A Zika Virus Primary Isolate Induces Neuroinflammation, Compromises the Blood-Brain Barrier, and Upregulates CXCL12 in Adult Macaques

Abstract

22Zika virus (ZIKV) is a neurotropic virus that can cause neuropathy in adults and fetal 23 neurologic malformation following infection of pregnant women. We used a nonhuman primate 24 model, the Indian-origin Rhesus macaque (IRM), to gain insight into virus-associated hallmarks 25 42 chemokine may be involved in virus-induced inflammation and/or in repair of virus-induced brain 43 damage. Our data are significant since they help in understanding the mechanism of brain 44 damage caused by ZIKV in adults. 45 3 46 Introduction 47 Zika virus (ZIKV), is a neurotropic flavivirus associated with Guillain-Barre' syndrome 48 (GBS) in adults and is also well-known for causing fetal neurologic malformation following 49 infection of pregnant women (1, 2). In addition to causing GBS, which features damage to the 50 protective myelin sheath surrounding axons, ZIKV can cause neuropathy in adults in the form of 51 meningioencephalitis and myelitis (3, 4). The pathogenesis of ZIKV and the host-pathogen 52 interactions important for the development of these lesions still need to be elucidated. 53The blood-brain barrier (BBB), the boundary between circulatory and CNS tissues, is 54 composed of brain microvascular endothelial cells (BMECs) and supporting associated pericytes 55 and astrocytes. Intercellular tight junction (TJ) and adherens junction (AJ) integrity is important 56 for maintenance of the intracellular network of MECs that comprises the vascular endothelium. 57 Disruption of the BBB occurs during the pathogenesis of a wide range of infectious, autoimmune, 58 and neurodegenerative diseases. Neurotropic flaviviruses, including Japanese Encephalitis virus 59 (JEV) and West Nile virus (WNV), disturb the BBB in adults through disruption of the BMEC 60 network (5, 6). 61The chemokine CXCL12 is a key regulator of both myelin formation during embryogenesis 62 and remyelination following neural damage in the CNS and peripheral nervous system (PNS) in 63 adults (7, 8). CXCL12 facilitates the migration and maturation of oligodendrocyte precursor cells 64 (OPCs) during CNS remyelination (7, 8). In the PNS, CXCL12 may similarly function in Schwann 65 cell migration (9), as CXCL12 is expressed by perisynaptic Schwann cells during recovery of 66 neuromuscular junctions following damage (10). In addition to serving as a key regulator of neural 67 repair, CXCL12 plays an important function in regulating lymphocyte migration through the BBB. 68During homeostasis CXCL12 is expressed by BMECs resulting in spatial restriction of 69 lymphocytes to the microvascular perivascular space, and changes in chemokine expression and 70 distribution can lead to neuroinflammation (11, 12). The role of CXCL12 in neural repair, 4 71 lymphocyte migration into the CNS parenchyma, and in multifarious functions during development 72 and immunity, are mediated through interaction of this chemokine with its primary receptor, 73 CXCR4 (13). Stimulation of CXCR4 by CXCL12 results in activation of an interwoven set of 74 downstream effector pathways (14, 15)....

Neuroinflammation in neurodegeneration via microbial infections

“…The Zika virus (ZIKV) is a neurotropic virus that induces adult neuropathy. ZIKV infection causes an increase in CXCL12, which regulates lymphocyte trafficking through the BBB ( 220 ). After infecting brain microvascular cells, ZIKV is released on the parenchyma side, and it initiates the alteration of BBB integrity and upregulation of inflammatory and cell adhesion molecules ( 221 ).…”

CNS Macrophages and Infant Infections

“…However, these findings need further evaluation in vivo . Another study performed ZIKV infections in adult macaques revealed a high incidence of neuroinflammation in infected animals and a disruption of the BBB ( Figure 2 ) ( 147 ). Here, long-term increased levels of C-X-C motif chemokine ligand 12 (CXCL12), which is a chemokine involved in lymphocyte trafficking and neural repair, were described.…”

“…Here, long-term increased levels of C-X-C motif chemokine ligand 12 (CXCL12), which is a chemokine involved in lymphocyte trafficking and neural repair, were described. Additionally, the authors observed inflammation in the perivascular space and meninges, accompanied by lymphocytic infiltrations ( 147 ). This was also reported in fetal human brains, where an infiltration of T and B cells was observed in the perivascular space during ZIKV infection ( Figure 2 ) ( 113 ).…”

Zika virus NS4A hijacks host ANKLE2 to promote viral replication

“…Gestational timing and type I interferon responses in utero are also critical in ZIKV susceptibility (16,17). Upon fetal infection, ZIKV also breaches the blood-brain barrier and infects susceptible neuronal tissue (18)(19)(20)(21)(22).…”

“…Gestational timing and type I interferon responses in utero are also critical in ZIKV susceptibility (17,18). Upon fetal infection, ZIKV also breaches the blood-brain barrier and infects susceptible neuronal tissue (19)(20)(21)(22)(23). Infection of these neuronal tissues is associated with direct tissue damage through the cytopathic effect (24)(25)(26), molecular level pathogenesis (27), disruption of cell division (24,(28)(29)(30), and dysregulation of developmental pathways (31)(32)(33)(34)(35)(36)(37).…”