Immunosuppression-induced Zika virus reactivation causes brain inflammation and behavioral deficits in mice
Clara de O. Nogueira,
Mariana Oliveira Lopes da Silva,
Emanuelle V. de Lima,
Raíssa Rilo Christoff,
Daniel Gavino-Leopoldino,
Felipe S. Lemos,
Nicolas E. da Silva,
Andrea T. Da Poian,
Iranaia Assunção-Miranda,
Claudia P. Figueiredo,
Julia R. Clarke
Affiliations
Clara de O. Nogueira
Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941902, RJ, Brazil
Mariana Oliveira Lopes da Silva
Instituto de Microbiologia Paulo de Goes, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941902, RJ, Brazil
Emanuelle V. de Lima
Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941902, RJ, Brazil; Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941902, RJ, Brazil
Raíssa Rilo Christoff
Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941902, RJ, Brazil
Daniel Gavino-Leopoldino
Instituto de Microbiologia Paulo de Goes, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941902, RJ, Brazil
Felipe S. Lemos
Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941902, RJ, Brazil
Nicolas E. da Silva
Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941902, RJ, Brazil
Andrea T. Da Poian
Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941902, RJ, Brazil
Iranaia Assunção-Miranda
Instituto de Microbiologia Paulo de Goes, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941902, RJ, Brazil
Claudia P. Figueiredo
Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941902, RJ, Brazil; Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941902, RJ, Brazil; Corresponding author
Julia R. Clarke
Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941902, RJ, Brazil; Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941902, RJ, Brazil; Corresponding author
Summary: Zika virus (ZIKV) is a neurotropic flavivirus that can persist in several tissues. The late consequences of ZIKV persistence and whether new rounds of active replication can occur, remain unaddressed. Here, we investigated whether neonatally ZIKV-infected mice are susceptible to viral reactivation in adulthood. We found that when ZIKV-infected mice are treated with immunosuppressant drugs, they present increased susceptibility to chemically induced seizures. Levels of subgenomic flavivirus RNAs (sfRNAs) were increased, relative to the amounts of genomic RNAs, in the brains of mice following immunosuppression and were associated with changes in cytokine expression. We investigated the impact of immunosuppression on the testicles and found that ZIKV genomic RNA levels are increased in mice following immunosuppression, which also caused significant testicular damage. These findings suggest that ZIKV can establish new rounds of active replication long after acute stages of disease, so exposed patients should be monitored to ensure complete viral eradication.
