higher B. burgdorferi s.l. prevalence in questing ticks. These hosts thus serve as amplification hosts.

Figure 2.. Classification of reptiles.

The class Reptilia consists of four clades (highlighted in green, bold), including Squamata, Sphenodontia, Testudines, and Crocodilia. These clades share a common tetrapod ancestor (i.e., four-limbed vertebrates) with mammals, separately characterized from fish and amphibians by their ability to lay eggs or produce offspring on land. Two major clades branch out from this ancient node, Diapsids, which includes modern reptiles, and Synapsids, modern mammals. These clades are classified by distinct anatomical morphologies. Diapsids are further organized into the Lepidosauria and Archosauria, characterized by three and four chambered hearts respectively. It is noteworthy that this phylogeny does not consider Aves as a class of Reptilia, although recent phylogenomic work has defined these modern endothermic dinosaurs as reptiles(Janes et al., 2010).

Figure 3.. Schematic diagram showing vertebrate complement and the lizard complement evasion strategy of B. burgdorferi s.l.

Activation of the vertebrate complement cascade is initiated by one of three canonical pathways, the classical (CP), lectin (LP) and alternative pathways (AP). CP an LP are triggered by the interaction of antibodies and antigens whereas LP is induced by the association of mannose binding lectin (MBL) with microbial carbohydrates. Downstream induction of both pathways drives C4 to cleave and deposit C4b on the microbial surface and feed into the common C3 junction. The AP continuously attempts to deposit C3b, a component of C3, on to the microbial surface. The activation of complement results in the formation of C3 convertases (i.e., C4b2a for CP and LP, C3bBb for AP) and then C5 convertases (i.e., C4b2a3b for CP and LP, C3bBb3b for AP). The formation of C5 convertases lead to the formation of a membrane attack complex (MAC) on B. burgdorferi s.l. surface, resulting in cell lysis. Several complement regulators, such as factor H (FH), can inhibit complement system to avoid the host cell damages in the absence of pathogens. B. burgdorferi s.l. produces several outer surface proteins to evade complement-mediated killing (detailed in (Skare & Garcia, 2020, Dulipati et al., 2020, Lin et al., 2020a). One of the examples is the outer surface protein, OspE, which binds to factor H from eastern fence lizards to inhibit complement activation to facilitate B. burgdorferi s.l. to circumvent killing by lizard complement.