Borrelia burgdorferi Promotes the Establishment of Babesia microti in the Northeastern United States

Babesia microti and Borrelia burgdorferi, the respective causative agents of human babesiosis and Lyme disease, are maintained in their enzootic cycles by the blacklegged tick (Ixodes scapularis) and use the white-footed mouse (Peromyscus leucopus) as primary reservoir host. The geographic range of both pathogens has expanded in the United States, but the spread of babesiosis has lagged behind that of Lyme disease. Several studies have estimated the basic reproduction number (R 0) for B. microti to be below the threshold for persistence (<1), a finding that is inconsistent with the persistence and geographic expansion of this pathogen. We tested the hypothesis that host coinfection with B. burgdorferi increases the likelihood of B. microti transmission and establishment in new areas. We fed I. scapularis larva on P. leucopus mice that had been infected in the laboratory with B. microti and/or B. burgdorferi. We observed that coinfection in mice increases the frequency of B. microti infected ticks. To identify the ecological variables that would increase the probability of B. microti establishment in the field, we integrated our laboratory data with field data on tick burden and feeding activity in an R 0 model. Our model predicts that high prevalence of B. burgdorferi infected mice lowers the ecological threshold for B. microti establishment, especially at sites where larval burden on P. leucopus is lower and where larvae feed simultaneously or soon after nymphs infect mice, when most of the transmission enhancement due to coinfection occurs. Our studies suggest that B. burgdorferi contributes to the emergence and expansion of B. microti and provides a model to predict the ecological factors that are sufficient for emergence of B. microti in the wild.

[1]  Niko Speybroeck,et al.  Consequences of Landscape Fragmentation on Lyme Disease Risk: A Cellular Automata Approach , 2012, PloS one.

[2]  S. Anderson,et al.  Babesiosis among Elderly Medicare Beneficiaries, United States, 2006–2008 , 2012, Emerging infectious diseases.

[3]  G. Wormser,et al.  Multilocus Sequence Typing of Borrelia burgdorferi Suggests Existence of Lineages with Differential Pathogenic Properties in Humans , 2013, PloS one.

[4]  L. Myer,et al.  Impact of HIV infection on the epidemiology of tuberculosis in a peri-urban community in South Africa: the need for age-specific interventions. , 2006, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[5]  S. Telford,et al.  Monitoring Human Babesiosis Emergence through Vector Surveillance New England, USA , 2014, Emerging infectious diseases.

[6]  E. Walker,et al.  Invasion of the Lyme Disease Vector Ixodes scapularis: Implications for Borrelia burgdorferi Endemicity , 2010, EcoHealth.

[7]  R. Ostfeld,et al.  Reservoir targeted vaccine against Borrelia burgdorferi: a new strategy to prevent Lyme disease transmission. , 2014, The Journal of infectious diseases.

[8]  D. Dykhuizen,et al.  Four Clones of Borrelia burgdorferiSensu Stricto Cause Invasive Infection in Humans , 1999, Infection and Immunity.

[9]  Barbara Mayer,et al.  Mathematical Epidemiology Of Infectious Diseases Model Building Analysis And Interpretation , 2016 .

[10]  D. P. Snyder Survival rates, longevity, and population fluctuations in the white-footed mouse, Peromyscus leucopus, in southeastern Michigan , 1956 .

[11]  David Hinkley,et al.  Bootstrap Methods: Another Look at the Jackknife , 2008 .

[12]  W. Gause,et al.  Effect of helminth-induced immunity on infections with microbial pathogens , 2013, Nature Immunology.

[13]  E. Fikrig,et al.  Prevention of Borrelia burgdorferi transmission in guinea pigs by tick immunity. , 1998, The American journal of tropical medicine and hygiene.

[14]  R. Nadelman,et al.  Molecular typing of Borrelia burgdorferi from Lyme disease patients by PCR-restriction fragment length polymorphism analysis , 1996, Journal of clinical microbiology.

[15]  D. Fish,et al.  Interference between the agents of Lyme disease and human granulocytic ehrlichiosis in a natural reservoir host. , 2001, Vector borne and zoonotic diseases.

[16]  C. Fuqua,et al.  Infection and Co-infection Rates of Anaplasma phagocytophilum Variants, Babesia spp., Borrelia burgdorferi, and the Rickettsial Endosymbiont in Ixodes scapularis (Acari: Ixodidae) from Sites in Indiana, Maine, Pennsylvania, and Wisconsin , 2008, Journal of medical entomology.

[17]  L. Bockenstedt,et al.  MyD88 Deficiency Enhances Acquisition and Transmission of Borrelia burgdorferi by Ixodes scapularis Ticks , 2006, Infection and Immunity.

[18]  J. Brownstein,et al.  Interaction and Transmission of Two Borrelia burgdorferi Sensu Stricto Strains in a Tick-Rodent Maintenance System , 2004, Applied and Environmental Microbiology.

[19]  R. Nadelman,et al.  Borrelia burgdorferi genotype predicts the capacity for hematogenous dissemination during early Lyme disease. , 2008, The Journal of infectious diseases.

[20]  A. Spielman,et al.  Comparative prevalence of Babesia microti and Borrelia burgdorferi in four populations of Ixodes dammini in eastern Massachusetts. , 1986, Acta tropica.

[21]  E. Fikrig,et al.  Human Borrelia miyamotoi infection in the United States. , 2013, The New England journal of medicine.

[22]  S. Davis,et al.  Loop analysis for pathogens: niche partitioning in the transmission graph for pathogens of the North American tick Ixodes scapularis. , 2011, Journal of theoretical biology.

[23]  P. Hudson,et al.  Pathogen Interactions, Population Cycles, and Phase Shifts , 2007, The American Naturalist.

[24]  R. Pollack,et al.  Concurrent Lyme disease and babesiosis. Evidence for increased severity and duration of illness. , 1996, JAMA.

[25]  T. Giraud,et al.  COMPETITION, COOPERATION AMONG KIN, AND VIRULENCE IN MULTIPLE INFECTIONS , 2011, Evolution; international journal of organic evolution.

[26]  R. C. Johnson,et al.  Coexistence of antibodies to tick-borne pathogens of babesiosis, ehrlichiosis, and Lyme borreliosis in human sera , 1995, Journal of clinical microbiology.

[27]  D. Fish,et al.  Coinfection with Borrelia burgdorferi and the agent of human granulocytic ehrlichiosis suppresses IL‐2 and IFNγ production and promotes an IL‐4 response in C3H/HeJ mice , 2000, Parasite immunology.

[28]  D. Brisson,et al.  The effect of spatial heterogenity on the aggregation of ticks on white-footed mice , 2012, Parasitology.

[29]  J. Anderson,et al.  Babesia microti, human babesiosis, and Borrelia burgdorferi in Connecticut , 1991, Journal of clinical microbiology.

[30]  M. Diuk-Wasser,et al.  Lyme disease risk not amplified in a species-poor vertebrate community: similar Borrelia burgdorferi tick infection prevalence and OspC genotype frequencies. , 2014, Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases.

[31]  M. Begon,et al.  Species Interactions in a Parasite Community Drive Infection Risk in a Wildlife Population , 2010, Science.

[32]  R. Nadelman,et al.  Babesiosis in Lower Hudson Valley, New York, USA , 2011, Emerging infectious diseases.

[33]  R. Nadelman,et al.  Genetic Diversity of Borrelia burgdorferi in Lyme Disease Patients as Determined by Culture versus Direct PCR with Clinical Specimens , 1999, Journal of Clinical Microbiology.

[34]  Lee R. Gibson,et al.  Treating cofactors can reverse the expansion of a primary disease epidemic , 2010, BMC infectious diseases.

[35]  H. Ginsberg Potential effects of mixed infections in ticks on transmission dynamics of pathogens: comparative analysis of published records , 2008, Experimental and Applied Acarology.

[36]  R. Ostfeld,et al.  Multiple causes of variable tick burdens on small-mammal hosts. , 2008, Ecology.

[37]  D. Fish,et al.  Sequence typing reveals extensive strain diversity of the Lyme borreliosis agents Borrelia burgdorferi in North America and Borrelia afzelii in Europe. , 2004, Microbiology.

[38]  R. C. Johnson,et al.  Prevalence of Borrelia burgdorferi and Babesia microti in mice on islands inhabited by white-tailed deer , 1987, Applied and environmental microbiology.

[39]  S. Telford,et al.  Increasing health burden of human babesiosis in endemic sites. , 2003, The American journal of tropical medicine and hygiene.

[40]  T. Hartung,et al.  Borrelia burgdorferi-Induced Tolerance as a Model of Persistence via Immunosuppression , 2003, Infection and Immunity.

[41]  C. Sokhna,et al.  Worms can worsen malaria: towards a new means to roll back malaria? , 2005, Trends in parasitology.

[42]  E. Walker,et al.  Synchronous phenology of juvenile Ixodes scapularis, vertebrate host relationships, and associated patterns of Borrelia burgdorferi ribotypes in the midwestern United States. , 2012, Ticks and tick-borne diseases.

[43]  N. Ogden,et al.  Predicting the rate of invasion of the agent of Lyme disease Borrelia burgdorferi , 2013 .

[44]  D. Fish,et al.  Borrelia burgdorferi infection in a natural population of Peromyscus Leucopus mice: a longitudinal study in an area where Lyme Borreliosis is highly endemic. , 2004, The Journal of infectious diseases.

[45]  D. Fish,et al.  Acquisition of Coinfection and Simultaneous Transmission of Borrelia burgdorferi and Ehrlichia phagocytophila by Ixodes scapularis Ticks , 2000, Infection and Immunity.

[46]  F. Cox Human babesiosis , 1980, Nature.

[47]  Durland Fish,et al.  Human risk of infection with Borrelia burgdorferi, the Lyme disease agent, in eastern United States. , 2012, The American journal of tropical medicine and hygiene.

[48]  A. Spielman,et al.  Babesia microti: infectivity of parasites from ticks for hamsters and white-footed mice. , 1982, Experimental parasitology.

[49]  D J Rogers,et al.  Seasonal synchrony: the key to tick-borne encephalitis foci identified by satellite data , 2000, Parasitology.

[50]  John F Anderson,et al.  Infection with Agents of Human Granulocytic Ehrlichiosis, Lyme Disease, and Babesiosis in Wild White-Footed Mice (Peromyscus leucopus) in Connecticut , 1999, Journal of Clinical Microbiology.

[51]  G. Wormser,et al.  Impact of Genotypic Variation of Borrelia burgdorferi Sensu Stricto on Kinetics of Dissemination and Severity of Disease in C3H/HeJ Mice , 2001, Infection and Immunity.

[52]  E. Belongia Epidemiology and impact of coinfections acquired from Ixodes ticks. , 2002, Vector borne and zoonotic diseases.

[53]  Choukri Ben Mamoun,et al.  Quantitative PCR for detection of Babesia microti in Ixodes scapularis ticks and in human blood. , 2013, Vector borne and zoonotic diseases.

[54]  Anne G. Hoen,et al.  Field and climate-based model for predicting the density of host-seeking nymphal Ixodes scapularis, an important vector of tick-borne disease agents in the eastern United States , 2010 .

[55]  S. Telford,et al.  Concurrent Borrelia burgdorferi and Babesia microti infection in nymphal Ixodes dammini , 1986, Journal of clinical microbiology.

[56]  S. Telford,et al.  Geographical and temporal distribution of babesial infection in Connecticut , 1991, Journal of clinical microbiology.

[57]  Stafford,et al.  ANTIBODIES TO MULTIPLE TICK-BORNE PATHOGENS OF BABESIOSIS, EHRLICHIOSIS, AND LYME BORRELIOSIS IN WHITE-FOOTED MICE , 1997, Journal of wildlife diseases.

[58]  A. Spielman,et al.  Duration of tick attachment and Borrelia burgdorferi transmission , 1987, Journal of clinical microbiology.

[59]  A. Spielman,et al.  Babesia microti Primarily Invades Mature Erythrocytes in Mice , 2006, Infection and Immunity.

[60]  D. Fish,et al.  Climate and Tick Seasonality Are Predictors of Borrelia burgdorferi Genotype Distribution , 2009, Applied and Environmental Microbiology.

[61]  Scott C. Williams,et al.  SERUM ANTIBODIES TO BORRELIA BURGDORFERI, ANAPLASMA PHAGOCYTOPHILUM, AND BABESIA MICROTI IN RECAPTURED WHITE-FOOTED MICE , 2013, Journal of wildlife diseases.

[62]  J A P Heesterbeek,et al.  The Basic Reproduction Number for Complex Disease Systems: Defining R0 for Tick‐Borne Infections , 2008, The American Naturalist.

[63]  Christopher J. Graves,et al.  Reductions in human Lyme disease risk due to the effects of oral vaccination on tick-to-mouse and mouse-to-tick transmission. , 2013, Vector borne and zoonotic diseases.

[64]  W. Lipkin,et al.  Assessment of polymicrobial infections in ticks in New York state. , 2010, Vector borne and zoonotic diseases.

[65]  D. Fish,et al.  Fitness Variation of Borrelia burgdorferi Sensu Stricto Strains in Mice , 2007, Applied and Environmental Microbiology.

[66]  I. Schwartz,et al.  Prevalence of tick-borne pathogens in Ixodes scapularis in a rural New Jersey County. , 1998, Emerging infectious diseases.

[67]  V. Ezenwa,et al.  From host immunity to pathogen invasion: the effects of helminth coinfection on the dynamics of microparasites. , 2011, Integrative and comparative biology.

[68]  D. Fish,et al.  An ecological approach to preventing human infection: Vaccinating wild mouse reservoirs intervenes in the Lyme disease cycle , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[69]  Frank Diederich,et al.  Mathematical Epidemiology Of Infectious Diseases Model Building Analysis And Interpretation , 2016 .

[70]  Kate E. Jones,et al.  Global trends in emerging infectious diseases , 2008, Nature.

[71]  S. Telford,et al.  Borrelia burgdorferi and Babesia microti: efficiency of transmission from reservoirs to vector ticks (Ixodes dammini). , 1990, Experimental parasitology.

[72]  R. Nadelman,et al.  Association of specific subtypes of Borrelia burgdorferi with hematogenous dissemination in early Lyme disease. , 1999, The Journal of infectious diseases.

[73]  B. Lina,et al.  Rhinoviruses delayed the circulation of the pandemic influenza A (H1N1) 2009 virus in France. , 2010, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[74]  D. Fish,et al.  A relapsing fever group spirochete transmitted by Ixodes scapularis ticks. , 2001, Vector borne and zoonotic diseases.

[75]  H. Ginsberg Ecology and environmental management of Lyme disease. , 1993 .

[76]  E. Belongia,et al.  Coinfections Acquired from Ixodes Ticks , 2006, Clinical Microbiology Reviews.

[77]  S. Davis,et al.  A simple model for the establishment of tick-borne pathogens of Ixodes scapularis: a global sensitivity analysis of R0. , 2013, Journal of theoretical biology.

[78]  V. Dennis,et al.  Borrelia burgdorferi Stimulates the Production of Interleukin-10 in Peripheral Blood Mononuclear Cells from Uninfected Humans and Rhesus Monkeys , 1998, Infection and Immunity.

[79]  R. Ostfeld,et al.  Reservoir Competence of Wildlife Host Species for Babesia microti , 2012, Emerging infectious diseases.

[80]  G. Ebel,et al.  Persistence of Pathogens with Short Infectious Periods in Seasonal Tick Populations: The Relative Importance of Three Transmission Routes , 2010, PloS one.