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Applied and Environmental Microbiology, January 2008, p. 153-157, Vol. 74, No. 1
0099-2240/08/$08.00+0     doi:10.1128/AEM.01567-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Fitness Variation of Borrelia burgdorferi Sensu Stricto Strains in Mice{triangledown}

Klára Hanincová,1* Nicholas H. Ogden,2 Maria Diuk-Wasser,1 Christopher J. Pappas,3 Radha Iyer,3 Durland Fish,1 Ira Schwartz,3 and Klaus Kurtenbach1,{dagger}

Department of Epidemiology and Public Health, Yale School of Medicine, Yale University, 60 College Street, New Haven, Connecticut 06520,1 Public Health Agency of Canada, Foodborne, Waterborne and Zoonotic Infections Divisions, Center for Infectious Disease Prevention and Control, Faculty of Veterinary Medicine, Université de Montréal, C.P. 5000, Saint-Hyacinthe, Québec J2S 7C6, Canada,2 Department of Microbiology and Immunology, New York Medical College, Valhalla, New York 105953

Received 10 July 2007/ Accepted 24 October 2007


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Lyme borreliosis in North America is caused by the tick-borne spirochete Borrelia burgdorferi, a zoonotic bacterium that is able to persistently infect a wide range of vertebrate species. Given the pronounced strain structure of B. burgdorferi in the northeastern United States, we asked whether the fitness of the different genotypes varies among susceptible vertebrate hosts. The transmission dynamics of two genetically divergent human isolates of B. burgdorferi, BL206 and B348, were analyzed experimentally in white-footed mice and in C3H/HeNCrl mice over a time period of almost 3 months. We found that the initially high transmission efficiency from white-footed mice to ticks declined sharply for isolate B348 but remained considerably high for isolate BL206. In contrast, in C3H/HeNCrl mice, high transmission efficiency persisted for both isolates. Our findings provide proof-of-principle evidence for intrinsic fitness variation of B. burgdorferi strains in vertebrate host species, perhaps indicating the beginnings of adaptive radiation.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
One of the most important parameters shaping the epidemiological behavior of microparasites is the duration of infectivity relative to the life span of the host (10). Microorganisms that persist in individual vertebrate hosts have evolved mechanisms of effective immune evasion, whereas short-lived microparasites are normally cleared by the immune system of the host, giving rise to recovery from infection. These differences in the infection dynamics can have particularly profound effects on the basic reproduction number (R0) of vector-borne pathogens because their transmission depends substantially on extrinsic factors determining vector contact. These differences also determine the choice of the mathematical models to study their ecology (2, 15).

Many zoonotic microparasites infect more than one vertebrate host species, and the epidemiological behavior of such microparasites is influenced by the intensity of inter- and intraspecific transmission (7). It is a common feature that the fitness of multihost microparasites varies across host species; that is, they show some level of adaptation to different hosts (35). We have previously emphasized that information on host specialization of microparasites is crucial to understand and predict the emergence and spread of zoonoses (11, 15).

The tick-borne pathogen Borrelia burgdorferi sensu stricto (referred to hereafter as B. burgdorferi) is the agent of Lyme borreliosis in North America. We have recently raised several hypotheses concerning the factors that shape the populations of B. burgdorferi in North America. First, modeling studies suggest that persistence of B. burgdorferi infection in individual reservoir hosts is essential for the long-term maintenance of B. burgdorferi among tick and host populations, at least in regions where the tick phenology is asynchronous; that is, the different developmental stages of the ticks are host-seeking at different times of the year (21). For example, in the northeastern United States, nymphal ticks are active in late spring, followed by larvae that feed mainly in late summer (9). Second, if persistent host infections are associated with increased fitness, specialization to reservoir host species is increasingly likely (15, 21). However, persistent infection in the host is not the only potential driver in the evolution of B. burgdorferi; a conflicting force may favor the generalist properties of B. burgdorferi because the principal tick vector, Ixodes scapularis, is a generalist ectoparasite. Host specialization, thus, would bear a fitness cost for any given strain of B. burgdorferi (15).

B. burgdorferi in the northeastern United States has been subtyped into nine major genotypes (5). Most of these genotypes or populations of B. burgdorferi do, indeed, maintain generalist properties, being capable of infecting a wide variety of vertebrates, including several rodent, carnivorous, and avian species (11). Despite the role of many other host species, the white-footed mouse (Peromyscus leucopus) seems to be the most important amplification host for B. burgdorferi in the region (4, 11, 18, 19). The prevalent view holds that B. burgdorferi causes a lifelong infection in white-footed mice (8), which permits transmission cycles to thrive in the face of seasonal asynchrony of infective nymphal and uninfected larval I. scapularis ticks (33). However, some experimental and theoretical studies have raised the possibility that lifelong persistence of B. burgdorferi in susceptible hosts may not be universal (6, 15, 16).

Here, we asked whether possible differences in fitness of B. burgdorferi strains in mice may indicate adaptation to alternative host species and whether the population structure of B. burgdorferi in North America could be shaped by host adaptation. Therefore, the present study was designed to experimentally evaluate transmission efficiency from mice to ticks and duration of infectivity for two genetically divergent B. burgdorferi strains. These parameters constitute important fitness measures of tick-borne pathogens (21, 25).


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Bacteria.
Low-passage blood isolate BL206 and skin isolate B348 of two Lyme disease patients who presented to the Lyme disease clinic at Westchester Medical Center, Valhalla, NY, were used in the study (31). BL206 represents the ribosomal DNA spacer restriction fragment-length polymorphism genotype RST1, the 16S-23S rDNA intergenic spacer genotype 1 (IGS1), and outer surface protein C (ospC) group A. B348 represents the RST3, IGS9 and ospC group E (5, 17, 31).

Experimental mice.
Female and male specific-pathogen-free adult C3H/HeNCrl mice (Mus musculus) were purchased from Charles River Laboratories (Wilmington, MA). Female and male specific-pathogen-free adult white-footed mice (P. leucopus) were obtained from the Peromyscus Genetic Stock Center (Columbia, SC) and bred at Yale University. Mice were handled in accordance with Yale University animal care and use guidelines.

Ticks.
I. scapularis larvae were derived from a specific-pathogen-free tick colony maintained at Yale University. Infected I. scapularis nymphs were generated by allowing larval ticks to feed upon either C3H/HeNCrl or CB-17/SCID mice inoculated intraperitoneally with BL206 or B348 isolates, respectively (6). PCR analysis showed that the infection prevalence of nymphs was higher than 90% for both B. burgdorferi strains.

Experimental design.
C3H/HeNCrl and white-footed mice were both divided into two treatment groups of four mice. Infections in mice were established via tick bites (10 nymphs/animal). White-footed mice in the PL-BL206 group and C3H/HeNCrl mice in group C3H-BL206 were fed upon by nymphal ticks infected with the BL206 isolate. White-footed mice in the PL-B348 group and C3H/HeNCrl mice in the C3H-B348 group were exposed to nymphal ticks infected with the B348 isolate. Engorged infected nymphs were allowed to molt to adult ticks, followed by PCR-based confirmation of the presence of B. burgdorferi. The infectivity of mice to ticks was assessed by larval xenodiagnosis on days 13, 40, and 79 after initial infection. Each animal was infested with approximately 100 uninfected larvae. After feeding to repletion, engorged larvae were allowed to molt to nymphs. Molted nymphs (10 nymphs/animal) were individually tested by PCR for the presence of B. burgdorferi. Blood samples from each mouse were collected at day 13 after infection.

DNA extraction and PCR.
DNA extraction from individual ticks was performed as described previously (3), using proteinase K (Roche Applied Science, Indianapolis, IN) and a DNeasy tissue kit (Qiagen, Valencia, CA). B. burgdorferi was detected by nested PCR, amplifying a fragment of 941 bp of the IGS, as reported elsewhere (17).

Serological analysis.
Sera taken from mice on day 13 postinfection were screened for immunoglobulin A (IgA), IgM, and IgG antibodies (Kirkegaard and Perry Laboratories, Gaithersburg, MD) by Western blot analysis as described previously (23). As antigens, total cell lysates of BL206 and B348 were used for isolate-specific comparison of antibodies.

Statistical analysis.
The likelihood that a tick acquired B. burgdorferi from an infected mouse was the outcome variable in general estimating equation models in STATA/SE, version 8.0, for Windows (STATA Corporation, College Station, TX). These models fit generalized linear models that yield logistic regression models via a Bernoulli distribution of the dependent variable and a logit link function. The models accounted for potential autocorrelation among observations in time series (in this case the xenodiagnosis at different time periods on the same mice) and, by including the individual rodent identification number as a random effect, the lack of independence of data from ticks collected from the same rodent at the same time. The explanatory variables were the xenodiagnosis number (the first xenodiagnosis was the reference for comparison) and a dummy variable for each "treatment," which was one of the four possible combinations of mouse strain/species and infecting strain of B. burgdorferi (treatment 1, C3H/HeNCrl mice infected with isolate BL206 [C3H-BL206]; treatment 2, C3H/HeNCrl mice infected with isolate B348 [C3H-B348]; treatment 3, white-footed mice infected with isolate BL206 [PL-BL206]; treatment 4, white-footed mice infected with isolate B348 [PL-B348]). Treatment 4 was the reference for comparison. Differences in transmission efficiency to ticks between the different treatments, at individual xenodiagnoses, were examined by comparisons (contrasts) among the coefficients that were obtained using the variance-covariance matrix of the full multivariable model reconstructed in SAS, version 9 (SAS Institute Inc, Cary, NC). Throughout, the level of significance was set at a P value of <0.05.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Infection of mice.
I. scapularis nymphs that were used to infect C3H/HeNCrl and white-footed mice were allowed to molt to adults. A subset of five adult ticks derived from each mouse was screened by PCR for the presence of B. burgdorferi. Each animal was found to have been infested with at least one infected tick. Thus, all mice in each of the four experimental groups were exposed to B. burgdorferi isolates BL206 or B348 via infected nymphs.

Duration of host infectivity for ticks.
After exposure to infected nymphs all mice transmitted spirochetes to xenodiagnostic larvae at day 13 postinfection. In the three experimental groups, C3H-BL206, C3H-B348, and PL-BL206, all but 2 of the 11 mice (1 mouse in the C3H-BL206 group died) remained infectious to ticks throughout the experiment. In contrast, only one of four white-footed mice infected with the B348 isolate (PL-B348 group) was found to be infectious to one I. scapularis larva on day 79 postinfection, when the last xenodiagnostic infestation was performed (Table 1).


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  		TABLE 1. Infection prevalence in xenodiagnostic ticks

 
Host-to-tick transmission.
At day 13 after infection (xenodiagnosis 1), host-to-tick transmission efficiency was high in all four experimental groups, when overall 117 of 145 ticks (80.6%) were PCR positive. Transmission efficiency declined in all groups at subsequent xenodiagnoses, with 56 of 150 (37.3%) and 34 of 150 (22.7%) xenodiagnostic ticks being PCR positive at days 40 and 79 postinfection, respectively (Table 1). There were significant differences among treatments and among xenodiagnoses (Table 1 and Fig. 1). Accounting for treatment groups, there were significant differences among xenodiagnoses in the likelihood that a tick acquired infection. Ticks that fed on rodents at days 40 and 79 postinfection (xenodiagnoses 2 and 3, respectively) were significantly less likely to acquire infection than ticks that fed at day 13 postinfection (odds ratios [ORs] of 0.11 and 0.05, 95% confidence intervals [CIs] of 0.06 to 0.20 and 0.03 to 0.10, respectively; P < 0.001 for each) (Table 1 and Fig. 1). Accounting for the xenodiagnosis number, the probability of a tick to acquire infection was significantly higher if ticks fed on white-footed mice infected with isolate BL206 or C3H/HeNCrl mice infected with either isolate than if ticks fed on white-footed mice infected with isolate B348 (ORs of 5.10, 6.92, and 4.79, respectively; 95% CIs of 2.25 to 11.54, 2.89 to 16.58, and 2.12 to 10.80, respectively; P < 0.001 for all). There was no significant difference in transmission efficiency between white-footed mice infected with isolate BL206 and C3H/HeNCrl mice infected with either isolate ({chi}2 of <1, df of 1, and P value of >0.1 for all comparisons) (Table 1 and Fig. 1). At day 13 after infection (xenodiagnosis 1) there was no significant variation in efficiency of host-to-tick transmission among the treatment groups (P > 0.1), except that ticks feeding on C3H/HeNCrl mice infected with B348 were significantly more likely to be infected than those feeding on white-footed mice infected with B348 (Tables 1 and 2). At day 40 postinfection, ticks feeding on C3H/HeNCrl mice infected with the BL206 strain were significantly more likely to acquire infection than ticks feeding on any other mouse/strain combination. The greatest differences observed were between white-footed mice infected with B348, for which transmission efficiency was particularly low, and all other mouse/isolate combinations (Tables 1 and 2). Similarly, at day 79 ticks feeding on white-footed mice infected with B348 were significantly less likely to acquire infection than ticks feeding on any other mouse/isolate combination (Tables 1 and 2).


Figure 1
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  		FIG. 1. Progression of B. burgdorferi BL206 and/or B348 host-to-tick transmission in four experimental groups of mice. Error bars indicate exact 95% CIs.

 

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  		TABLE 2. Comparisons among individual treatments at individual xenodiagnosesa

 
Western blot analysis.
All mice, regardless of mouse strain or spirochete isolate used, developed antibodies to a variety of spirochetal proteins but not to proteins in the molecular mass range of 31 to 32 kDa, the approximate molecular mass of OspA (data not shown). While there was some minor variation in the banding patterns among individual mice, none of the antibody profiles was specific for persistent or short-lived infections.


   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
By comparing the dynamics of host-to-tick transmission efficiencies in two different mouse models, we show that the fitness of two clinical B. burgdorferi isolates, BL206 and B348, varies considerably within as well as among two different rodent species. We found that the B348 isolate was more fit in C3H/HeNCrl than in white-footed mice, where its infectivity to ticks declined sharply over time. On the other hand, the BL206 isolate was more fit than B348 in both white-footed mice and C3H/HeNCrl mice. These results suggest, in principle, that the degree of host adaptation may differ substantially among strains of B. burgdorferi.

The two clinical isolates of B. burgdorferi were chosen based on the following properties. First, they represent the genetically most divergent major genotypes within B. burgdorferi, using the IGS and ospC gene as molecular markers (4, 5, 32). Second, the kinetics of spirochete dissemination in laboratory mice from the site of initial needle inoculation with cultured bacteria differs, such that the BL206 isolate is an efficient and rapid disseminator and the B348 strain is a moderate and slow disseminator (31).

Our study indicates that efficient dissemination of B. burgdorferi is positively correlated with fitness in a mouse-tick transmission system. A previous study has addressed the question of whether the transmission dynamics of BL206 and B348 in white-footed mice are affected by strain interference (6). However, the design of that study did not allow us to determine whether the two strains differ intrinsically in fitness due to possible immunity induced by superinfection with homologous and heterologous isolates. Our study, analyzing single infection regimes, clearly shows that the fitness of these two North American B. burgdorferi isolates in white-footed mice is an intrinsic property of B. burgdorferi and related to the genetic background of the bacteria.

In a previous mathematical modeling study, a theoretical tick-borne pathogen with the same assumed infection dynamics in the vertebrate host as that experimentally observed for isolate B348 (using a susceptible-infected-carrier model) survived in I. scapularis-P. leucopus transmission cycles (15, 22). However, the simulated transmission cycles were more sensitive to any reductions in tick vector abundance and rodent survival than simulations of the transmission dynamics of a strain like BL206 that persists in individual hosts. In other words, the R0 of both spirochetal pathogens could be greater than 1 in an I. scapularis-P. leucopus transmission cycle, but much smaller perturbations in tick and rodent population ecology are needed to drive the R0 of strain B348 below 1, that is, to extinction (22). Such perturbations are frequent in woodland ecosystems in the northeastern United States (12, 24).

It has been demonstrated earlier that the duration of infectiousness in white-footed mice infected with B. burgdorferi may exceed 200 days (8). Consistent with this, we demonstrated that all of the tested white-footed mice infected with isolate BL206 retained their infectiousness for at least 79 days. Although it would be premature to conclude that BL206 persists lifelong in white-footed mice, the duration of infectivity of 79 days is sufficient to span the nymphal to larval feeding interval as observed in the northeastern United States (9, 21).

White-footed mice play an important role in the maintenance of B. burgdorferi in North America (4, 11, 18, 19). It has recently been suggested that the asynchronous activity of the immature tick stages selects against short-lived infections because, in order to play effective roles as reservoirs, hosts infected during the nymphal season must remain infectious until the tick larvae emerge (15, 22, 27). Thus, as previously shown for tick-borne encephalitis virus in Europe, the overall R0 value of B. burgdorferi is directly affected by the intensity of host-to-tick transmission during the tick larval season (26). Our previous models (15, 21) allow the conclusion that both the BL206 and the B348 isolates will survive in natural I. scapularis-P. leucopus cycles; however, the R0 value and, therefore, the fitness of the isolate B348 will be considerably lower than that of BL206. This is corroborated by the much lower prevalence of B. burgdorferi IGS9 or the ospC group E (represented here by isolate B348) than IGS1 or the ospC group A (represented by isolate BL206) in questing nymphs collected in habitats of white-footed mice across the northeastern United States (4, 11, 32). It remains to be seen whether ISG9 strains of B. burgdorferi are more abundant in other parts of North America with different host communities and, potentially, different tick phenologies (22).

All mice analyzed in this study seroconverted, irrespective of whether their infectivity to ticks persisted or not. While the mice recognized a number of spirochetal proteins, none of the mice had developed antibodies to OspA, a finding that is consistent with earlier studies comparing the immune responses of mice to tick-borne infections with immune responses to needle inoculations with high numbers of cultured spirochetes (14). It is now established that, throughout the natural transmission cycle, OspA is expressed only by spirochetes present in the midgut of the tick but not by those infecting the vertebrate host (13, 28). The antibody profiles generated by the mice examined in this study did not correlate with the intensity and longevity of spirochete transmission to ticks, suggesting that antibody-mediated immune responses are not the primary forces of differential fitness of the spirochetal isolates. It remains to be analyzed whether adaptive cellular immunity or innate immunity differentially controls transmission of B. burgdorferi strains from hosts to ticks.

For a number of European isolates of B. burgdorferi sensu lato, it has been shown that host association is mediated by the alternative pathway of host complement, an important arm of innate immunity (1, 13, 15). Thus, it is possible that the differential fitness of North American strains of B. burgdorferi in white-footed mice is also driven by innate immunity. Spirochetal genotypes that can infect a particular host species strongly bind complement inhibitors, such as factor H, thereby evading complement-mediated lysis (1, 29). Several outer surface proteins are involved in binding complement inhibitors; a number of these are encoded by paralogous genes located on the cp32 circular plasmids of the spirochetes. It is interesting that B. burgdorferi isolate B348 lacks cp32-1 and cp32-8 (30), which encode two members of the PF162 paralogous gene family (BBP38 and BBL39) that have been shown to possess factor H-binding activity (1, 20). In contrast, BL206 harbors all known cp32 plasmids (30). Although B348 possesses two other members of the PF162 family (BBN38 and BBR40), it is possible that isolate B348 has a reduced repertoire of factor H-binding proteins and has, therefore, partially lost its ability to bind factor H of white-footed mice. On the other hand, a recent study has suggested that binding of factor H is not the only mechanism whereby transmissible spirochetes evade complement-mediated killing (34).

In conclusion, our results provide proof-of-principle evidence for fitness variation of B. burgdorferi genotypes among vertebrate species. Thus, while most genotypes of B. burgdorferi circulating in the northeastern United States are more or less generalist microparasites (11), the finding of our study that some strains are short-lived in white-footed mice may indicate the beginnings of diversification and adaptive radiation of this spirochetal species into subtypes or "races" that are more specialized to other vertebrate species (13).


   ACKNOWLEDGMENTS
 
This research was supported by National Institutes of Health grant AR41511 (to I.S.); the Wellcome Trust, London, United Kingdom (to K.K.); the U.S. Department of Agriculture, Agriculture Research Service Cooperative Agreements 58-0790-7-073 and 58-079-5-068; and the G. Harold and Leila Y. Mathers Charitable Foundation (to D.F.).

We thank L. Rollend for technical assistance.


   FOOTNOTES
 
* Corresponding author. Present address: Department of Microbiology and Immunology, New York Medical College, Valhalla, NY 10595. Phone: (914) 594-4185. Fax: (914) 594-4176. E-mail: klara_hanincova{at}nymc.edu Back

{triangledown} Published ahead of print on 2 November 2007. Back

{dagger} Present address: Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, United Kingdom. Back


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Applied and Environmental Microbiology, January 2008, p. 153-157, Vol. 74, No. 1
0099-2240/08/$08.00+0     doi:10.1128/AEM.01567-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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