Abstract
Zika virus (ZIKV) strains are classified into the African and Asian genotypes. The higher virulence of the African MR766 strain, which has been used extensively in ZIKV research, in adult IFNα/β receptor knockout (IFNAR-/-) mice is widely viewed as an artifact associated with mouse adaptation due to at least 146 passages in wild-type suckling mouse brains. To gain insights into the molecular determinants of MR766’s virulence, a series of genes from MR766 were swapped with those from the Asian genotype PRVABC59 isolate, which is less virulent in IFNAR-/- mice. MR766 causes 100% lethal infection in IFNAR-/- mice, but when the prM gene of MR766 was replaced with that of PRVABC59, the chimera MR/PR(prM) showed 0% lethal infection. The reduced virulence was associated with reduced neuroinvasiveness, with MR766 brain titers ≈3 logs higher than those of MR/PR(prM) after subcutaneous infection, but was not significantly different in brain titers of MR766 and MR/PR(prM) after intracranial inoculation. MR/PR(prM) also showed reduced transcytosis when compared with MR766 in vitro. The high neuroinvasiveness of MR766 in IFNAR-/- mice could be linked to the 10 amino acids that differ between the prM proteins of MR766 and PRVABC59, with 5 of these changes affecting positive charge and hydrophobicity on the exposed surface of the prM protein. These 10 amino acids are highly conserved amongst African ZIKV isolates, irrespective of suckling mouse passage, arguing that the high virulence of MR766 in adult IFNAR-/- mice is not the result of mouse adaptation.
Highlights
The World Health Organization declared the outbreak of Zika virus (ZIKV) infection on the American continent a public health emergency of international concern in February 2016
Several studies have reported that African ZIKV strains are more virulent in adult IFNα/β receptor knockout (IFNAR-/-) mice, the representative African ZIKV strain MR766 is believed to have artefactually high virulence in adult IFNAR-/- mice due to its extensive passage history in suckling wild-type mouse brains
We provide evidence that the lethality of MR766 in the adult IFNAR-/- mice is associated with 10 amino acid residues in the prM protein that are associated with an increased ability to cross the blood-brain barrier
Summary
The World Health Organization declared the outbreak of Zika virus (ZIKV) infection on the American continent a public health emergency of international concern in February 2016. This flavivirus induces a recognized spectrum of congenital neurological malformations (including but not restricted to microcephaly) termed Congenital Zika Syndrome (CZS) that will likely be associated with complex and life-long disabilities in children born to women infected with ZIKV during pregnancy [1,2]. Maturation of the virus particles involves cleavage of the prM protein by the host protease furin. The prM protein has been associated with the virulence of ZIKV [14,15,16] and other flaviviruses [4,17,18]
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