Coinfection by Ixodes Tick-Borne Pathogens: Ecological, Epidemiological, and Clinical Consequences

Abstract

Ixodes ticks maintain a large and diverse array of human pathogens in the enzootic cycle, including Borrelia burgdorferi and Babesia microti. Despite the poor ecological fitness of B. microti, babesiosis has recently emerged in areas endemic for Lyme disease. Studies in ticks, reservoir hosts, and humans indicate that coinfection with B. burgdorferi and B. microti is common, promotes transmission and emergence of B. microti in the enzootic cycle, and causes greater disease severity and duration in humans. These interdisciplinary studies may serve as a paradigm for the study of other vector-borne coinfections. Identifying ecological drivers of pathogen emergence and host factors that fuel disease severity in coinfected individuals will help guide the design of effective preventative and therapeutic strategies.

Keywords: Babesia; Borrelia; Lyme disease; babesiosis; coinfection; tick.

Figure 1. Geographic distribution of Ixodes ticks involved in human disease

The vast majority of Ixodes-borne human diseases are transmitted by four species of the Ixodes ricinus species complex [10]. In the United States, Ixodes pacificus is found along the Pacific coast (orange) whereas Ixodes scapularis is encountered along the eastern seaboard and inland into the upper Midwest and across the South down to the Gulf of Mexico (red). I. pacificus is a competent vector for Borrelia burgdorferi but its role in the transmission of Babesia duncani is uncertain. I. scapularis maintains three major human pathogens in their enzootic cycle, namely B. burgdorferi, Babesia microti and Anaplasma phagocytophilum. Other human pathogens of lesser incidence include Borrelia miyamotoi, Ehrlichia muris-like agent and deer tick virus (Powassan virus type II). In most of Europe (blue), I. ricinus is the major Ixodes vector for transmission of human pathogens, including several Borrelia spp. (notably B. burgdorferi, B. afzelli and B. garini), A. phagocytophilum, several Rickettsia spp. (notably R. helvetica and R. monacensis), three Babesia spp. (B. divergens, B. venatorum and B. microti) and tick-borne encephalitis virus (TBEV) [15]. I. ricinus also is found in parts of North Africa, Turkey and the Caucasus. Ixodes persulcatus is sympatric with I. ricinus around the Baltic Sea and in northwestern Russia (turquoise), but is the predominant vector across southern Russia into the Far East (green). I. persulcatus is well known as a vector for TBEV, but also can transmit Borrelia burgdorferi sensu lato, A. phagocytophilum, Ehrlichia muris, and several Babesia species including B. divergens, B. venatorum and B. caucasica [23, 97]. Adapted from Brown et al. [98].

Figure 2. Human babesiosis is emerging in areas endemic for Lyme disease

Lyme disease and human babesiosis have been nationally notifiable conditions since 1991 and 2011, respectively. The names of counties that reported cases of Lyme disease and/or babesiosis from 2011 to 2013 were obtained from the Centers for Disease Control and Prevention. Counties with three or more cases of Lyme disease but fewer than three cases of babesiosis are depicted in green. Counties with three or more cases of Lyme disease and three or more cases of babesiosis are depicted in gray. No county reported three or more cases of babesiosis but fewer than three cases of Lyme disease.

Figure 3. The enzootic cycle of Borrelia burgdorferi and Babesia microti in the Northeast and upper Midwest of the United States

Ixodes scapularis ticks undergo a three-stage life cycle. Adult female ticks lay eggs in the spring (first year, top left panel). Although adult females may carry Borrelia burgdorferi and/or Babesia microti, their eggs do not because these agents do not reach the tick ovaries (no transovarial transmission). Larvae hatch in the early summer and become infected with B. burgdorferi and/or B. microti (red circle) as they take a blood meal from infected white-footed mice (Peromyscus leucopus) in late summer. White-footed mice are the primary reservoir host, but other small- and medium-sized mammals can harbor these agents. Birds also are reservoirs but more so for B. burgdorferi than for B. microti. Once the blood meal is completed, B. microti gametocytes fuse to form zygotes that cross the tick midgut epithelium and become ookinetes. Ookinetes eventually reach the salivary glands where they differentiate into dormant sporoblasts. B. burgdorferi spirochetes replicate but remain in the tick midgut where they lose motility, although they are not dormant. Larvae molt to nymphs in the fall or the following spring (second year, bottom left panel). When nymphs feed in late spring or early summer, reservoir hosts may become infected. Humans are accidental hosts; most cases occur from late spring through summer (as illustrated by the row of infected people). Of all tick stages, the nymph is the primary vector for transmission of B. burgdorferi and B. microti to humans. Following nymphal tick attachment, sporogony is initiated and leads to the accumulation of B. microti sporozoites in the tick salivary glands. B. burgdorferi spirochetes that had remained in the midgut undergo replication and progress toward the basement membrane of the gut epithelium. Some spirochetes reach the basement membrane, become motile and reach the salivary glands. By 48–72 hours after attachment, B. burgdorferi and B. microti are deposited in the dermis. Some B. burgdorferi strains remain at the bite site whereas other strains disseminate to various organs, including heart, joints and central nervous system. B. microti sporozoites reach the bloodstream where they readily invaded red blood cells. In the fall, nymphs molt to adults that feed on white-tailed deer (Odocoileus virginianus) but rarely on humans. White-tailed deer do not become infected with B. burgdorferi or B. microti but amplify the tick population by providing a blood meal for adult ticks. The following spring, adult female ticks lay eggs and the cycle is repeated. Adapted from Vannier and Krause [9].

Figure 4. Hierarchy of frameworks and data sources to predict the effect of coinfection on the emergence of tick-borne human disease

Green boxes highlight the sources of key model parameters that are measured in laboratory or field studies or derived from ancillary models. Pink boxes highlight hierarchy of modeling frameworks in which coinfection should be incorporated to predict the emergence of tick-borne human disease. At the individual host level, longitudinal laboratory and field studies provide information on how coinfection affects pathogen-pathogen interactions, pathogen interactions with host immune mechanisms and the effect of these interactions on pathogen persistence and transmission duration and intensity to ticks. At the population or community level, ecological contextual parameters measured at various geographic locations are integrated into (i) basic reproduction number, R₀, models to assess the probability of pathogen establishment given coinfection, (ii) pathogen population dynamics once coinfecting pathogens become established and (iii) effects of coinfection in the context of a network of pathogen-tick-host interactions. For regional models of pathogen enzootic invasion, pathogen spread can be inferred from ancillary models that estimate rates and patterns of spread using historical datasets of infection in ticks, reservoir hosts, and/or humans (disease cases) and from pathogen phylogeographic studies. Models of disease emergence integrate pathogen invasion models with epidemiological data to assess the likelihood of spillover to humans and the human health burden (disease incidence and severity), accounting for spatiotemporal heterogeneities in pathogen virulence, host susceptibility and reporting biases.