Zika virus replicates in adult human brain tissue and impairs synapses and memory in mice
Authors: Newton G Castro
Fernanda G Q Barros-Arag√£o
Julianna D Zeidler
Andr√© Luis A Guimar√£es
Virginia L de Sousa
Fernanda G De Felice
Iranaia Assun√ß√£o-Miranda
Claudia P Figueiredo
Maria Bellio
R√¥mulo L S Neris
Daniele C Zamberlan
Andrea T Da Poian
Sergio T Ferreira
Heitor A Paula-Neto
Soniza V Alves-Leon
Gilda A Neves
Isis N O Souza
Amanda S Souza
Paula S Frost
Carolina Soares
Jorge Marcondes de Souza
Julia R Clarke
Journal: Nature Communications (2019)
Discipline: Multidisciplinary
Keywords: Zika virus; neurological complications; central nervous system; adult patients; brain tissue
Affiliations: School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 21944-590, Brazil. ., School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 21944-590, Brazil., Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 21944-590, Brazil., Institute of Microbiology Paulo de Goes, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 21944-590, Brazil., Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 21944-590, Brazil., Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 21944-590, Brazil., Division of Neurosurgery and Division of Neurology/Epilepsy Program, Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 21944-590, Brazil., Graduate Program in Neurology, Federal University of Rio de Janeiro State, Queen's University, Kingston, ON, Canada., Centre for Neuroscience Studies & Department of Psychiatry, Queen's University, Kingston, ON, Canada., Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 21944-590, Brazil. ., Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 21944-590, Brazil. .

Abstract:  Neurological complications affecting the central nervous system have been reported in adult patients infected by Zika virus (ZIKV) but the underlying mechanisms remain unknown. Here, we report that ZIKV replicates in human and mouse adult brain tissue, targeting mature neurons. ZIKV preferentially targets memory-related brain regions, inhibits hippocampal long-term potentiation and induces memory impairment in adult mice. TNF-Œ± upregulation, microgliosis and upregulation of complement system proteins, C1q and C3, are induced by ZIKV infection. Microglia are found to engulf hippocampal presynaptic terminals during acute infection. Neutralization of TNF-Œ± signaling, blockage of microglial activation or of C1q/C3 prevent synapse and memory impairment in ZIKV-infected mice. Results suggest that ZIKV induces synapse and memory dysfunction via aberrant activation of TNF-Œ±, microglia and complement. Our findings establish a mechanism by which ZIKV affects the adult brain, and point to the need of evaluating cognitive deficits as a potential comorbidity in ZIKV-infected adults. 

Retracted: No

PubPeer comments:
 I analyzed the raw data of this article and I have found some patterns that I d like to share with the authors. There are several duplicated values across different experiments, some of which are particularly unexpected. I have included some examples below and it is not clear why these patterns occur. Could the authors please explain? And, could the authors provide the raw file of IL-1beta qPCR? This may help clarify the source of these patterns.      , 
 Figure 6 and Figure 7: It looks like the authors used the same mock representative image to represent two different experiments (The data on the graphs are not the same). Also, the ZIKV panel is different between the experiments.  , 
 We have examined the Figures, and we agree that the highlighted panels are duplicated. We would like to thank this attentive researcher for identifying this error and bringing it to our attention. We also would like to sincerely apologize to the Nature Comm editorial team, reviewers, and other scientific community members for the inconvenience caused by our unintended oversight. We would like to emphasize that our editorial mistake does not alter the study s conclusion, and we are confident about the integrity of our work. Please note that Figures 6F and 7G simply display images selected to represent the overall group quantitative data presented in Figure 6I-K and Figure 7K-M. We are currently attempting to retrieve the original data to correct the figure, and we are in contact with the Nat Comm editorial team to provide an Errata to the paper. Sincerely, , 
 In Fig. 3e, 3f, argued that the passive avoidance was only affected by ZIKV at 10 dpi, but it was normalized at 60 dpi  A potential concern for the interpretation of this result can be found at the supplemental data related to this figure, where it was shown that the mock condition had a 5-fold difference between these two experiments during Test (mean around 250s at 10 dpi, and 50s only at 60 dpi). That variability between assays is almost as big as the effect of the 10 dpi ZIKV itself.  ,