What distinguishes ZIKV from other arboviruses is its extraordinary propensity to affect the nervous system and there are 2 ways: one through direct infection to produce manifestations like microcephaly and some of the adult and paediatric manifestations as well as encephalitis myelitis; the second area is the auto-immune manifestations – most notably Guillain-Barré syndrome. This is important to understand as it profoundly affects the approaches to treatment – one being centered on anti-viral therapies and the other on anti-inflammatory therapies.
“Our aim is to dissect at the laboratory level to understand the molecular pathogenesis of brain infection – why this virus occurs and how it affects the survival and development of brain cells in different model systems.”
Prof. Hugh Willison, University of Glasgow
This group aims to discover and characterize the mechanistic pathways of Zika virus infection in the pathogenesis of central (CNS) and peripheral nervous system (PNS) injury, focusing on direct viral invasion and immune and autoimmune responses to viral infection.
Working closely with the NEURO-ZIKA: Neurological Manifestations of Zika group, researchers have been working to:
- define Zika virus tropism in the peripheral and central nervous systems (PNS and CNS, respectively), in vitro and in vivo,
- determine the consequences for PNS and CNS cell health, function and survival of direct Zika virus infection, in vitro and in vivo,
- investigate intra- and intercellular trafficking of Zika virus within and between the periphery and the PNS and CNS,
- characterize the nature of Zika virus' main cellular receptors on human neural cells, screening proteins, glycoproteins, proteoglycans, glycolipids, and thereby identify candidates used by Zika virus to attach to neural cells,
- determine if humoral factors from Zika-GBS patient and control sera are pathogenic to PNS and CNS cells in vitro and ex vivo,
- examine sera from Zika-GBS cases and controls for antigen targets known to be associated with conventional GBS, principally peripheral nerve glycolipids, using sensitive immunoassays,
- examine differential immune responses in patients with non-neurological ZIKV infection, patients with viral invasion of the CNS (e.g. encephalitis) and patients with autoimmune neurological disease.
Results and Achievements
- Zika virus tropism in the peripheral and central nervous systems (PNS and CNS, respectively), has now been performed in vitro and these data are guiding progress to in vivo work. Different viral isolates show different tropism for nervous system cells. Infection of neurons clearly leads to a specific axonal phenotype without inducing neuronal cell death which will be investigated in trafficking studies once reagents become available. Infection of induced pluripotent neural stem cells can be used to successfully perform drug screens.
- Progress in characterizing the nature of Zika virus’ main cellular receptors on human neural cells is well developed, with suspected and unknown candidates being investigated.
- Studies to investigate whether humoral factors from Zika-GBS patient and control sera are pathogenic to PNS and CNS cells in vitro are progressing well. Sera from Zika-GBS cases and controls have been screened for antigen targets known to be associated with conventional GBS using sensitive immunoassays: preliminary data does not indicate that Zika-GBS has a unique autoimmune signature. This is important because we urgently need to identify biomarkers to help with diagnosis and case ascertainment and provide clues about causation. This is currently being investigated using different in vitro culture systems.
The cellular studies to examine differential immune responses in patients with non-neurological ZIKV infection, patients with viral invasion of the CNS (e.g. encephalitis) and patients with autoimmune neurological disease are awaiting collection of clinical samples.
MERG and NEURO-ZIKA Networks
Group leader: Prof. Hugh Willison, University of Glasgow
- Umeå University
- University of Leuven (KU Leuven)
- The University of Liverpool
- La Jolla Institute for Allergy and Immunology
- Fundação Oswaldo Cruz (Fiocruz)