Asian Zika virus strains target CD14+ blood monocytes and induce M2-skewed immunosuppression during pregnancy

Abstract

Blood CD14+ monocytes are the frontline immunomodulators categorized into classical, intermediate or non-classical subsets, subsequently differentiating into M1 pro- or M2 anti-inflammatory macrophages upon stimulation. While Zika virus (ZIKV) rapidly establishes viremia, the target cells and immune responses, particularly during pregnancy, remain elusive. Furthermore, it is unknown whether African- and Asian-lineage ZIKV have different phenotypic impacts on host immune responses. Using human blood infection, we identified CD14+ monocytes as the primary target for African- or Asian-lineage ZIKV infection. When immunoprofiles of human blood infected with ZIKV were compared, a classical/intermediate monocyte-mediated M1-skewed inflammation by African-lineage ZIKV infection was observed, in contrast to a non-classical monocyte-mediated M2-skewed immunosuppression by Asian-lineage ZIKV infection. Importantly, infection of pregnant women’s blood revealed enhanced susceptibility to ZIKV infection. Specifically, Asian-lineage ZIKV infection of pregnant women’s blood led to an exacerbated M2-skewed immunosuppression of non-classical monocytes in conjunction with global suppression of type I interferon-signaling pathway and an aberrant expression of host genes associated with pregnancy complications. 30 ZIKV+ sera from symptomatic pregnant patients also showed elevated levels of M2-skewed immunosuppressive cytokines and pregnancy complication-associated fibronectin-1. This study demonstrates the differential immunomodulatory responses of blood monocytes, particularly during pregnancy, upon infection with different lineages of ZIKV.

Toll-like receptor agonist R848 blocks Zika virus replication by inducing the antiviral protein viperin

“…To test the ability of CHME3 cells to support ZIKV replication, we infected them and after 24h quantified intracellular viral RNA and compared the results to blood-derived monocytes and MDMs infected in parallel (Foo, Chen et al 2017, Van der Hoek, Eyre et al 2017). CHME3 cells supported robust ZIKV replication, replicating to a level comparable to that in monocytes.…”

“…Infection has been linked to several neurological disorders, particularly congenital microcephaly (Brasil and Nielsen-Saines 2016, Mlakar, Korva et al 2016, White, Wollebo et al 2016). Epidemic strains have the capacity to replicate in diverse cell types of human origin including monocytes, monocytes-derived macrophages (MDMs) and glial cells (Foo, Chen et al 2017, Meertens, Labeau et al 2017, Van der Hoek, Eyre et al 2017). In light of the increased threat posed by the ZIKV epidemic, the development of antiviral therapies to control ZIKV-related disease is a high priority.…”

Immunological observations and transcriptomic analysis of trimester‐specific full‐term placentas from three Zika virus‐infected women

“…Interestingly, EGF and IP‐10 are typically expressed at higher levels in women carrying a foetus with developmental anomalies . The association of neutrophils with the acute phase should also be given more attention since most studies have focused on the role of monocytes during ZIKV infection thus far . Neutrophils have been shown to infiltrate the central nervous system of ZIKV‐infected immunocompromised mice and may therefore be a causative element in Zika‐induced neurologic damage.…”

Transcriptional Changes during Naturally Acquired Zika Virus Infection Render Dendritic Cells Highly Conducive to Viral Replication

“…Notably, recent studies also demonstrated that myeloid cells, including specific monocyte subsets, are highly susceptible to ZIKV during pregnancy and in infants, and highlighted the fact that ZIKV can reprogram their gene expression patterns to limit antiviral immune defense. (Foo et al, 2017; Michlmayr et al, 2017). …”