Multi-Omics Analysis Of Antiviral Interactions OfElizabethkingia anophelisAnd Zika Virus

Abstract

ABSTRACTBackgroundThe microbial communities residing in the mosquito midgut play a key role in determining the outcome of mosquito pathogen infection.Elizabethkingia anophelis, originally isolated from the midgut ofAnopheles gambiae, has drawn much attention due to its close association withAedesandAnophelesmosquitoes, primary vectors of dengue virus and malaria parasites, respectively.E. anophelispossesses a broad-spectrum antiviral phenotype, yet a gap in knowledge regarding the mechanistic basis of its interaction with viruses exists.Methodology/Principal findingsTo further understand the antiviral interactions betweenE. anophelisand Zika virus (ZIKV), we utilized a non-targeted multi-omics approach, analyzing lipids, proteins, and metabolites of cell monolayers co-infected with ZIKV andE. anophelis. We further assessed the gene expression of ZIKV when cultured in the presence ofE. anophelis. ZIKV cultured in the presence ofE. anophelisresulted in an attenuated replicative fitness and unproductive virus infection. Further, in this treatment, we observed lower levels of the nonstructural protein 5 (NS5) and RNA-directed RNA polymerase (RdRp) protein. Lastly, a significant decrease in arginine levels, an essential requirement for viral replication and progression of viral infection was observed.Conclusions/SignificanceThis study provides insights into the molecular basis ofE. anophelisantiviral phenotype. These findings improve our knowledge of how microbes and viruses interact to impact viral replication. In the future, our findings can be utilized to unravel the mechanism behind the antiviral phenotype ofE. anophelis,and this can help develop novel paradigms for viral therapeutics.AUTHOR SUMMARYZika is a re-emerging disease and is endemic in many regions of sub-Saharan Africa, Asia and Latin America. It remains a major public health threat and lacks FDA-approved therapeutics or vaccines, hence the urgent need for the identification of alternative approaches that limit the transmission of the pathogens by its primary vector,Aedesspp. The microbial communities residing in the mosquito midgut play a key role in determining the outcome of mosquito pathogen infection. Flavobacteria dominates the mosquito midgut includingElizabethkingia, which is a gram-negative bacillus prevalent inAedesandAnophelesspecies of mosquitoes.E. anophelis, a poorly studied midgut microbe, has a broad-spectrum antiviral phenotype, yet the mechanism of its antiviral action is unknown. In this study, we have identified several pathways as well as Zika virus proteins perturbed when the Zika virus is cultivated in the presence ofE. anophelis. Our findings do not only provide insights into microbial, virus interaction but could be harnessed to develop novel antiviral tools.