The transneuronal spread phenotype of herpes simplex virus type 1 infection of the mouse hind footpad.

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The mouse hind footpad inoculation model has served as a standard laboratory system for the study of the neuropathogenesis of herpes simplex virus type 1 (HSV-1) infection. The temporal and spatial distribution of viral antigen, known as the transneuronal spread phenotype, has not previously been described; nor is it understood why mice develop paralysis in an infection that involves sensory nerves. The HSV-as-transneuronal-tracer experimental paradigm was used to define the transneuronal spread of HSV-1 in this model. A new decalcification technique and standard immunocytochemical staining of HSV-1 antigens enabled a detailed analysis of the time-space distribution of HSV-1 in the intact spinal column. Mice were examined on days 3, 4, 5, and 6 postinoculation (p.i.) of a lethal dose of wild-type HSV-1 strain 17 syn+. Viral antigen was traced retrograde into first-order neurons in dorsal root ganglia on day 3 p.i., to the dorsal spinal roots on days 4 and 5 p.i., and to second- and third-order neurons within sensory regions of the spinal cord on days 5 and 6 p.i. HSV-1 antigen distribution was localized to the somatotopic representation of the footpad dermatome within the dorsal root ganglia and spinal cord. Antigen was found in the spinal cord gray and white matter sensory neuronal circuits of nociception (the spinothalamic tract) and proprioception (the dorsal spinocerebellar tract and gracile fasciculus). Within the brain stems and brains of three paralyzed animals examined late in infection (days 5 and 6 p.i.), HSV antigen was restricted to the nucleus subcoeruleus region bilaterally. Since motor neurons were not directly involved, we postulate that hindlimb paralysis may have resulted from intense involvement of the posterior column (gracile fasciculus) in the thoracolumbar spinal cord, a region known to contain the corticospinal tract in rodents.

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