On the other hand, simple in vitro cell culture fails to account for the unique characteristics of complex organ systems. Such in vivo animal models can be costly and logistically challenging. (27,28) This highlights the complexity of TBV pathogenesis in hosts and the need to model infections in multiple mammal systems consisting of both susceptible and reservoir hosts. For example, the response to POWV infection in laboratory mice appears to mimic human disease syndromes, but the reservoir species Peromyscus leucopus restricts the infection and does not suffer any obvious disease. Suitable mammal models exist to study both viremic and nonviremic transmission (25,26) however, these studies may underestimate the complexity of in vivo infections and may not faithfully recapitulate disease in all potential mammal hosts. ![]() The precise mechanism of nonviremic transmission is unclear, but it may involve a combination of migrating immune cells and potential effects from tick saliva during tick feeding. Nonviremic transmission involves the transfer of virus from an infected tick to an uninfected tick when ticks are “cofeeding” in a localized area on the skin. (20−24) Viremic transmission occurs in the context of a tick taking a bloodmeal on a viremic mammal. In nature, ticks can become infected by both viremic and nonviremic transmission. In this brief perspective, we describe how ex vivo cultures can be combined with modern technologies to advance research on TBV infections. They can also be combined with in vitro and in vivo studies to tease out possible host factors and potential vaccine or therapeutic candidates. These ex vivo model systems are convenient for testing methods involving transcript knockdown and small molecules under tightly controlled conditions. Mammal ex vivo organ slice and, more recently, organoid cultures are additional models that can be used to elucidate direct tissue-specific responses to infection. The use of ex vivo tick cultures in TBV research provides a unique way to look at infection in specific tick organs. Experimental tick and mammal models of infection can be used to characterize determinants of infection, transmission, and virulence and to test candidate countermeasures. The application of contemporary technologies to TBV infections presents an excellent opportunity to develop improved, effective countermeasures. Furthermore, effective vaccines, diagnostic tools, and other countermeasures are limited. Although TBVs are currently identified as neglected vector-borne pathogens and receive less attention than mosquito-borne viruses, TBVs are expanding into new regions, and infection rates are increasing. These illnesses occur worldwide and can range from very mild illness to severe encephalitis and hemorrhagic fever. ![]() Each year there are more than 15 000 cases of human disease caused by infections with tick-borne viruses (TBVs).
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