Genetic contributions to influenza virus attenuation in the rat brain

Author： Qi Li Carbone Kathryn Ye Zhiping Liu Teresa Ovanesov Mikhail Pletnikov Mikhail Sauder Christian Rubin Steven

ISSN： 1355-0284

Source： Journal of NeuroVirology, Vol.14, Iss.2, 2008-03, pp. : 136-142

Disclaimer: Any content in publications that violate the sovereignty, the constitution or regulations of the PRC is not accepted or approved by CNPIEC.

Previous Menu Next

Abstract

Influenza is generally regarded as an infection of the respiratory tract; however, neurological involvement is a well-recognized, although uncommon, complication of influenza A virus infection. The authors previously described the development of a rat model for studying influenza virus infection of the central nervous system (CNS). This model was used here to study the role of virus genes in virus replication and spread in brain. In the present work, an infectious cDNA clone of the neurotoxic WSN strain of influenza virus (rWSN) was altered by site-directed mutagenesis at five loci that corresponded to changes previously shown to confer temperature sensitivity and attenuation of the A/Ann Arbor/6/60 strain (PB1∆ 391, PB1∆ 581, and PB1∆ 661; PB2∆ 265, and NP∆ 34). Whereas rWSN and its mutated derivative (mu-rWSN) replicated equally well in MDCK cells at 37°C (the body temperature of rats), rWSN grew to higher titers and infection was more widespread compared to mu-rWSN in rat brain. These results demonstrate that the five mutations that confer attenuation of the A/Ann Arbor/6/60 influenza virus strain for the respiratory system also confer attenuation for the central nervous system. Further in vivo and in vitro examination of these five mutations, both individually and in combination, will likely provide important information on the role of specific virus genes in virulence and pathogenesis.