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Journal of Virology, March 2004, p. 2956-2966, Vol. 78, No. 6
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.6.2956-2966.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Influence of Tegument Proteins of Pseudorabies Virus on Neuroinvasion and Transneuronal Spread in the Nervous System of Adult Mice after Intranasal Inoculation

Robert Klopfleisch,1 Jens P. Teifke,2 Walter Fuchs,1 Martina Kopp,1 Barbara G. Klupp,1 and Thomas C. Mettenleiter1*

Institutes of Molecular Biology,1 Infectology, Friedrich-Loeffler-Institutes, Federal Research Centre for Virus Diseases of Animals, D-17493 Greifswald-Insel Riems, Germany2

Received 5 August 2003/ Accepted 19 November 2003

Pseudorabies virus (PrV) is a neurotropic alphaherpesvirus that, after intranasal infection of adult mice, enters peripheral neurons and propagates to the central nervous system. In recent years we have analyzed the contribution of virus-encoded glycoproteins to neuroinvasion and transneuronal spread (reviewed in T. C. Mettenleiter, Virus Res. 92:197-206, 2003). We now extend our studies to analyze the role of tegument proteins in these processes. To this end, PrV mutants unable to express the UL11, UL37, UL46, UL47, and UL48 tegument proteins, as well as the corresponding rescued viruses, were intranasally instilled into 6- to 8-week-old CD1 strain mice. First, mean survival times were determined which showed that mice infected with the UL46 deletion mutant succumbed to the disease as early as wild-type PrV-infected animals. Survival times increased in the order: PrV-{Delta}UL47-, PrV-{Delta}UL11-, and PrV-{Delta}UL48-infected animals, a finding which parallels the growth phenotype of these viruses in cell culture. In contrast, none of the PrV-{Delta}UL37-infected animals died. Upon closer histological examination, all viruses except PrV-{Delta}UL37 were able to infect the nasal cavity and propagate to first- and second-order neurons as shown by two-color immunofluorescence. However, neuroinvasion was delayed in PrV-{Delta}UL47, PrV-{Delta}UL11, and PrV-{Delta}UL48, a finding that correlated with the extended survival times. Surprisingly, whereas PrV-{Delta}UL48 and PrV-{Delta}UL37 replicated to similar titers in cell culture which were ~500-fold lower than those of wild-type virus, after intranasal infection of mice PrV-{Delta}UL48 was able to infect areas of the brain like wild-type PrV, although only after a considerably longer time period. In contrast, PrV-{Delta}UL37 was not able to enter neurons and was restricted to the infection of single cells in the nasal respiratory epithelium. Thus, our data demonstrate the importance of herpesviral tegument proteins in neuronal infection and show a different contribution of tegument proteins to the neuroinvasion phenotype of a neurotropic alphaherpesvirus.

* Corresponding author. Mailing address: Institute of Molecular Biology, Friedrich-Loeffler-Institutes, Federal Research Centre for Virus Diseases of Animals, Boddenblick 5A, D-17493 Greifswald-Insel Riems, Germany. Phone: 49-38351-7250. Fax: 49-38351-7151. E-mail: mettenleiter{at}rie.bfav.de.

Journal of Virology, March 2004, p. 2956-2966, Vol. 78, No. 6
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.6.2956-2966.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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