| Summary: | Over 600,000 vector-borne disease cases were reported in the United States (U.S.) in the past 13 years, of which more than three-quarters were tick-borne diseases. Although Lyme disease accounts for the majority of tick-borne disease cases in the U.S., tularemia cases have been increasing over the past decade, with >220 cases reported yearly. However, when comparing <i>Borrelia burgdorferi</i> (causative agent of Lyme disease) and <i>Francisella tularensis</i> (causative agent of tularemia), the low infectious dose (<10 bacteria), high morbidity and mortality rates, and potential transmission of tularemia by multiple tick vectors have raised national concerns about future tularemia outbreaks. Despite these concerns, little is known about how <i>F. tularensis</i> is acquired by, persists in, or is transmitted by ticks. Moreover, the role of one or more tick vectors in transmitting <i>F. tularensis</i> to humans remains a major question. Finally, virtually no studies have examined how <i>F. tularensis</i> adapts to life in the tick (vs. the mammalian host), how tick endosymbionts affect <i>F. tularensis</i> infections, or whether other factors (e.g., tick immunity) impact the ability of <i>F. tularensis</i> to infect ticks. This review will assess our current understanding of each of these issues and will offer a framework for future studies, which could help us better understand tularemia and other tick-borne diseases.
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