Abstract
Zika virus (ZIKV) infection is currently one of the major concerns in human public health due to its association with neurological disorders. Intensive effort has been implemented for the treatment of ZIKV, however there are not currently approved vaccines or antivirals available to combat ZIKV infection. In this sense, the identification of virulence factors associated with changes in ZIKV virulence could help to develop safe and effective countermeasures to treat ZIKV or to prevent future outbreaks. Here, we have compared the virulence of two related ZIKV strains from the recent outbreak in Brazil (2015), Rio Grande do Norte Natal (RGN) and Paraiba. In spite of both viruses being identified in the same period of time and region, significant differences in virulence and replication were observed using a validated mouse model of ZIKV infection. While ZIKV-RGN has a 50% mouse lethal dose (MLD50) of ~105 focus forming units (FFUs), ZIKV-Paraiba infection resulted in 100% of lethality with less than 10 FFUs. Combining deep-sequencing analysis and our previously described infectious ZIKV-RGN cDNA clone, we identified a natural polymorphism in the non-structural protein 2 A (NS2A) that increase the virulence of ZIKV. Moreover, results demonstrate that the single amino acid alanine to valine substitution at position 117 (A117V) in the NS2A was sufficient to convert the attenuated rZIKV-RGN in a virulent Paraiba-like virus (MLD50 < 10 FFU). The mechanism of action was also evaluated and data indicate that substitution A117V in ZIKV NS2A protein reduces host innate immune responses and viral-induced apoptosis in vitro. Therefore, amino acid substitution A117V in ZIKV NS2A could be used as a genetic risk-assessment marker for future ZIKV outbreaks.
Highlights
Zika virus (ZIKV) infection is currently one of the major concerns in human public health due to its association with neurological disorders
Mice infected with only 10 focus forming units (FFUs) of ZIKV-Paraiba showed clear disease signs, had a dramatic weight loss, and all of them succumbed to viral infection with a calculated MLD50 < 10 FFU
Only mice infected with 105 FFU of rZIKV-Rio Grande do Norte Natal (RGN) showed clear signs of infection, loss significant body weight and succumbed to viral infection, with a calculated MLD50 of ~7.5 × 104 FFU (Fig. 1)
Summary
Zika virus (ZIKV) infection is currently one of the major concerns in human public health due to its association with neurological disorders. Extensive efforts have been made to develop in vitro and in vivo approaches to study ZIKV infection and pathogenesis, including reverse genetic systems[34] and suitable animal models of infection[45] In this sense, the emergence of ZIKV has promoted the rapid development of numerous reverse genetic approaches[34], which constitute an essential tool for research to generate recombinant viruses containing specific substitutions to evaluate their contribution in viral replication or transcription, pathogenicity, virus-host interaction, viral tropism and transmissibility[46,47,48]. These animal models are currently used to study ZIKV infection in vivo, including the development of new therapeutic approaches to combat and/or prevent ZIKV infections[24,45,50,52,55]
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