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Molekulare Mechanismen der Zikavirus-assoziierten Neuropathogenese und mögliche Rolle der Virusevolution

Fachliche Zuordnung Virologie
Förderung Förderung von 2018 bis 2022
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 391587080
 
Erstellungsjahr 2022

Zusammenfassung der Projektergebnisse

Zika virus (ZIKV) belongs to the Flavivirus genus of the Flaviviridae family, which includes other globally relevant arthropod-transmitted human pathogens such as dengue virus (DENV). ZIKV is an enveloped positive-strand RNA virus. It encodes a single polyprotein, which is cleaved into 3 structural proteins (capsid, pre-membrane (prM), and envelope (E)) and 7 non-structural (NS) proteins. The structural proteins are the building blocks for infectious progeny virus, the NS proteins catalyze viral genome replication and dampen host antiviral responses. ZIKV was classified by the World Health Organization (WHO) as public health emergency of international concern in 2016, and it is still identified as a priority disease. Between 2013 and 2014, a ZIKV outbreak in French Polynesia was the first to reveal an association between ZIKV infection and congenital syndrome, Guillain-Barre syndrome (GBS) and microcephaly. In early 2015, ZIKV was recognized to be associated with microcephaly of newborns in Brazil. These observations suggested that severe neurological complications of ZIKV infections are associated with mutations in recently emerged ZIKV strains. The collaborative project between the Long and Bartenschlager labs aimed to examine the cellular mechanisms underlying ZIKV replication and the link to neuro-pathology and viral evolution. To reach this goal, they conducted annual research discussions as planned and arranged for joint complementary project parts, including exchange of personnel. However, due to the COVID-19 pandemic, most of that could not be realized. Nevertheless, both labs jointly completed the construction of infectious full length clones of multiple ZIKV strains (Münster et al., 2018; Zhao et al., 2018) that were used in various follow-up studies focusing on virus evolution (Zhao et al., 2018), virus-host cell interactions (Scaturro et al., 2018) and the role of the innate immune response in neuronal cells to control ZIKV infection (Plociennikowska, et al., 2021). Based on the original observation that ZIKV remodels the cytoskeleton and the possible impact this might have on integrity of neuronal cells, a panel of cytoskeleton inhibitors was tested for their impact on viral replication in various cell systems. Amongst those, inhibitors of vimentin had the strongest effect. In line, ZIKV induces formation of a vimentin “cage” around the viral replication organelles. However, a knock-out of vimentin did not affect viral replication suggesting that the used drug had an off-target effect and that reorganization of vimentin does not contribute to the viral replication cycle. In a search for mutations in ZIKV contributing to replication and pathogenesis, a series of mutations detected in ZIKV strains that are associated with more severe neurological symptoms were introduced into the original epidemic ZIKV strain detected first in Brazil in 2015. By using in vivo studies it was found that a mutation in the M protein (N139S), affecting the cleavage between prM and E, significantly enhanced ZIKV load in multiple organs and increased pathogenic potential of this virus. Interestingly, another mutation residing in the E-protein significantly attenuated viral lethality and decreased viral load in vivo. These results suggest that ZIKV virulence is variable and depends on distinct mutations that have emerged during the major epidemic. Given the difficulties to conduct joint studies between Germany and China during the COVID-19 pandemic and based on obtained results, the Bartenschlager and the Long lab readjusted the project and studied two different aspects. First, the role of host cell lipids (cholesterol, which is of high relevance of functionality of neurons) in ZIKV replication and the relevance of extracellular vesicles (EVs) released from ZIKV infected cells for disease pathogenesis. With respect to the first project, a chemo-proteomic approach was employed, identifying strong cholesterol interaction with prM. Two cholesterol binding motifs in prM were identified and mechanistic follow-up studies revealed that one motif is required for virus entry and the other for the assembly of infectious virus particles. Thus, drugs interfering with cholesterol biosynthesis or deposition in membranes might be a novel approach to treat ZIKV infection. With respect to the second project, it was found that ZIKV infected cells release EVs that are unable to transmit infectious virus genomes from cell to cell, but contain high amounts of E-protein. These EVs were found to interfere with antibody-dependent-enhancement of ZIKV infection in vitro and in vivo. Thus, ZIKV infection and pathogenesis is modulated by EVs released from infected cells and decorated with high amounts of the E-protein.

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