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Review

Human Borrelia miyamotoi Infection in North America

by
Jed Burde
1,
Evan M. Bloch
2,
Jill R. Kelly
3 and
Peter J. Krause
1,4,*
1
Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT 06520, USA
2
Division of Transfusion Medicine, Department of Pathology, Johns Hopkins University, Baltimore, MD 21217, USA
3
Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT 06520, USA
4
Department of Medicine, Yale School of Medicine, New Haven, CT 06510, USA
*
Author to whom correspondence should be addressed.
Pathogens 2023, 12(4), 553; https://doi.org/10.3390/pathogens12040553
Submission received: 31 January 2023 / Revised: 27 March 2023 / Accepted: 29 March 2023 / Published: 3 April 2023
(This article belongs to the Special Issue Pathogenesis, Epidemiology, Host Response and Control of Lyme Disease and Other Tick-Borne Diseases)
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Abstract

:
Borrelia miyamotoi is an emerging pathogen that causes a febrile illness and is transmitted by the same hard-bodied (ixodid) ticks that transmit several other pathogens, including Borrelia species that cause Lyme disease. B. miyamotoi was discovered in 1994 in Ixodes persulcatus ticks in Japan. It was first reported in humans in 2011 in Russia. It has subsequently been reported in North America, Europe, and Asia. B. miyamotoi infection is widespread in Ixodes ticks in the northeastern, northern Midwestern, and far western United States and in Canada. In endemic areas, human B. miyamotoi seroprevalence averages from 1 to 3% of the population, compared with 15 to 20% for B. burgdorferi. The most common clinical manifestations of B. miyamotoi infection are fever, fatigue, headache, chills, myalgia, arthralgia, and nausea. Complications include relapsing fever and rarely, meningoencephalitis. Because clinical manifestations are nonspecific, diagnosis requires laboratory confirmation by PCR or blood smear examination. Antibiotics are effective in clearing infection and are the same as those used for Lyme disease, including doxycycline, tetracycline, erythromycin, penicillin, and ceftriaxone. Preventive measures include avoiding areas where B. miyamotoi-infected ticks are found, landscape management, and personal protective strategies such as protective clothing, use of acaricides, and tick checks with rapid removal of embedded ticks.

1. Epidemiology

1.1. Introduction

Scientists discovered a new Borrelia species in 1994 while screening Ixodes persulcatus ticks and Apodemus argenteus field mice for Borrelia infection in Hokkaido, Japan [1]. The microorganism was named Borrelia miyamotoi in honor of Kenji Miyamoto, an entomologist who was the first to isolate spirochetes from hard-bodied ticks in Japan. Phylogenetic analysis confirmed that this microorganism belongs to the relapsing fever Borrelia group. This is surprising because relapsing fever Borrelia are characteristically transmitted by soft-bodied (argasid) ticks, while Lyme disease Borrelia are transmitted by hard-bodied (ixodid) ticks [2,3]. The discovery of B. miyamotoi-infected I. scapularis ticks in Connecticut, USA confirmed that these bacteria were transmitted by Ixodes ticks and that it had a broad geographic distribution [4]. B. miyamotoi was thought to be an endosymbiont until 2011 when human B. miyamotoi infection was described by Platonov and colleagues in 46 residents of Yekaterinburg City, Russia [5]. All patients experienced a viral-like illness and about a tenth had relapsing fever. Relapsing fever may have been more common had the patients not been treated with antibiotic relatively early in the course of their disease. Numerous cases and serological evidence of past B. miyamotoi infection in humans subsequently were described in North America, Europe, and Asia [6,7,8,9,10,11]. Genotypic and phenotypic features of B. miyamotoi that are characteristic of relapsing fever Borrelia include transstadial and transovarial tick transmission, generation of a higher Borrelia burden in the blood than in the skin, relapsing fever, and a glycerophosphodiester phosphodiesterase (GlpQ) protein that is found in relapsing fever Borrelia but not in Lyme disease Borrelia [12,13,14,15,16]. B. miyamotoi-infected female ticks can pass the infection to their eggs, so that some larval ticks are infected and can then transmit the infection to a vertebrate host (transovarial transmission) [17,18]. Other larvae become infected after taking a blood meal on an infected mouse reservoir host, molt to the nymphal stage, and then transmit infection to another mouse or human (transstadial transmission). Transovarially infected larvae may be the primary source of B. miyamotoi infection in vertebrate hosts [18]. The presence of high blood concentrations of B. miyamotoi on blood smear and the detection of antibodies in a GlpQ-based antibody assay help to confirm B. miyamotoi infection and distinguish it from Lyme disease [7,8,14]. In this review, we focus on the epidemiology and clinical manifestations of B. miyamotoi in North America. We discuss the frequency and location of infection in ticks and people, clinical presentation and complications, diagnosis, treatment, and prevention.

1.2. The Organism

B. miyamotoi is a relapsing fever spirochete in the genus Borrelia. Borrelia is divided into two main clades, the Borrelia burgdorferi sensu lato group and the relapsing fever group. The B. burgdorferi sensu lato group contains 20 species, including the causative agents of Lyme borreliosis, and are solely transmitted by hard-bodied ticks. The relapsing fever group consists of 25 species that includes Borrelia miyamotoi [10,11]. Most of the relapsing fever species are transmitted by soft-bodied ticks but some species are transmitted by hard-bodied ticks (B. miyamotoi, Borrelia lonestari, Borrelia theileri) or by lice (Borrelia recurrentis). B. miyamotoi shares phenotypic characteristics of the relapsing fever group such as relapsing fever, a high level of spirochetemia in blood, and transovarial transmission; however, it also has some characteristics of the B. burgdorferi sensu lato group, most notably transmission by hard-bodied ticks. [7,8,10,13,19].
Phylogenetic analyses of the B. miyamotoi genome have provided important insights into the differences between B. miyamotoi, the Lyme disease Borrelia, and other relapsing fever Borrelia [12,19,20,21,22,23,24,25,26,27,28]. A complete genomic sequencing revealed that the genome consists of 1362 genes on one linear chromosome and 12 linear and 2 circular plasmids [26,27]. There are genetic similarities between B. miyamotoi and other relapsing fever Borrelia spp., as reflected by broadly cross-reacting antibodies that may complicate diagnostic identification of B. miyamotoi from other relapsing fever species [29]. At the same time, there is strong evidence of genetic differences between B. miyamotoi and other relapsing fever Borrelia and between different B. miyamotoi isolates. Genetic analysis of B. miyamotoi tick isolates suggest that these microorganisms belong to a species complex (B. miyamotoi sensu lato) with Asian, European, and North American genotypes. Differences between isolates may not be due to geographic location, however, but rather to vector competence or host range [8,11,19,27,28]. Further investigation is needed to confirm this hypothesis. Genes that encode for variable membrane proteins (VMPs) have been found in various plasmids of B. miyamotoi [24,27]. Similar gene families in other relapsing fever species trigger change in outer membrane proteins during the course of infection as a host immune evasion strategy. These changes render antibodies that are directed against previous outer membrane proteins of the microorganism ineffective against the new gene-altered outer membrane. Recurrent clinical relapses are characteristic of relapsing fever Borrelia infections. Another relapsing fever Borrelia gene of interest is the glycerophosphodiester phosphodiesterase (GlpQ) biosynthetic gene that is absent in B. burgdorferi species [14]. The presence of antibodies against B. miyamotoi GlpQ antigen thus helps to distinguish illness due to B. miyamotoi infection from that due to B. burgdorferi [7,14,16,30].

1.3. Ecology

Borrelia miyamotoi is transmitted to humans by Ixodes ticks after they acquire the spirochete from animal reservoirs (Figure 1). Four tick species account for most transmission: Ixodes scapularis and Ixodes pacificus in North America, Ixodes ricinus in Europe, and Ixodes persulcatus in Eurasia. Ixodes ovatus and Ixodes pavlovskyi transmit B. miyamotoi in northern Asia. An analysis of 101 studies of B. miyamotoi infection in 165,637 questing ticks revealed average infection values of 2.8% (95% CI 2.4–3.1%) in I. persulcatus, 1.1% (95% CI 1.0–1.2%) in I. scapularis, 1·0% (95% CI 1.0–1.1%) in I. ricinus, and 0.7% (95% CI 0.6–0.8%) in I. pacificus [6]. There is marked variability in tick infection frequencies, which may be as high as 8.9% for I. persulcatus, 5.5% for I. scapularis, and 3.8% for I. ricinus. Tick infection values of B. miyamotoi are approximately 5- to 20-fold less than for the agents of Lyme disease, anaplasmosis, and babesiosis. Coinfections occur in reservoir hosts, ticks, and humans with up to four pathogens infecting a single I. scapularis tick [31].
There are three active stages in the I. scapularis tick life cycle (larva, nymph, and adult). Each takes a blood meal from a vertebrate host in order to mature to the next stage (Figure 1). Once ingested, B. miyamotoi travels to the salivary glands and then may be transmitted to a new, uninfected reservoir host. That host then serves as a source of infection for uninfected ticks [33]. Sequential transmission from one life stage to the next (e.g., from larvae to nymph) is known as transstadial passage. B. miyamotoi also may invade the ovaries of a gravid I. scapularis female and pass transovarially to larvae. When larvae transmit the infection to vertebrates, all three tick life cycle stages transmit infection [17,18]. Although larvae, nymphs, and adults can feed on humans, nymphs are the primary vector for most Ixodes-transmitted pathogens. Interestingly, transovarially-infected larvae may be the most common tick stage transmitting B. miyamotoi infection [18,33]. Adult ticks preferentially feed on white-tailed deer (Odocoileus virginianus). An increase in the deer population during the past few decades is thought to be a major factor in the spread and increased number of I. scapularis ticks and the resulting increase in human I. scapularis-transmitted infections [33]. Although the reservoir hosts of B. miyamotoi are uncertain or unknown throughout much of its distribution, the white-footed mouse (Peromyscus leucopus) appears to be the most common reservoir host in the United States [4,33,34]. Other potential reservoir species include birds, different species of field mice, and voles [35,36,37].

1.4. Location and Prevalence

1.4.1. USA

B. miyamotoi infection is widespread in Ixodes scapularis ticks in the northeastern, northern Midwestern, and western United States [4,34,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69] (Figure 2). We analyzed the combined results of multiple studies of field collected nymphal I. scapularis ticks that were tested for both B. miyamotoi and B. burgdorferi between 1998 and 2019. An average of 1.5% ticks were infected with B. miyamotoi, and 20.4% were infected with B. burgdorferi in the Northeast (Table 1) [4,34,38,39,40,41,42,43,44,45,46,47]. Studies carried out in I. scapularis ticks in the Midwest and I. pacificus ticks in the far West from 2000 to 2016 showed an average of 2.1% and 1.2% B. miyamotoi-infected nymphal ticks, and 17.7% and 3.9% B. burgdorferi-infected nymphal ticks, respectively (Table 1) [34,38,39,48,49,50,51,52,53,54,55,56,57,58,59,60]. In contrast, the average human B. miyamotoi and B. burgdorferi seroprevalence of residents of the Northeast enrolled in four serosurveillance studies was 3.0% (0.6–5.3%) for B. miyamotoi and 10.8% (6.8–15.6%) for B. burgdorferi [16,59,70,71].

1.4.2. Canada

B. miyamotoi-infected Ixodes ticks have been detected in all Canadian provinces except Newfoundland and Labrador [72,73,74,75,76,77,78,79,80,81,82,83]. Among studies where both B. miyamotoi and B. burgdorferi infection were found at the same study sites in nymphal ticks, an average of 0.6% of ticks were infected with B. miyamotoi and 18.9% with B. burgdorferi [71,77]. No human B. miyamotoi cases have yet been reported in Canada, but a serosurvey of 10,000 blood donors in Manitoba revealed that 3% were seropositive for B. miyamotoi [81]. An increase in the tick vector population and its geographic range in Canada has been accompanied by a marked increase in Lyme disease cases. Warmer temperatures due to climate change have been implicated as a major cause of the northern expansion of I. scapularis ticks in North America [79,80,81,82]. A similar increase can be anticipated for human B. miyamotoi infection.
Table
Table 1. B. miyamotoi and B. burgdorferi infection in nymphal Ixodes ticks and humans in North America.
Table 1. B. miyamotoi and B. burgdorferi infection in nymphal Ixodes ticks and humans in North America.
SurveyLocationDatesB. miyamotoi-Infected
Average % (Range)		B. burgdorferi-Infected Average % (Range)
Human infection [16,59,70,71]
(seroprevalence)		USA Northeast1991–20183.0 (0.6–5.2)10.8 (6.8–15.6)
I. scapularis infection [4,34,38,39,40,41,42,43,44,45,46,47]USA Northeast1998–20191.5 (0–10.5)20.4 (2.6–49.7)
I. scapularis infection [34,40,44,45,46,63]USA Midwest1998–20152.1 (0–12)17.7 (3.7–41)
I. pacificus infection [48,51,53,54,55,56,57,58,60]USA
Far West		2000–20161.2 (0–3.7)3.9 (0.6–7.1)
I. scapularis infection [71,77]Canada2011–20200.6 (0–0.7)17.4 (0–33.3)
Human B. miyamotoi infection has been noted in most areas where infected ticks have been identified, although more limited in geographic range than tick infection (Figure 2). Explanations for this disparity include the possible absence of a threshold number of B. miyamotoi organisms in ticks to effectively transmit infection in some areas; missed diagnosis of human B. miyamotoi infections because patients do not seek medical care; or because healthcare workers do not make the diagnosis or do not report B. miyamotoi infections to public health authorities [84,85]. B. miyamotoi infection is not nationally reportable in the United States and is reportable in only a few states, including Connecticut, Maine, Massachusetts, Minnesota, New Jersey, Vermont, and Wisconsin. The symptoms of B. miyamotoi are usually non-specific and make diagnosis difficult. Confirmation of the diagnosis depends on laboratory testing that may not be readily available [7,8]. In contrast, Lyme disease is accompanied in most cases by a diagnostic erythema migrans rash that is usually easy to recognize and Lyme disease is nationally reportable. Nonetheless, the actual number of Lyme disease cases is thought to be about 10-fold greater than the reported number of cases [85]. The discrepancy between diagnosed and undiagnosed infection is probably even greater for B. miyamotoi, a tick-borne disease that lacks an easily identifiable clinical marker, such as the erythema migrans rash, and is less well known by health care workers and the general public.

2. Clinical Manifestations

2.1. General Clinical Course

B. miyamotoi symptoms usually begin 14 days (10–18 days) after a tick bite [6]. The most common presentation is a non-specific viral-like illness with fever that may exceed 40 °C, chills, headache, myalgia, fatigue, arthralgia, and gastrointestinal complaints (Table 2). An erythema migrans rash has been noted in about 5 % of cases [5,16,30,86,87,88,89]. The most striking clinical feature of B. miyamotoi is relapsing fever with an initial febrile episode followed by a period of wellness and then one or more additional febrile episodes. In the first report of B. miyamotoi in humans, about a tenth of 46 Russian B. miyamotoi cases experienced two to three episodes of relapsing fever [5]. The average time between relapses was 9 days with a range of 2 days to 2 weeks. In the largest case series of B. miyamotoi cases in the US, only 2 of 51 cases (4%) developed relapsing fever [5]. All other case series with 50 or more subjects have been reported from Russia, where about a tenth of patients developed relapsing fever and 5 to 9% had an erythema migrans rash [88,89,90,91]. Differences in the frequency of febrile relapses may be due in part to differences in antibiotic prescribing for a non-specific febrile illness. Frequent empiric use of antibiotics for such patients might clear the infection after the first episode of “relapsing fever” and thus prevent relapses. Such practices will decrease the number of reported cases. Differences in the frequency of relapses also may be due to different strains of B. miyamotoi or host immune differences. As many as six febrile relapses over many months have been described for relapsing fever species [2].

2.2. Coinfection

Ixodes ticks transmit six other pathogens besides B. miyamotoi, and coinfection in ticks is commonly described. Previous studies have found that coinfection of B. burgdorferi with either Babesia microti or with Anaplasma phagocytophilum are often associated with more severe disease compared with that caused by B. burgdorferi infection alone [92,93,94,95]. Human B. miyamotoi coinfection with B. burgdorferi and/or B. microti has been documented [16,30,86,88,89,96]. It is unclear whether B. miyamotoi and B. burgdorferi coinfection leads to more severe disease in humans, but no significant increase in disease complications has been noted thus far in B. miyamotoi-B. burgdorferi coinfected patients.
Table
Table 2. Common symptoms of Borrelia miyamotoi infection. US case data are derived from 4 studies that enrolled more than 5 cases [30,86,97,98]. An asterix (*) denotes symptoms that were not listed in one of the four studies. Worldwide cases are abstracted from Hoomstra et al. [6].
Table 2. Common symptoms of Borrelia miyamotoi infection. US case data are derived from 4 studies that enrolled more than 5 cases [30,86,97,98]. An asterix (*) denotes symptoms that were not listed in one of the four studies. Worldwide cases are abstracted from Hoomstra et al. [6].
SymptomUS Cases (85)
No. (%) with Symptom		Worldwide Cases (504)
No. (%) with Symptom
Fever80 (94%)479 (95%)
Chills/rigors67 (79%)343 (68%)
Headache61 (72%)432 (86%)
Myalgia60 (71%)328 (65%)
Fatigue59 (69%)197 (39%)
Arthralgia46 (54%) *225 (45%)
Abdominal complaints9 (11%) *214 (42%)
Relapsing fever3 (4%)47 (9%)
Erythema migrans rash021 (4%)

2.3. Complications

Reported complications of B. miyamotoi infection include relapsing fever that is reported in an average of 8% (range 4% to 14%) of patients and meningoencephalitis, which is a rare complication [5,30,86,87,88,89,90,91,97,98,99,100,101,102,103,104]. Advanced age and compromised immune status appear to be associated with the development of B. miyamotoi meningoencephalitis. Seven cases of B. miyamotoi meningoencephalitis (four women and three men) have been reported from Germany, the Netherlands, Sweden, and the United States, with a mean age of 68 years (range 53–80 years) [99,100,101,102,103,105]. Immune suppression was present in five of the cases; three had non-Hodgkin lymphoma, one had rheumatoid arthritis, and one had primary membranous nephropathy. Signs and symptoms included headache, fever, fatigue, confusion, cognitive slowing, memory loss, dizziness, hearing loss, neck stiffness, photophobia, ataxia, facial droop and numbness, and uveitis. The duration from disease onset to hospital admission averaged 11 weeks (range 5 days–9 months). Treatment consisted of ampicillin, ceftriaxone, doxycycline, and/or penicillin, and all but one had initial IV therapy. One patient developed a Jarisch–Herxheimer reaction after IV infusion of ceftriaxone and was switched to IV penicillin. Another experienced persistent facial numbness but the other patients had complete recovery following antibiotic therapy [98]. None of the B. miyamotoi meningoencephalitis patients experienced coinfection.
It is possible that one or more additional complications described for other tick-borne relapsing fever Borrelia spp. might occur with B. miyamotoi infections. These include transfusion-transmitted disease, pregnancy complications and neonatal death, iritis, uveitis, and cranial nerve neuropathy [2]. The potential for B. miyamotoi transmission through blood donation has been supported by a few studies. Other relapsing fever species (Borrelia recurrentis and Borrelia duttoni) were reported to have been transmitted through blood transfusion [106]. B. miyamotoi transfusion transmission was studied in a murine model, where mice were transfused with B. miyamotoi infected blood [107]. The blood was either transfused fresh (i.e., shortly following collection) or stored for 7 days under blood-banking conditions prior to transfusion. Immunocompetent mice receiving B. miyamotoi transfused blood developed transient spirochetemia, while transfused immunocompromised (SCID) mice had motile B. miyamotoi spirochetes in their blood for up to 28 days following transfusion. Another study demonstrated similar findings and found that B. miyamotoi could remain viable in blood after one month under standard blood banking storage conditions [108]. Studies of blood donors in Austria, California, and the Netherlands have found antibody evidence of previous B. miyamotoi infection [109,110,111].
Pregnant women infected with relapsing fever Borrelia, such as B. duttoni, experience severe disease and can transmit the infection to their newborn infants. Spontaneous abortion or perinatal death are common in pregnant women with relapsing fever infection but can be cleared in mother and infant with appropriate antibiotic therapy [2,3,112,113]. One case of B. miyamotoi infection with possible Lyme disease coinfection in a pregnant woman has been described. She developed a febrile illness in the 28th week of gestation, was hospitalized, and responded well to IV ceftriaxone therapy. She delivered a healthy child at 37 weeks gestation [113].

3. Diagnosis, Treatment, and Prevention

The possibility of B. miyamotoi infection should be considered in any patient with a febrile illness who resides in or has recently traveled to a region where Lyme disease is endemic, especially during the late spring, summer, or early fall. Additional clinical findings such as chills, headache, myalgia, and fatigue provide support for the diagnosis but similar symptoms may occur with other Ixodes-transmitted diseases and acute viral infections, leading to underdiagnosis and misdiagnosis. Diagnosis requires confirmation using specific laboratory tests that include blood smear, polymerase chain reaction (PCR), and/or antibody determination. B. miyamotoi can sometimes be identified by microscopic examination of thin blood smears or a spun sample of cerebrospinal fluid stained with Giemsa or Wright stain. Motile spirochetes may be detected by dark-field or phase contrast microscopy. Several PCR assays have been described for the detection of B. miyamotoi DNA in whole blood, plasma, CSF, and tissues, using primers specific for 16S ribosomal RNA and for the flaB and glpQ genes [7,8].
Serologic testing may be useful for diagnosis of B. miyamotoi, including a fourfold rise in anti-B. miyamotoi IgM and IgG antibody in acute and convalescent-phases of infection. Glycerophosphodiester phosphodiesterase (GlpQ) antigen is produced by B. miyamotoi but not by B. burgdorferi and has been used in ELISA and Western blot assays to distinguish B. miyamotoi from B. burgdorferi [7,14,114,115,116]. Although the diagnostic value of the GlpQ antibody assay has been questioned, results of a recent study have confirmed that as a single antigen, GlpQ, remains the primary discriminatory marker for B. miyamotoi disease [111,116]. Sensitivity and specificity of B. miyamotoi assays can be improved by use of variable membrane protein (Vamp) antigens together with GlpQ antigen [72,114,115,116]. B. miyamotoi and other relapsing fever spirochetes share multiple antigens which complicate serodiagnosis of B. miyamotoi in relapsing fever endemic areas [29]. B. miyamotoi antibody also has been found to cross react against the C6 antigen used in some Lyme disease antibody assays [117]. Patients suspected of having Lyme disease because of typical symptoms and a positive C6 ELISA test may actually have B. miyamotoi infection. In such cases, the Lyme disease Western blot assay will be negative. In vitro cultivation of B. miyamotoi isolates using specialized media is available at selected research laboratories.
Although no prospective trials have been carried out to evaluate antibiotic treatment for B. miyamotoi disease, case series and case reports have indicated that treatment of B. miyamotoi infection with the same antibiotics that are used for Lyme disease are effective in clearing symptoms and infection [6,7]. These include doxycycline, tetracycline, erythromycin, penicillin, and ceftriaxone. Physicians should be aware of the small possibility of Jarisch–Herxheimer reaction following the first dose of antibiotic, primarily for those receiving intravenous antibiotic.
B. miyamotoi infection can best be prevented by avoiding areas where B. miyamotoi-infected ticks are found [118,119]. These include wooded, brush, and tall grass areas in B. miyamotoi-endemic regions. Landscape alterations that limit tick habitat include maintaining a well cut lawn, eliminating leaf litter, spraying yards with tick-repellant (either natural or synthetic products), and separating lawn from wooded areas using a wood chip or pebble barrier [118,120]. Personal protective measures include wearing long pants and long sleeved shirts with pants tucked into socks, and use of acaracides on self (DEET) or clothing (Permethrin). Tick checks and rapid removal of embedded ticks using tweezers and saving them for subsequent species identification are useful [121,122]. Tick-bite antibiotic prophylaxis is available for Lyme disease, but the effect of antibiotic prophylaxis to prevent B. miyamotoi infection is unknown. No B. miyamotoi vaccine is available.

4. Conclusions

Borrelia miyamotoi disease is an emerging tick-borne infection caused by a relapsing fever spirochete and transmitted by the same hard-bodied ticks that transmit Lyme disease, babesiosis, and human granulocytic anaplasmosis. It is found worldwide and causes a febrile illness that can sometimes relapse and rarely causes meningoencephalitis, but the full extent of the health burden of B. miyamotoi has yet to be determined.

Author Contributions

Conceptualization, J.B., E.M.B. and P.J.K.; methodology, J.B., E.M.B., J.R.K. and P.J.K.; software, J.R.K.; validation, J.B., E.M.B., J.R.K. and P.J.K.; formal analysis, J.R.K. and P.J.K.; investigation, J.B., E.M.B., J.R.K. and P.J.K.; resources, P.J.K.; data curation, J.B., E.M.B., J.R.K. and P.J.K.; writing—original draft preparation, J.B.; writing—review and editing, J.B., E.M.B., J.R.K. and P.J.K.; visualization, P.J.K.; supervision, P.J.K.; project administration, P.J.K.; funding acquisition, P.J.K. All authors have read and agreed to the published version of the manuscript.

Funding

This work was funded by the Gordon and Llura Gund Foundation and the Llura A. Gund Labor-atory for Vector-borne Disease Research.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

We thank Brooklynn Sigmon for her assistance in data gathering for this manuscript.

Conflicts of Interest

P.J.K. is a member of the Board of Directors for the American Lyme Disease Foundation, for which he receives no remuneration. He contributed three chapters on babesiosis to Up to Date, Inc. and receives royalties for this work.

Disclaimer

E.M.B. is a member of the United States Food and Drug Administration (FDA) Blood Products Advisory Committee. Any views or opinions that are expressed in this manuscript are those of the authors, based on their own scientific expertise and professional judgment; they do not necessarily represent the views of either the Blood Products Advisory Committee or the formal position of FDA and do not bind or otherwise obligate or commit either Advisory Committee or the Agency to the views expressed.

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Figure 1. Ixodes scapularis life cycle. Female I. scapularis lay eggs in the spring that hatch in early summer and produce larvae (1 and 2). Larval I. scapularis ticks become infected with B. miyamotoi when they take a blood meal from infected white-footed mice (Peromyscus leucopus) or other small rodent hosts in late summer (3). Larvae molt into nymphs and overwinter (4). The following late spring, summer, and early autumn, infected nymphs transmit B. miyamotoi to uninfected mice or humans when they take a blood meal (5). During the following autumn, nymphs molt into adults (6). Adults feed on white-tailed deer (Odocoileus virginianus) but rarely on humans (7). Adults overwinter and the females lay eggs in the early spring to complete the tick life cycle. White-tailed deer amplify the tick population by providing a breeding site for male and female ticks and a blood meal that allows female ticks sufficient protein to lay eggs in the spring (adapted from New England Journal of Medicine, Vannier E., Krause P.J. Human babesiosis. 2012; 366: 2399. Copyright 2019 Massachusetts Medical Society. Reprinted with permission) [32].
Figure 1. Ixodes scapularis life cycle. Female I. scapularis lay eggs in the spring that hatch in early summer and produce larvae (1 and 2). Larval I. scapularis ticks become infected with B. miyamotoi when they take a blood meal from infected white-footed mice (Peromyscus leucopus) or other small rodent hosts in late summer (3). Larvae molt into nymphs and overwinter (4). The following late spring, summer, and early autumn, infected nymphs transmit B. miyamotoi to uninfected mice or humans when they take a blood meal (5). During the following autumn, nymphs molt into adults (6). Adults feed on white-tailed deer (Odocoileus virginianus) but rarely on humans (7). Adults overwinter and the females lay eggs in the early spring to complete the tick life cycle. White-tailed deer amplify the tick population by providing a breeding site for male and female ticks and a blood meal that allows female ticks sufficient protein to lay eggs in the spring (adapted from New England Journal of Medicine, Vannier E., Krause P.J. Human babesiosis. 2012; 366: 2399. Copyright 2019 Massachusetts Medical Society. Reprinted with permission) [32].
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Figure 2. Borrelia miyamotoi infection in Ixodes ticks and humans by county in the USA 2013–2021.
Figure 2. Borrelia miyamotoi infection in Ixodes ticks and humans by county in the USA 2013–2021.
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Burde, J.; Bloch, E.M.; Kelly, J.R.; Krause, P.J. Human Borrelia miyamotoi Infection in North America. Pathogens 2023, 12, 553. https://doi.org/10.3390/pathogens12040553

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Burde J, Bloch EM, Kelly JR, Krause PJ. Human Borrelia miyamotoi Infection in North America. Pathogens. 2023; 12(4):553. https://doi.org/10.3390/pathogens12040553

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Burde, Jed, Evan M. Bloch, Jill R. Kelly, and Peter J. Krause. 2023. "Human Borrelia miyamotoi Infection in North America" Pathogens 12, no. 4: 553. https://doi.org/10.3390/pathogens12040553

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