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

doi:10.1016/j.pt.2015.09.008

Trends in Parasitology

Volume 32, Issue 1, January 2016, Pages 30-42

https://doi.org/10.1016/j.pt.2015.09.008 Get rights and content

Trends

Coinfection by Borrelia burgdorferi, the primary agent of Lyme disease, and Babesia microti, the primary agent of babesiosis, is a useful model to study vector-borne pathogen interaction.

Borrelia burgdorferi increases B. microti transmission from Peromyscus leucopus mice to Ixodes scapularis ticks. Coinfection likely contributes to the emergence of babesiosis in areas endemic for Lyme disease.

The frequency of concurrent Lyme disease and babesiosis varies temporally and geographically. The number and duration of symptoms are greater in coinfected patients than in those with Lyme disease alone.

Modeling the emergence of tick-borne infections should incorporate pathogen interactions within realistic epidemiological and ecological contexts.

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.

Section snippets

Ixodes-Borne Pathogens as a Model System to Study Vector-Borne Coinfection

Wildlife and humans are frequently infected by multiple pathogens or several genotypes of a single pathogen 1, 2. Coinfecting pathogens can interact among themselves and with host symbionts for utilization of host resources or through modulation of host immunity 3, 4. Positive interactions (facilitation) may favor the emergence (see Glossary) of an invading pathogen or increase the prevalence of an established pathogen. Negative interactions (competition) may prevent the establishment of an

Coinfection with Ixodes-Borne Pathogens is Prevalent Worldwide

Ticks in the I. ricinus species complex have a Holartic distribution but are restricted to the regions with temperate climates 5, 10. Four species within this complex account for most of the transmission of human Ixodes-borne pathogens: Ixodes pacificus is primarily found along the Pacific coast of the USA; Ixodes scapularis in the Northeast, upper Midwest and South of the USA; I. ricinus across Europe, in parts of northern Africa, Turkey, and the Caucasus; and Ixodes persulcatus from

The emergence of babesiosis occurs within Lyme disease-endemic areas

The first case of babesiosis caused by B. microti in the USA was identified in 1969 in an immunocompetent individual who had summered on Nantucket Island, MA [8]. Shortly thereafter, the disease was recognized on other islands off the coast of southern New England and on the mainland, particularly in coastal counties ranging from MA to NJ. Another endemic area was identified in the upper Midwest. Over the following two decades, the number of cases reported to local public health departments

Coinfection facilitates maintenance of B. burgdorferi and B. microti in the enzootic cycle

Single and concurrent B. burgdorferi and B. microti infections have been well documented in I. scapularis ticks and enzootic reservoir hosts (Table 1). Single infections with Borrelia burgdorferi are consistently more prevalent than single infections with B. microti in both ticks and reservoir hosts. Among ticks, the prevalence of B. burgdorferi and B. microti coinfection ranges from 0% to 19% in nymphs and from 0% to 17% in adults 17, 22, 50, 56, 57, 58, 59, 60, 61, 62, 63. The prevalence of

Concurrent babesiosis exacerbates and prolongs the symptoms of Lyme disease

Initial case reports suggested that concurrent Lyme disease and babesiosis are associated with severe illness. Each of the first three reported cases of Lyme disease and babesiosis coinfection was admitted to the hospital 74, 75, 76. One patient required blood transfusion and multiple joint aspirations for a recurrent swollen knee, another developed pulmonary edema despite appropriate antibiotic therapy, and a third died of fatal pancarditis. The first prospective study of Lyme disease and

Future Directions

Lyme disease and babesiosis are expected to remain serious health threats and other tick-borne diseases are likely to emerge. Predicting the enzootic emergence of tick-borne pathogens will help anticipate the increase in incidence of tick-borne human diseases and may help develop ecological and public health measures to manage these health threats.

Concluding Remarks

The geographic expansion of I. scapularis has greatly contributed to increase the incidence of tick-borne diseases in the USA. Of the six human pathogens that I. scapularis transmits separately or in combination 8, 11, 14, 28, 30, 31, 44, 97, we focused on B. burgdorferi and B. microti because coinfection with these two pathogens is frequent in the enzootic cycle and can cause severe disease in humans. The emergence of babesiosis on the heels of Lyme disease is explained, in part, by the effect

Acknowledgments

The authors thank Kiersten Kugeler and Elizabeth Gray for providing surveillance data on Lyme disease and babesiosis; Stephen Davis, Aurelie Kern, and Max McClure for helpful discussions; and Sarah States for help with figure production. The authors acknowledge support by the Gordon and Llura Gund Foundation (to P.J.K. and E.V.) and the National Institutes of Health (R01 GM105246 to M.A.D-W. and R44HL127698 to P.J.K.).

Glossary

Basic reproductive number (R₀): a standard measure of pathogen transmissibility. R₀ measures the average number of secondary cases caused by a pathogen in a completely susceptible population. It is also considered a measure of population fitness and can be interpreted as the likelihood that a pathogen will become established (R₀ >1) or extinct (R₀ <1) when introduced into a population of naive, fully susceptible hosts.
Coinfection: simultaneous infection of a host by two or more pathogen species or

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Ticks are important vectors of many pathogens in Europe, where the most impactful species is Ixodes ricinus. Recently, the geographical distribution of this tick species has been expanding, resulting in an increased risk of human exposure to tick bites. With the present study, we aimed to screen 350 I. ricinus specimens collected from humans and wild animals (mainly ungulates), to have a broader understanding of the tick-borne pathogens circulating in the Lombardy region, in northern Italy. To do so, we took advantage of a high-throughput real-time microfluidic PCR approach to screen ticks in a cost-effective and time-saving manner. Molecular analysis of the dataset revealed the presence of four genera of bacteria and two genera of protozoa: in ungulates, 77 % of collected ticks carried Anaplasma phagocytophilum, while the most common pathogen species in ticks removed from humans were those belonging to Borrelia burgdorferi sensu lato group (7.6 %). We also detected other pathogenic microorganisms, such as Rickettisa monacensis, Rickettsia helvetica, Neoehrlichia mikurensis, Babesia venatorum, and Hepatozoon martis. Besides, we also reported the presence of the pathogenic agent Borrelia miyamotoi in the area (1.4 % overall). The most common dual co-infection detected in the same tick individual involved A. phagocytophilum and Rickettsia spp. Our study provided evidence of the circulation of different tick-borne pathogens in a densely populated region in Italy.
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Trends in Parasitology

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

Trends

Section snippets

Ixodes-Borne Pathogens as a Model System to Study Vector-Borne Coinfection

Coinfection with Ixodes-Borne Pathogens is Prevalent Worldwide

The emergence of babesiosis occurs within Lyme disease-endemic areas

Coinfection facilitates maintenance of B. burgdorferi and B. microti in the enzootic cycle

Concurrent babesiosis exacerbates and prolongs the symptoms of Lyme disease

Future Directions

Concluding Remarks

Acknowledgments

Glossary

Trends Parasitol.

Infect. Dis. Clin. North Am.

Clin. Microbiol. Infect.

Lancet Infect. Dis.

Int J. Parasitol.

Infect. Dis. Clin. North Am.

Exp. Parasitol.

J. Theor. Biol.

Am. J. Med.

Epidemics

Epidemics

Epidemics

Trends Ecol. Evol.

Infect. Dis. Clin. North Am.

J. Theor. Biol.

Why infectious disease research needs community ecology

Science

Analysis of a summary network of co-infection in humans reveals that parasites interact most via shared resources

Proc. Biol. Sci.

Ecological rules governing helminth-microparasite coinfection

Proc. Natl. Acad. Sci. U.S.A.

Coinfections acquired from Ixodes ticks

Clin. Microbiol. Rev.

Serum antibodies to Borrelia burgdorferi, Anaplasma phagocytophilum, and Babesia microti in recaptured white-footed mice

J. Wildl Dis.

Lyme disease

N. Engl. J. Med.

Human babesiosis

N. Engl. J. Med.

Borrelia burgdorferi promotes the establishment of Babesia microti in the northeastern United States

PLoS ONE

Molecular phylogenetic analyses indicate that the Ixodes ricinus complex is a paraphyletic group

J. Parasitol.

Phylogeny of North American Powassan virus

J. Gen. Virol.

Emergence of a new pathogenic Ehrlichia species, Wisconsin and Minnesota, 2009

N. Engl. J. Med.

Ixodes ricinus and its transmitted pathogens in urban and peri-urban areas in Europe: new hazards and relevance for public health

Front. Public Health

Molecular detection of Rickettsia, Borrelia, and Babesia species in Ixodes ricinus sampled in northeastern, central, and insular areas of Italy

Exp. Appl. Acarol.

Co-infection of blacklegged ticks with Babesia microti and Borrelia burgdorferi is higher than expected and acquired from small mammal hosts

PLoS ONE

Infections and coinfections of questing Ixodes ricinus ticks by emerging zoonotic pathogens in Western Switzerland

Appl. Environ. Microbiol.

High-throughput screening of tick-borne pathogens in Europe

Front. Cell. Infect. Microbiol.

Comparison of tick-borne microorganism communities in Ixodes spp. of the Ixodes ricinus species complex at distinct geographical regions

Exp. Appl. Acarol.

Meta-analysis of coinfection and coexposure with Borrelia burgdorferi and Anaplasma phagocytophilum in humans, domestic animals, wildlife, and Ixodes ricinus-complex ticks

Vector Borne Zoonotic Dis.

Prevalence of Borrelia burgdorferi (Spirochaetales: Spirochaetaceae), Anaplasma phagocytophilum (Rickettsiales: Anaplasmataceae), and Babesia microti (Piroplasmida: Babesiidae) in Ixodes scapularis (Acari: Ixodidae) collected from recreational lands in the Hudson Valley Region, New York State

J. Med. Entomol.

Cosegregation of a novel Bartonella species with Borrelia burgdorferi and Babesia microti in Peromyscus leucopus

J. Infect. Dis.

Prospective assessment of the etiology of acute febrile illness after a tick bite in Slovenia

Clin. Infect. Dis.

Co-infections with Borrelia species, Anaplasma phagocytophilum and Babesia spp. in patients with tick-borne encephalitis

Eur. J. Clin. Microbiol. Infect. Dis.

Coinfecting deer-associated zoonoses: Lyme disease, babesiosis, and ehrlichiosis

Clin. Infect. Dis.

Borrelia miyamotoi disease in the Northeastern United States: a case series

Ann. Intern. Med.

Borrelia miyamotoi sensu lato seroreactivity and seroprevalence in the northeastern United States

Emerg. Infect. Dis.

Disease-specific diagnosis of coinfecting tickborne zoonoses: babesiosis, human granulocytic ehrlichiosis, and Lyme disease

Clin. Infect. Dis.

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