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  • br Materials and methods br Results br Discussion The innate

    2021-09-10


    Materials and methods
    Results
    Discussion The innate immune system plays an important role in protecting against IAV infections. However, the virus has the ability of escaping the innate immune system. Activating or enhancing an innate immune response before or during a viral infection will help increase the host's ability to fight the virus. In our previous study, we showed that HO-1 has the ability to activate IFN-α/β that inhibits replication of influenza virus. However, it is unclear about the mechanism underlying HO-1-mediated activation of IFN-α/β. Hererin, we show that CoPP, a specific activator of HO-1 expression, induces IFN-α/β Octyl-α-ketoglutarate and significantly inhibits the replication of influenza virus. Furthermore, we show that IRF3 involves in HO-1-mediated upregulation of IFN-α/β through the direct binding to HO-1. The proposed mechanism of CoPP anti-IAV effects is illustrated in Fig. 6. Cobalt protoporphyrin (CoPP) is a type of metalloporphyrins, conjugates of metals binding to porphyrins. CoPP is known as a potent and effective inducer of HO-1 (Shan et al., 2006). Much evidence in vivo and in vitro models shows CoPP protection from a variety of damages via upregulation of HO-1 (Schmidt, 2007). However, CoPP is not considered as a potential therapeutic agent in view of many side effects at therapeutic doses such as depletion of hepatic cytochrome P450, loss of weight and transient hepatotoxicity (Schmidt, 2007). Hence, CoPP is more suitable as a tool medicine to study the protective effects and mechanisms of HO-1, and alternative HO-1 inducers like hemin or CoPP modifications might be of therpeutic value in clinic when a patient is suffering from infection of drug-resistant or emerging influenza viruses. HO-1 is a stress-induced and cytoprotective enzyme expressed in most cell types in the organism. HO-1 is known to have anti-inflammatory and antioxidant activities. Recently, HO-1 has been shown to play an important role in modulating immune responses. The immunomodulatory effects of HO-1 have been revealed in several studies, such as HO-1 deficiency-induced chronic inflammation in which HO-1 deficiencies increased counts in blood leukocytes and levels of Th1 cell cytokines including IL-6, IFN-γ and TNF-α (Riquelme et al., 2016). Similar immunomodulatory effects have been observed in HO-1-knockout macrophages in which IFN-β production was impaired after stimulating TLR4 or TLR3. Furthermore, HO-1 deficencies in macrophages and mice result in the deminish of immune responses to bacterial and viral infections (Tzima et al., 2009). CoPP, as a specific activator of HO-1, decreased viral replication and lung inflammation through increasing the production of IFN-α/β in the lung infected with hRSV (Espinoza et al., 2017). Consistent with these findings, in our previous study, we showed that overexpression or pharmacological induction of HO-1 stimulated significant upregulation of IFN-α/β and inhibited replication of influenza virus. In the present study, we again showed that induction of HO-1 expression by CoPP treatment enchanced IFN-α/β expression in the RAW264.7 cells. We obesrved that CoPP dose-dependently inhibit replication of influenza A and B viruses including clinical isolates and drug-resistant strains. HO-1-mediated inhibition of viral replication is at least partly associated with IFN-α/β induction. The function of IFN-α/β to inhibit IAV replication is mainly attributable to the increased expression of ISG genes including IFIT, IFITM3, OAS, PKR and MX1 (Diamond and Farzan, 2013; Tecle et al., 2005). The protein products translating from these ISG genes have strong antiviral effects through several mechanisms. For instance, IFIT proteins restrict viral replication by inhibiting the crucial steps in the translation of viral mRNA (Hui et al., 2003). In addition, IFITM3 inhibiting IAV infection by restrecting IAV fuse in late endosomes essential for releasing IAV genetic code (Brass et al., 2009; Huang et al., 2011). In the present study, HO-1 upregulation induced by CoPP siginicantly promotes the production of IFN-α/β and the expression of downstream IFITM3, OAS1 and PKR, which subsequently inhibits replication of the panel of influenza viruses including clincial strains resistant to OC and AH. Thus, the broad-spectrum antiviral activities of CoPP is much likely to be associated with induction of ISGs. These results are consistent with our previous study showing that HO-1 upregualtion induced by another small molecular results in inhibition of a panel of influenza viruses (Ma et al., 2016). It should be noted that one study recently reported HO-1-mediated inhibition of influenza virus replication in MDCK (Hossain et al., 2018), which Octyl-α-ketoglutarate was considered as the result of HO-1 protective effects against oxidative stress and cell death. Considering that type I intreferon response is weak in MDCK, HO-1-mediated anti-oxidative stress might be also important to inhibit IAV replication. Collectively, therapeutic induction of HO-1 is probably a novel method to prevent the epidemics of influenz viruses. An exceptional study indicated that down-regulation of HO-1 inhibits H9N2 replication in chicken oviduct epithelial cells (COECs) (Qi et al., 2017), this singular inconsistence may be due to the different cells or virus used in their study.