Rapid Evolution of Enhanced Zika Virus Virulence during Direct Vertebrate Transmission Chains

Abstract

Zika virus (ZIKV) has the unusual capacity to circumvent natural alternating mosquito-human transmission and be directly transmitted human-to-human via sexual and vertical routes. The impact of direct transmission on ZIKV evolution and adaptation to vertebrate hosts is unknown. Here we show that molecularly barcoded ZIKV rapidly adapted to a mammalian host during direct transmission chains in mice, coincident with the emergence of an amino acid substitution previously shown to enhance virulence. In contrast, little to no adaptation of ZIKV to mice was observed following chains of direct transmission in mosquitoes or alternating host transmission. Detailed genetic analyses revealed that ZIKV evolution in mice was generally more convergent and subjected to more relaxed purifying selection than in mosquitoes or alternate passages. These findings suggest that prevention of direct human transmission chains may be paramount to resist gains in ZIKV virulence. Importance We used experimental evolution to model chains of direct and indirect Zika virus (ZIKV) transmission by serially passaging a synthetic swarm of molecularly barcoded ZIKV within and between mosquitoes and mice. We observed that direct mouse transmission chains facilitated a rapid increase in ZIKV replication and enhanced virulence in mice. These findings demonstrate that ZIKV is capable of rapid adaptation to a vertebrate host and indicate that direct human-to-human transmission could pose a greater threat to public health than currently realized.

Using Wolbachia to Eliminate Dengue: Will the Virus Fight Back?

“…In blood-fed mosquitoes, only a small number of infectious units are thought to seed infection in the mosquito midgut ( 53 , 54 ). This reduction in virus population size, known as a population bottleneck, decreases the genetic diversity of the infective virus population ( 55 , 56 ). This event may cause low-frequency Wolbachia -resistant DENV variants already present in the incoming blood meal to be filtered out ( Fig.…”

A road map for in vivo evolution experiments with blood‐borne parasitic microbes

“…Thus, this system is representative of a major group of blood‐borne parasitic microbes that are transmitted by arthropod vectors. Working with vector‐borne microbes adds another complication for in vivo evolution experiments, because one must either include the vectors in the host‐to‐host transmission process or perform laboratory procedures that emulate the transmission by vectors (e.g., Riemersma et al, 2021 ). In any case, studying vector‐borne microbes offers an opportunity to gain insights into how evolution proceeds when parasites are propagated through multiple host types (i.e., the vector and the host).…”

Molecular adaptations during viral epidemics

“…The export of strains that have neutrally evolved within a small, stable epidemiological niche into a much larger community of susceptible hosts not only increases the epidemic potential in the short term but also introduces new selective pressures as a result of interstrain competition which can lead to more robust human adaptation. Furthermore, the landscape of intrahost adaptations observed within model systems studying maternal‐fetal transfer(Lemos et al , 2020) or other direct transmission chains (Riemersma et al , 2021) are different from those improving vector‐mediated transmission, suggesting the possibility that Zika could diversify into primarily vector‐mediated and sexually‐transmitted subtypes, dramatically increasing the complexity of its evolutionary landscape.…”

“…The direct transmission of Zika (Lemos et al , 2020; Riemersma et al , 2021), persistent infections of HIV (Holmes, 2001) and Ebola (Blackley et al , 2016; Whitmer et al , 2018), and familiar mammalian host reservoirs of MERS (Mohd et al , 2016; El‐Kafrawy et al , 2019; Memish et al , 2020), SARS‐CoV‐2 (Fischhoff et al , 2021; Hale et al , 2022), and influenza viruses (Olsen, 2002; Zimmer & Burke, 2009) all provide avenues for viral diversification, speciation, and outbreaks. Extending sequencing efforts to divergent viruses and diverse hosts, combined with focused experimentation, can be expected to reveal the roots of past epidemics, and possibly predict and mitigate the next.…”