Abstract
ABSTRACT Viruses transmit via the environmental and social interactions of their hosts. Herpesviruses have colonized mammals since their earliest origins, suggesting that they exploit ancient, common pathways. Cytomegaloviruses (CMVs) are assumed to enter new hosts orally, but no site has been identified. We show by live imaging that murine CMV (MCMV) infects nasally rather than orally, both after experimental virus uptake and during natural transmission. Replication-deficient virions revealed the primary target as olfactory neurons. Local, nasal replication by wild-type MCMV was not extensive, but there was rapid systemic spread, associated with macrophage infection. A long-term, transmissible infection was then maintained in the salivary glands. The viral m131/m129 chemokine homolog, which influences tropism, promoted salivary gland colonization after nasal entry but was not required for entry per se. The capacity of MCMV to transmit via olfaction, together with previous demonstrations of experimental olfactory infection by murid herpesvirus 4 (MuHV-4) and herpes simplex virus 1 (HSV-1), suggest that this is a common, conserved route of mammalian herpesvirus entry.
Highlights
Viruses transmit via the environmental and social interactions of their hosts
Infection at 5 days cannot be interpreted as host entry: by this time after inhalation, herpes simplex virus 1 (HSV-1) has spread via the trigeminal ganglia to the facial skin [13], and inhaled murid herpesvirus 4 (MuHV-4) colonizes the nasal-associated lymphoid tissue only as a secondary site [14]
Weak signals were seen in livers at up to 2 weeks of age (Fig. 1a and b, open arrowheads), but these were unrelated to infection, as they occurred in naive mice, and unlike nasal signals were not abolished by preincubating the virus with sera from immune mice (0.5-l serum per 3 ϫ 104 PFU virus, 2 h at 23°C)
Summary
Viruses transmit via the environmental and social interactions of their hosts. Herpesviruses have colonized mammals since their earliest origins, suggesting that they exploit ancient, common pathways. We show by live imaging that murine CMV (MCMV) infects nasally rather than orally, both after experimental virus uptake and during natural transmission. Murine CMV (MCMV) infected not orally but nasally Limited functional separation of the nasopharynx and oropharynx in breast-feeding infants (for example, nasal milk regurgitation is common) further warns against inferring oral entry without identifying the infected cells. Another report identified MCMV infection of olfactory epithelial cells and nasal-associated lymphoid tissue 5 days after a high-volume combined oral/nasal inoculation [11]. Infection at 5 days cannot be interpreted as host entry: by this time after inhalation, HSV-1 has spread via the trigeminal ganglia to the facial skin [13], and inhaled MuHV-4 colonizes the nasal-associated lymphoid tissue only as a secondary site [14]. It is necessary to look early, ideally with a virus limited to a single infection cycle
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