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The anterior commissure is a pathway for contralateral spread of herpes simplex virus type 1 after olfactory tract infection

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Abstract

Herpes simplex encephalitis (HSE), targeting the limbic system, is the most common cause of viral encephalitis in the Western world. Two pathways for viral entry to the central nervous system (CNS) in HSE have been suggested: either via the trigeminal nerve or via the olfactory tract. This question remains unsettled, and studies of viral spread between the two brain hemispheres are scarce. Here, we investigated the olfactory infection as a model of infection and tropism of herpes simplex virus 1 (HSV-1), the causative agent of HSE, in the CNS of rats. Rats were instilled with HSV-1 in the right nostril and sacrificed 1–6 days post-infection, and tissues were analysed for viral spread using immunohistochemistry and quantitative PCR (qPCR). After nasal instillation, HSV-1 infected mitral cells of the olfactory bulb (OB) on the right side only, followed by limbic encephalitis. As a novel finding, the anterior commissure (AC) conveyed a rapid transmission of virus between the right and the left OB, acting as a shortcut also between the olfactory cortices. The neuronal cell population that conveyed the viral infection via the AC was positive for the water channel protein aquaporin 9 (AQP9) by immunohistochemistry. Quantification of AQP9 in cerebrospinal fluid samples of HSE patients showed increment as compared to controls. We conclude that the olfactory route and the AC are important for the spread of HSV-1 within the olfactory/limbic system of rats and furthermore, we suggest that AQP9 is involved in viral tropism and pathogenesis of HSE.

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Acknowledgments

We would like to thank Maria Johansson for skilful technical assistance, Rickard Nordén and Anette Roth for technical advice and Oluf Andersen for fruitful discussions.

This work was supported by grants from the ALF Foundation at Sahlgrenska University Hospital (grant no 145–841) and the Swedish Research Council, Medicine (grant no 521-2011-3297).

Conflict of interest

The authors declare no competing financial interests.

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    Authors and Affiliations

    1. Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden

      Eva Jennische

    2. Department of Infectious Diseases, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden

      Charlotta E. Eriksson, Stefan Lange, Edward Trybala & Tomas Bergström

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    1. Eva Jennische
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    2. Charlotta E. Eriksson
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    Correspondence to Tomas Bergström.

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    E. Jennische and C. E. Eriksson have contributed equally to this work.

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    Jennische, E., Eriksson, C.E., Lange, S. et al. The anterior commissure is a pathway for contralateral spread of herpes simplex virus type 1 after olfactory tract infection. J. Neurovirol. 21, 129–147 (2015). https://doi.org/10.1007/s13365-014-0312-0

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