Jp. Engel et al., THE TRANSNEURONAL SPREAD PHENOTYPE OF HERPES-SIMPLEX VIRUS TYPE-1 INFECTION OF THE MOUSE HIND FOOTPAD, Journal of virology, 71(3), 1997, pp. 2425-2435
The mouse hind footpad inoculation model has served as a standard labo
ratory 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 no
t previously been described; nor is it understood why mice develop par
alysis in an infection that involves sensory nerves. The HSV-as-transn
euronal-tracer experimental paradigm was used to define the transneuro
nal spread of HSV-1 in this model. A new decalcification technique and
standard immunocytochemical staining of HSV-1 antigens enabled a deta
iled analysis of the time-space, distribution of HSV-1 in the intact s
pinal column. Mice were examined on days 3, 4, 5, and 6 postinoculatio
n (p.i.) of a lethal dose of wild-type HSV-1 strain 17 syn(+). Viral a
ntigen was traced retrograde into first-order neurons in dorsal root g
anglia 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 locali
zed to the somatotopic representation of the footpad dermatome within
the dorsal root ganglia and spinal cord. Antigen was found in the spin
al cord gray and white matter sensory neuronal circuits of nociception
(the spinothalamic tract) and proprioception (the dorsal spinocerebel
lar tract and gracile fasciculus). Within the brain stems and brains o
f three paralyzed animals examined late in infection (days 5 and 6 p.i
.), HSV antigen was restricted to the nucleus subcoeruleus region bila
terally. 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.