Induction of HOXA3 by Porcine Reproductive and Respiratory Syndrome Virus Inhibits Type I Interferon Response through Negative Regulation of HO-1 Transcription.

Type I interferons (IFN-Is) play a key role in host defense against virus infection, but porcine reproductive and respiratory syndrome virus (PRRSV) infection does not effectively activate IFN-I response, and the underlying molecular mechanisms are poorly characterized. In this study, a novel transcription factor of the heme oxygenase-1 (HO-1) gene, homeobox A3 (HOXA3), was screened and identified. Here, we found that HOXA3 was significantly increased during PRRSV infection. We demonstrated that HOXA3 promotes PRRSV replication by negatively regulating the HO-1 gene transcription, which is achieved by regulating IFN-I production. A detailed analysis showed that PRRSV exploits HOXA3 to suppress beta interferon (IFN-β) and IFN-stimulated gene (ISG) expression in host cells. We also provide direct evidence that the activation of IFN-I by HO-1 depends on its interaction with IRF3. Then we further proved that a deficiency of HOXA3 promoted the HO-1-IRF3 interaction and subsequently enhanced IRF3 phosphorylation and nuclear translocation in PRRSV-infected cells. These data suggest that PRRSV uses HOXA3 to negatively regulate the transcription of the HO-1 gene to suppress the IFN-I response for immune evasion. IMPORTANCE Porcine reproductive and respiratory syndrome (PRRS), caused by PRRSV, causes significant worldwide economic losses in the pork industry. HOXA3 is generally considered to be an important molecule in the process of body development and cell differentiation. Here, we found that a novel transcription factor of the HO-1 gene, HOXA3, can negatively regulate the transcription of the HO-1 gene and play an important role in the suppression of IFN-I response by PRRSV. PRRSV induces the upregulation of HOXA3, which can negatively regulate HO-1 gene transcription, thereby weakening the interaction between HO-1 and IRF3 for inhibiting the type I IFN response. This study extends the function of HOXA3 and provides new insights into the PRRSV immune evasion mechanism.