http://journals.plos.org/plosone/articl ... ne.0099348
Michelle H. Hersh , Richard S. Ostfeld, Diana J. McHenry, Michael Tibbetts, Jesse L. Brunner, Mary E. Killilea, Kathleen LoGiudice,
Kenneth A. Schmidt, Felicia Keesing
PLOS
Published: June 18, 2014
• http://dx.doi.org/10.1371/journal.pone.0099348
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Introduction
Co-infections from tickborne diseases are a threat to human health in the northeastern and midwestern United States, but the risk of acquiring a co-infection is not fully understood. Lyme disease, caused by the spirochete pathogen Borrelia burgdorferi, is an established public health problem in the United States, with >25,000 reported cases annually from 2008–2011 (CDC, 2013). Annual cases of human granulocytic anaplasmosis, caused by the gram-negative intracellular bacterium Anaplasma phagocytophilum, have been increasing in the last decade [1]. Human babesiosis, caused by the protozoan blood parasite Babesia microti, has also been increasing in prevalence, especially in the northeastern United States [2]–[4]. These three tickborne pathogens – A. phagocytophilum, B. microti, and B. burgdorferi – are transmitted by the same vector, Ixodes scapularis, the blacklegged tick, with the great majority of human cases transmitted by the nymphal stage of these ticks [5]. I. scapularis ticks can be infected with any combination of these pathogens or all three simultaneously [6]. The risk to humans of acquiring co-infection depends on both their exposure to tick bites and the infection status of the ticks.
Co-infection of multiple tickborne pathogens can affect the intensity and duration of symptoms in humans, and make diagnosis and treatment more challenging. Co-infection of Babesia microti and Borrelia burgdorferi has been the most frequently observed human co-infection in several studies of regions in which all three pathogens are endemic [7], [8]. B. microti/B. burgdorferi co-infection can cause more severe or persistent symptoms in human patients [7], [9]–[13] (but see also [14], [15]). Humans could in theory become co-infected either through the bite of a single co-infected tick, or sequential bites of ticks each transmitting a different pathogen; in this study we focus on the risk of exposure to multiple pathogens that arises from bites of co-infected ticks. Rates of transmission from infected ticks to vertebrate hosts can vary with co-infection (e.g. [16]).
The risk of exposure to more than one pathogen from a single bite of a co-infected tick depends on both: (1) the prevalence of co-infections in questing nymphs, and (2) the prevalence of co-infections in the wildlife hosts these ticks feed on as larvae. As none of these pathogens are known to be vertically transmitted [6], co-infected questing nymphs must have obtained multiple infections from feeding on a co-infected host as larvae. Few consistent patterns have emerged from observations of co-infection in questing ticks. Since larval I. scapularis ticks typically only have a single blood meal, co-infected nymphal ticks are likely a result of larval ticks feeding on co-infected hosts. Pathogens interacting within a single host could in theory facilitate one another, directly or indirectly compete, or have no additive effects [17], evidenced by positive, negative, or neutral relationships in pathogen infection status or abundance within hosts. Negative, positive, and neutral relationships of pathogen occurrence in both nymphal and adult questing ticks have been reported [18]. We focus this study on nymphs as this stage is responsible for the majority of human infections with tick-borne disease [5]. Co-infection studies to date have focused on either questing ticks or a few reservoir hosts, but have neglected simultaneous assessment of co-infection frequencies in both questing nymphs and the wildlife hosts from which they acquire pathogens.
In wildlife hosts, co-infection studies on tickborne pathogens include both observational studies based on serology and experimental studies on laboratory animals. Within a host, multiple parasite infections can be modulated by host immune responses, priority effects, and interactions among pathogens [17], [19]. In a long-term study of field voles (Microtus agrestis), evidence for both positive and negative interactions between B. microti and A. phagocytophilum was documented, with the outcome dependent on the duration of A. phagocytophilum infection [20]. Experimentally, independent transmission of B. burgdorferi and A. phagocytophilum both to and from I. scapularis ticks has been demonstrated [16]. However in white-footed mouse (Peromyscus leucopus) hosts, prior infection with either pathogen inhibits establishment of the second [21], reducing the likelihood of co-transmission to ticks. In contrast, prior ecological research on associations between vertebrate hosts and these three zoonotic pathogens suggests that co-infection in ticks could be common. Certain host species, such as P. leucopus, have high reservoir competence (probability of transmitting infection to uninfected ticks) for all three pathogens [22]–[24], potentially facilitating tick co-infection. In addition, 45% of 463 antibody-positive wild white-footed mice sampled in Connecticut were shown to be seropositive for all three pathogens [25], suggesting high exposure rates. These conflicting results yield limited predictive power concerning co-infection patterns and an incomplete understanding of underlying processes.
In this study, we sought to improve our understanding of the pattern and processes of co-infection. Our first aim was to quantify patterns of co-infection of A. phagocytophilum, B. microti, and B. burgdorferi in questing I. scapularis nymphs, given their importance in human infections [5]. Our second aim was to determine whether co-infection in questing nymphs was caused by transmission biases within groups of hosts. To accomplish this, we surveyed both questing nymphal ticks and newly molted nymphs fed as larvae on specific host species (hereafter ‘host-collected ticks’) in an area endemic to all three pathogens (Dutchess County, NY, USA). Our general strategy was to assess infection status of: (1) questing nymphs sampled from many different landscape contexts likely representing different vertebrate host communities; and (2) host-collected ticks from known mammalian and avian hosts. This allowed us to determine whether co-infection rates were different from what would be predicted if pathogens were assorting independently and to assess which hosts might be responsible for deviations from independent assortment.
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Discussion
Patterns of co-infection of both questing nymphs and host-collected ticks deviated from co-infection patterns predicted by independent assortment in several ways. Co-infection of questing nymphal ticks with Babesia microti and Borrelia burgdorferi occurred more often than expected by chance. This pattern also appeared in small mammal hosts but not other host groups (sciurids, meso-mammals, birds). Co-infection with A. phagocytophilum and B. microti in questing nymphs was less common than expected given independent assortment, and again this pattern was seen in small mammal hosts but not other host groups.
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