Zika virus (ZIKV) is a mosquito-borne Flavivirus that causes Zika disease characterized by fever, rash, arthralgia and conjunctivitis which, given the rapid worldwide spread of the virus, is now considered an emerging infectious disease. Of particular concern are recent reports of neurological complications, such as Guillain-Barré Syndrome and congenital microcephaly associated with Zika disease. To date no strategies for ZIKV control are available, hence the urgency to initiate the development of antiviral strategies. The partners of the ZIKAHOST proposal consortium were the first to explore and to report on the biology of ZIKV. They have also recently discovered that the TAM receptor Axl is a major ZIKV entry molecule into microglia and astrocytes in the developing brain. Our recent findings also show that ZIKV infection of primary human fetal neural progenitors (hNPC) is independent of Axl, which points to the involvement of other receptors in this process. Viral infection of the brain induces inflammation associated with exacerbated immune responses, leading to brain injury. Indeed, preliminary data of ZIKAHOST show that ZIKV modulates gene expression in hNPC involved in neurogenesis dependent on the nature of the viral strain. At present, the precise molecular mechanisms permitting ZIKV to escape the host antiviral response in human brain cells remain to be determined. In addition, many questions remain unanswered regarding the complications caused by different primary isolates of ZIKV. The specific aims of the ZIKAHOST consortium are:
1) To identify key entry factors involved in ZIKV infection and to determine their involvement in ZIKV neurotropism
Our preliminary data point to a new ZIKV candidate receptor, referred to as RcpA, that strongly enhances ZIKV infection when overexpressed in 293T cells. RcpA is expressed in developing brain but not in hNPC. We will use organotypic cultures and isolate RcpA expressing cells to investigate its implication in ZIKV infection of brain cells. We will use a combination of gain & loss of function screens to identify receptors that mediate ZIKV entry into hNPC.
2) To determine the cellular responses of human brain cells to ZIKV infection
We will investigate the host innate immune response induced by different strains of ZIKV infection of human brain cells in order to (a) characterize the molecular mechanisms that define the neuropathogenicity of ZIKV to understand how they may affect neurogenesis and (b) elucidate the mechanisms by which ZIKV can counteract the innate immune response.
3) To characterize the different steps of ZIKV-induced brain injury in the developing human brain cells and tissue
We will take into account the gestational age, a factor that is likely to critical for ZIKV-induced neuropathology to (a) determine how organotypic cultures and key primary cell type from fetal prefrontal cortex respond to ZIKV infection and (b) monitor interactions between ZIKV and major cell types from the frontal cortex of developing brain.
ZIKAHOST is based on a collaboration between three partners, the Institut de Recherche pour le Développement (IRD), INSERM UMR 7212, and INSERM U1141 that have complementary expertise in research on ZIKV, entry receptors, innate immunity, as well as neurobiology and that have long-standing fruitful scientific exchanges. Our project will be crucial for a better understanding of how ZIKV hijacks cellular functions and is able to avoid antiviral mechanisms in human brain cells and tissue. We expect that our findings will provide major insights into ZIKV pathogenesis and will uncover host factors that might serve as therapeutic targets to block ZIKV infection. ZIKAHOST is particularly timely, relevant and original in the international context. The originality of ZIKAHOST is its focus on factors associated with ZIKV neuropathogenesis taking into account the gestational age and clinically relevant strains of ZIKV.
Madame Dorothée Missé (INSTITUT DE RECHERCHE POUR LE DEVELOPPEMENT)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
INSERM U1141 INSERM U1141
INSERM UMR 7212 Pathologie et virologie moléculaire
IRD - UMR MIVEGEC INSTITUT DE RECHERCHE POUR LE DEVELOPPEMENT
Help of the ANR 519,488 euros
Beginning and duration of the scientific project: January 2018 - 48 Months