Viral receptors for flaviviruses: Not only gatekeepers

Abstract

Arboviruses have been a huge threat for human health since the discovery of yellow fever virus in 1901. Arboviruses are arthropod born viruses, mainly transmitted by mosquitoes and ticks, responsible for more than thousands of deaths annually. The Flavivirideae family is probably the most clinically relevant, as it is composed of very important agents, such as dengue, yellow fever, West Nile, Japanese encephalitis, and, recently, Zika virus. Intriguingly, despite their structural and genomic similarities, flaviviruses may cause conditions ranging from mild infections with fever, cutaneous rash, and headache, to very severe cases, such as hemorrhagic fever, encephalitis, Guillain‐Barré syndrome, and microcephaly. These differences may greatly rely on viral burden, tissue tropism, and mechanisms of immune evasion that may depend on both viral and host genetic factors. Unfortunately, very little is known about the biology of these factors, and how they orchestrate these differences. In this context, viral structural proteins and host cellular receptors may have a great relevance, as their interaction dictates not only viral tissue tropism, but also a plethora on intracellular mechanisms that may greatly account for either failure or success of infection. A great number of viral receptors have been described so far, although there is still a huge gap in understanding their overall role during infection. Here we discuss some important aspects triggered after the interaction of flaviviruses and host membrane receptors, and how they change the overall outcome of the infection.

Does the human placenta express the canonical cell entry mediators for SARS-CoV-2?

“…Notably, all of these receptors were highly expressed in several placental cell types ( Figure 2 , CMV and Figure 2—figure supplement 2 ). Next, we investigated the expression of the AXL receptor for ZIKV ( Richard et al, 2017 ; Persaud et al, 2018 ) as well as other related molecules such as CD209 ( Carbaugh et al, 2019 ) and TYRO3 ( Oliveira and Peron, 2019 ). Consistent with vertical transmission, AXL, the preferred receptor for ZIKV, was highly expressed by the cells of the human placenta and chorioamniotic membranes throughout gestation ( Figure 2 , ZIKV).…”

Does the human placenta express the canonical cell entry mediators for SARS-CoV-2?

“…S2). Next, we investigated the expression of the AXL receptor for ZIKV [85,86] as well as other related molecules such as CD209 [87] and TYRO3 [88]. Consistent with vertical transmission, AXL, the preferred receptor for ZIKV, was highly expressed by the cells of the human placenta and chorioamniotic membranes throughout gestation (Fig.…”

Gas6 drives Zika virus-induced neurological complications in humans and congenital syndrome in immunocompetent mice

“…In our experiments, this mechanism was confirmed by restoration of antiviral response and complete blockage of production of infective viral particles when monocytes were treated with warfarin. These findings implicate that, by tethering ZIKV to TAM receptors, Gas6 mediates the pivotal suppression of type I interferon receptor (IFNAR) signalling, thereby favouring ZIKV evasion from antiviral immunity and sustained replication, pointing out how interactions with membrane receptors go beyond attachment and internalization of viral particles[54].We demonstrate a correlation between Gas6 protein expression, ZIKV RNA load and production of infecting particles associated with suppression of type I IFN response in human cells infected in vitro. Although we did not detect difference in ZIKV RNA load in the peripheral blood specimens in our cross-sectional cohort, this could probably be due to the…”