Resumo

Herpes Simplex Virus Type 1 (HSV-1) is ubiquitous, neurotropic and the most common pathogenic cause of sporadic acute encephalitis in humans. Herpes simplex encephalitis is associated with a high mortality rate and significant neurological, neuropsychological, and neurobehavioral sequelae, which afflict patients for life. HSV-1 is able to infect and establish latency in neurons of the central nervous system (CNS), and has been considered a possible risk factor for Alzheimer's disease. Currently, it is unclear whether asymptomatic recurrent reactivations of HSV-1 occur in CNS of infected people and if these events could lead to a progressive deterioration of neuronal function. In a previous study we demonstrated that HSV-1 triggers hyperphosphorylation and cleavage of tau protein in neuronal primary cultures, resembling the pattern observed in neurodegenerative diseases. The aim of this study was to evaluate if this pattern could be reproduced in vivo by intranasal inoculation of HSV-1 in mice. Tau protein modifications were analyzed by immunohistochemistry in neurons of trigeminal ganglion of HSV-1-infected animals. Our results showed that the number of cells that display early neurodegenerative markers such as Tau phosphorylated at serine residues 396 and cleaved by caspase 3 (recognized by antibody TauC3) was increased during productive and latent infection, reaching a maximum after 15 days post-infection. Moreover these markers remained elevated even when symptoms disappeared during the latency phase of infection (60 dpi). These findings suggest that acute HSV-1 infection is able to generate changes characteristic of neurodegenerative diseases in vivo and also that recurrent reactivations could be associated with cumulative neuronal damage. Funding FONDECYT 11080067 and 1120464.