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Link to original content: https://pubmed.ncbi.nlm.nih.gov/21825120
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. 2011 Aug 16;108(33):13734-9.
doi: 10.1073/pnas.1105143108. Epub 2011 Aug 8.

Human herpesvirus-6 entry into the central nervous system through the olfactory pathway

Erin Harberts  1 , Karen Yao, Jillian E Wohler, Dragan Maric, Joan Ohayon, Robert Henkin, Steven Jacobson
Affiliations

Human herpesvirus-6 entry into the central nervous system through the olfactory pathway

Erin Harberts et al. Proc Natl Acad Sci U S A. .

Abstract

Viruses have been implicated in the development of neurodegenerative diseases, such as Alzheimer's, Parkinson's, and multiple sclerosis. Human herpesvirus-6 (HHV-6) is a neurotropic virus that has been associated with a wide variety of neurologic disorders, including encephalitis, mesial temporal lobe epilepsy, and multiple sclerosis. Currently, the route of HHV-6 entry into the CNS is unknown. Using autopsy specimens, we found that the frequency of HHV-6 DNA in the olfactory bulb/tract region was among the highest in the brain regions examined. Given this finding, we investigated whether HHV-6 may infect the CNS via the olfactory pathway. HHV-6 DNA was detected in a total of 52 of 126 (41.3%) nasal mucous samples, showing the nasal cavity is a reservoir for HHV-6. Furthermore, specialized olfactory-ensheathing glial cells located in the nasal cavity were demonstrated to support HHV-6 replication in vitro. Collectively, these results support HHV-6 utilization of the olfactory pathway as a route of entry into the CNS.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Survey of autopsy brain specimens for HHV-6. Primers specific for the U67 gene region of HHV-6 were used for nested PCR amplification. Tissues from various regions of the brain obtained from three NIH autopsy patients were categorized into the indicated groups based on anatomical locations. The percentages of HHV-6 positivity in each category are expressed on the y axis. The numbers above each region indicate the number of samples positive for HHV-6 of the total number of specimen tested in each category.
Fig. 2.
Fig. 2.
Detection of HHV-6 DNA in autopsy olfactory specimens. (A) HHV-6 variant B was amplified by real-time quantitative PCR from olfactory bulb specimens from two NIH autopsy cases (MS and leukemia, respectively) and the insular cortex of a patient with HHV-6–associated encephalitis for comparison. (B) Olfactory bulb (n = 10) and tract (n = 10) specimens ascertained from the UCLA brain bank were tested using nested PCR for the U67 gene of HHV-6. A high prevalence of HHV-6 DNA was detected in the olfactory tissues.
Fig. 3.
Fig. 3.
Characterization of cultured OECs by immunofluorescence staining. (A) Primary human OECs were labeled using anti–vimentin-Alexa Fluor 488 (green), anti–GFAP-AMCA (azure), anti–O4-Alexa Fluor 546 (orange), anti–TUJ1-Alexa Fluor 647 (red), and anti–PCNA-biotin-streptavidin-Alexa Fluor 750 (pink). After imaging the above labels, the remaining AMCA signal was photobleached and the cell nuclei were counterstained with DAPI (blue) to facilitate cell visualization. (B) Primary human OECs from a separate culture probed with anti–vimentin-Alexa Fluor 488 (green), anti-GFAP-Alexa Fluor 350 (azure), anti–NGFPp75-Alexa Fluor 546 (orange), anti–MAP2-Alexa Fluor 647 (red), anti-PCNA-biotin-streptavidin-Alexa Fluor 750 (pink) and DAPI (blue) using the same labeling strategy as in A. Astroglial and oligodendroglial markers such as vimentin, GFAP, NGFRp75, and O4 were widely expressed in OECs. Many of these cells were PCNA+ and thus actively proliferating. Cells of the neuronal lineage were absent in the OEC cultures as indicated by negative TUJ1 and MAP2 staining.
Fig. 4.
Fig. 4.
HHV-6A infects olfactory ensheathing cells in vitro. (A) OEC cultures were infected with HHV-6A or HHV-6B and cells were harvested for analysis of de novo virus transcript with the U12 primers. The higher 202-bp band corresponds to the nonspliced HHV-6 precursor RNA and the lower 113-bp PCR product represents de novo RNA transcript. Lanes 1, 2, and 3 are 3 h postinfection of mock, OEC+U1102, and OEC+Z29, respectively. Lanes 4 and 5 are 2 d postinfection of mock and OEC+U1102, respectively. Lanes 6, 7, and 8 are 4 d postinfection of OEC+U1102, OEC+Z29, and mock, respectively. Lane 9 is the positive control from HHV-6 infected U251 human astrocyte cell line. (B) HHV-6A infected OECs were harvested 3 and 7 d postinfection for viral load analysis by real time quantitative Taqman. Calculated viral loads were normalized to β-actin. (C) Cytokine production measured on day 3 of HHV-6A infection in OECs. Cell-culture supernatants were analyzed using a cytokine antibody array as described in Methods. The data shown are from a representative experiment and mean intensities were normalized to controls on each membrane (n = 2). Statistical significance was measured using ANOVA (* indicates P < 0.05).
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