Global Virology I - Identifying and Investigating Viral Diseases by Paul Shapshak John T. Sinnott Charurut Somboonwit & Jens H. Kuhn

Author:Paul Shapshak, John T. Sinnott, Charurut Somboonwit & Jens H. Kuhn
Language: eng
Format: epub
Publisher: Springer New York, New York, NY

1.3 Experimental Models

The main in vivo model used to study flavivirus infection is the mouse. However, in addition to standard differences in experimental approaches by different investigators and the investigative modalities used, variations in mouse strain (e.g. BALB/c and C57BL/6 mice in TBEV [59] and WNV models [60]), mouse age (whether the BBB has fully formed, the maturity of the immune system), peripheral route of inoculation (subcutaneous [61], intravenous [37], intraperitoneal [62], intradermal [30, 31], intranasal [58], intravaginal [60] and oral [63] routes are all used for different reasons) and gene status (the use of transgenic mice or mice with inactivated, mostly immune response-related, genes), as well as virus strain, dose and provenance can make generalizable conclusions difficult. Peripheral inoculation at different sites with the same virus can produce markedly different results on rechallenge at a single site [60]. High and low dose inoculation produces immunologically different outcomes [37] and unlike infection by most other viruses, where mice survive according to a standard virus dose response curve, unless flaviviruses have direct access to the CNS they tend to produce ragged, unpredictable survival outcomes [64, 65]. Nevertheless, as models for WNV, TBEV and JEV disease, mice reliably develop active infection and CNS pathology similar to that observed in humans, with neuronal damage and mononuclear infiltration being the most prominent constituents of encephalitic disease [66]. In JEV peripheral inoculation models, the i.p. route may be more reliable if mice develop resistance to subcutaneous (s.c.) infection with age, although some results do not support this [67]. In DENV infection, on the other hand, one of the main obstructions to the study of neurological disease is the difficulty in establishing a suitable animal model. DENV is quickly controlled in immunocompetent mice and in order to study this virus, mouse-adapted virus strains, immunocompromised mice lacking Type-1 and -2 interferon (IFN) receptors, and humanised mice have been used to date, with consequent inconsistencies and difficulties in interpretation amongst published studies [68]. Thus, a suitable murine model for in vivo studies of neurologic DENV disease is still needed.

Other models for flaviviral disease include non-human primates, for example, i.n. inoculation of macaques with JEV resembles human encephalitic disease occurring after natural infection, while other routes usually result in asymptomatic infection. Thus, these animals have been used for surrogate studies of viral persistence in the blood of asymptomatic human WNV infection [69]. Their closer genetic kinship to humans justifies the choice of macaques to test vaccines and other antiviral therapies [67] and much of the earlier work on YFV was done in macaques and other non-human primates, since they develop symptoms most closely resembling human disease. Stricter regulations and ethical concerns have driven the search for alternative models that have included the golden hamster as a model for YFV [70], as well as persistent WNV [71, 72]. Limitations associated with virus adaptation, however, have also resulted in the use of A129 mice, deficient in IFN-α/β receptor, in which viscerotropic disease is achieved without requiring YFV adaptation [73].

Although few animal

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