Impact of Zika Virus on adult human brain structure and functional organization

Abstract

ObjectiveTo determine the impact of Zika virus (ZIKV) infection on brain structure and functional organization of severely affected adult patients with neurological complications that extend beyond Guillain–Barré Syndrome (GBS)‐like manifestations and include symptoms of the central nervous system (CNS).MethodsIn this first case–control neuroimaging study, we obtained structural and functional magnetic resonance images in nine rare adult patients in the subacute phase, and healthy age‐ and sex‐matched controls. ZIKV patients showed atypical descending and rapidly progressing peripheral nervous system (PNS) manifestations, and importantly, additional CNS presentations such as perceptual deficits. Voxel‐based morphometry was utilized to evaluate gray matter volume, and resting state functional connectivity and Network Based Statistics were applied to assess the functional organization of the brain.ResultsGray matter volume was decreased bilaterally in motor areas (supplementary motor cortex, specifically Frontal Eye Fields) and beyond (left inferior frontal sulcus). Additionally, gray matter volume increased in right middle frontal gyrus. Functional connectivity increased in a widespread network within and across temporal lobes.InterpretationWe provide preliminary evidence for a link between ZIKV neurological complications and changes in adult human brain structure and functional organization, comprising both motor‐related regions potentially secondary to prolonged PNS weakness, and nonsomatomotor regions indicative of PNS‐independent alternations. The latter included the temporal lobes, particularly vulnerable in a range of neurological conditions. While future studies into the ZIKV‐related neuroinflammatory mechanisms in adults are urgently needed, this study indicates that ZIKV infection can lead to an impact on the brain.

Zika virus replicates in adult human brain tissue and impairs synapses and memory in mice

“…In conclusion, we have established that ZIKV infects and replicates in adult human brain tissue. Further, our findings identify a possible mechanism underlying neurological complications in adults infected with ZIKV 8–23 . Results revealed that ZIKV caused brain inflammation and that elevated TNF-α led to microglial activation and phagocytosis of hippocampal synapses in mice.…”

“…ZIKV infection during pregnancy causes serious neurological conditions in newborns, including microcephaly 4,6 . Though initially considered a self-limited febrile state in adults, ZIKV infection was recently linked to the development of neurological complications 8–23 , including acute myelitis 13,21 , encephalitis, 8,10,11,16,21 and meningoencephalitis 18,19 . Indeed, ZIKV infection has been associated with increased incidence of a broad spectrum of neurological disorders in adult patients 8 .…”

“…In addition to complications arising from congenital infection, a number of reports have shown that adult individuals are susceptible to neurological complications following ZIKV infection 8–23 . These include Guillain-Barré syndrome 8,9,11,12,21 , acute myelitis 8,13,21 , encephalomyelitis 8,11,14,15,22 , encephalitis 8,11,16,21 , meningoencephalitis, 18,19 and sensory polyneuropathy 20 .…”

Zika Virus Infection Leads to Demyelination and Axonal Injury in Mature CNS Cultures

“…Using ZIKV strain PE243, a patient-derived isolate obtained during the outbreak in Brazil, we showed that in myelinating cultures oligodendrocytes are proportionally more targeted by this virus than other cell types, affecting ongoing myelination and resulting in axonal injury [ 44 ]. ZIKV infection has been increasingly linked to CNS pathology, including myelin injury in adults: acute myelitis, encephalitis, meningoencephalitis, and encephalomyelitis [ 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 ]. Furthermore, ZIKV has been detected in adult human brain tissue [ 57 ].…”

Zika Virus Pathogenesis: A Battle for Immune Evasion

“…ZIKV has been found in the cerebrospinal fluid (CSF) and brain of adults infected by the virus who manifested neurological disorders [ 24 , 36 , 37 , 38 , 39 ]. This flavivirus causes harmful effects in the adult brain, such as GBS [ 36 , 38 , 40 , 41 , 42 ], encephalitis [ 36 , 41 , 42 , 43 ], meningoencephalitis [ 24 , 44 ], acute myelitis [ 36 , 42 , 45 ] and encephalomyelitis [ 36 , 39 , 41 , 46 , 47 ], among sensory polyneuropathy [ 48 ] and other neurological complications [ 49 , 50 ]. After Brazil, other ZIKV outbreaks and rapid transmission were subsequently reported throughout the Americas and Africa, as well as other regions of the world [ 12 , 23 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 ].…”