6  Models of influenza-associated neurologic disease
Because a number of studies have described neurological sequelae from influenza virus infections, an animal model in which such complications can be studied and treatment can be tested would be of importance (Mizuguchi et al., 2007, Steininger et al., 2003). A summary of current animal models available for studying influenza virus-associated neurotropic disease is presented in Table 7 .
Table 7 Summary of current animal models available for studying influenza virus-associated neurotropic disease.
Virus Animal Model References
Influenza A H1N1 Mouse (C57BL/6-BJ6) Aronsson et al. (2003)
A/WSN/33



Influenza A H5N1 Mouse (C57BL/6) Mori et al. (2002)
Recombinant R404BP
A/WSN/33 X A/Aichi/2/68



Influenza A H5N1 Mouse (BALB/cA Jcl) Park et al. (2002)
A/Hong Kong/483/97

6.1  Seasonal influenza
Mori et al. (2002) have used a highly neurovirulent recombinant R404BP strain of influenza A (H1N1) virus to test amantadine therapy in mice. Stereotaxic microinjection of virus into the olfactory bulb of the animal results in outward spread to neurons in broad areas of the brain parenchyma, leading to apoptotic neurogeneration and fatal edema, beginning on day 8. However, amantadine treatment beginning as late as 7 days after virus injection protected the animals. The disadvantage of this clinically relevant model is that only researchers having stereotaxic microinjection equipment could use it.
A second study in mice used a neurovirulent A/WSN/33 strain of H1N1 influenza A virus administered intranasally, resulting in infection of olfactory neurons and anterograde axonal transport to the olfactory bulbs (Aronsson et al., 2003). Using immunodefective mutant mice to examine how the immune system controls the spread and persistence of the virus, the authors showed that an absence of T and B cells allowed the infection to spread fully into the brain.

6.2  H5N1 avian influenza
In a simplified neurovirulence model, Park et al. (2002) demonstrated that simple intranasal instillation of influenza A (H5N1) virus isolated from a patient during the 1997 Hong Kong outbreak could result in the infection of the murine central nervous system. After initial replication in the respiratory mucosa, the virus apparently traveled through afferent fibers of the olfactory, vagal, trigeminal, and sympathetic nerves, where it was detected by immunohistochemical and in situ hybridization. This study demonstrates the feasibility of using intranasal installation of viruses isolated directly from patients to establish an encephalitis-like infection, an ideal way for quickly evaluating antiviral inhibitors.
Yun et al. (2008) injected peramivir intramuscularly into ferrets infected intranasally with the highly neurovirulent A/Vietnam/1203/04 (H5N1) influenza virus and were able to show that peramavir delivered in this manner ameliorated virus-induced disease by reducing infectious virus titers in the lungs and brains and promoted survival in ferrets.