AHR is a Zika virus host factor and a candidate target for antiviral therapy

Abstract

Zika virus (ZIKV) is a flavivirus linked to multiple birth defects including microcephaly, known as congenital ZIKV syndrome. The identification of host factors involved in ZIKV replication may guide efficacious therapeutic interventions. In genome-wide transcriptional studies, we found that ZIKV infection triggers aryl hydrocarbon receptor (AHR) activation. Specifically, ZIKV infection induces kynurenine production, which activates AHR limiting the production of type I interferons involved in anti-viral immunity. Moreover, ZIKV-triggered AHR activation suppresses intrinsic immunity driven by the promyelocytic leukemia protein (PML), which limits ZIKV replication. AHR inhibition suppressed the replication of multiple ZIKV strains in vitro, and also of the related flavivirus dengue. Finally, AHR inhibition with a nanoparticle-delivered AHR antagonist or an inhibitor developed for human use limited ZIKV replication and ameliorated newborn microcephaly in a murine model. In summary, we identified AHR as a host factor for ZIKV replication, and PML as a driver of anti-ZIKV intrinsic immunity.

MAFB and MAF Transcription Factors as Macrophage Checkpoints for COVID-19 Severity

“…In this scenario, MAFB and MAF differentially affect the expression of AHR, and an enhanced MAFB/MAF ratio correlates with an increased expression of AHR, as it is also seen in macrophages activated by TLR4 or TLR7 ligands (our transcriptional information in GSE156921). The MAFB/MAF ratio-AHR expression link is of special relevance because AhR is activated during coronavirus infection and the constitutive AhR activation constrains type I IFN-mediated antiviral innate defense (44,45). In fact, a role for AhR in SARS-CoV-2 pathology has been recently proposed (46), and AhR antagonists have been propositioned as potential therapy for coronavirus-infected patients (46).…”

A potential role for AHR in SARS-CoV-2 pathology

“…AHR activation by metabolites produced by tumors 14,15 or in the context of viral infection 16 interferes with the generation of protective immunity. Indeed, AHR suppresses the production of type I interferons (IFN-I) 17,18 , probably as part of a feedback negative mechanism because IFN-I induce AHR expression 19 . We recently showed that AHR activation during the infection with Zika or dengue virus suppresses IFN-I-dependent and IFN-I-independent anti-viral innate and intrinsic immunity 17 .…”

“…Indeed, AHR suppresses the production of type I interferons (IFN-I) 17,18 , probably as part of a feedback negative mechanism because IFN-I induce AHR expression 19 . We recently showed that AHR activation during the infection with Zika or dengue virus suppresses IFN-I-dependent and IFN-I-independent anti-viral innate and intrinsic immunity 17 . Most importantly, an AHR antagonist optimized for human use boosted anti-viral immunity, interfered with viral replication and ameliorated multiple aspects of Zika congenital syndrome including microcephaly in animal models 17 , identifying AHR as a candidate target for therapeutic intervention.…”

“…We recently showed that AHR activation during the infection with Zika or dengue virus suppresses IFN-I- dependent and IFN-I-independent anti-viral innate and intrinsic immunity 17 . Most importantly, an AHR antagonist optimized for human use boosted anti-viral immunity, interfered with viral replication and ameliorated multiple aspects of Zika congenital syndrome including microcephaly in animal models 17 , identifying AHR as a candidate target for therapeutic intervention. Based on these findings and the urgent need for therapies for SARS-CoV-2, we investigated the potential role of AHR in coronavirus infection.…”

Metadichol®, A Novel Nano Lipid Formulation that Inhibits SARS-CoV-2 and a Multitude of Pathological Viruses in Vitro

“…It has been suggested that the aryl hydrocarbon receptor (AHR) is activated during coronavirus infections, impacting antiviral immunity and lung cells associated with repair [40]. Signalling via AHR may dampen the immune response against coronavirus [41]. It has been reported that although some signalling is needed for coronavirus replication, excessive activation of this pathway may be deleterious for the virus.…”