5.2 - AnxA1 and viral infections
Annexin-A1 (AnxA1) exhibits a complex relationship with various viruses. In addition to its involvement in resolving inflammation, recent studies have demonstrated its interaction with several processes crucial for the replication of specific viruses and antiviral host responses. For instance, AnxA1 was found to enhance the expression of the cytoplasmic sensor retinoic acid-inducible gene I (RIG-1) both before and after infection with influenza A virus (IAV) in A549 cells (Yap et al., 2020). Furthermore, the overexpression of AnxA1 resulted in an increase in IFN-β levels, while silencing AnxA1 impaired IFN-β and IFN-stimulated responsive element activation. This stimulation of IFN-β expression occurs through a physical interaction between AnxA1 and a cytoplasmic protein known as tank binding kinase 1 (TBK-1) (Bist et al., 2013). Interestingly, Ma et al. demonstrated that the 3A protein of foot and mouth disease virus (FMDV) hinders the formation of the AnxA1-TBK-1 complex, thereby inhibiting the AnxA1-mediated increase in IFN-β (Ma et al., 2022). The inhibitory effect of AnxA1 has also been observed in hepatitis C virus (HCV) infection. In vitro studies using human hepatoma cell line Li23-derived D7 cells, which express exogenous AnxA1, showed a significant inhibition of viral RNA replication compared to wild-type cells, demonstrating the inhibitory effect of AnxA1 against HCV (Hiramoto et al., 2015).
Significantly, it has been shown that AnxA1 can facilitate viral binding and/or replication in several viral infections. In the case of reovirus and measles virus infections in vitro , AnxA1 promotes the formation of syncytia both within the cytoplasm and in the extracellular space (Ciechonska et al., 2014). Regarding HIV, solid evidence suggests that the FPR2 receptor serves as a co-receptor for viral entry, independent of AnxA1 (Shimizu et al., 2008; Nedellec et al., 2009; Jiang et al., 2011; Cashin et al., 2013). Furthermore, herpes virus and IAV exploit the AnxA1 pathway by utilizing the FPR2 receptor to enhance virus uptake by host cells. Both the glycoprotein E (gE) of herpes virus and the envelope protein of IAV bind to AnxA1 and utilize FPR2 for cell entry (Wang et al., 2022; Arora et al., 2016; Tcherniuk et al., 2016).
In the case of IAV infection, the AnxA1/FPR2 axis triggers specific signaling pathways that favor various steps of viral replication, including endosomal export of the virus, endosomal trafficking to the nucleus, and enhanced autophagy and apoptosis (Rahman et al., 2018; Arora et al., 2016; Cui et al., 2020). Consequently, FPR2 inhibitors have shown antiviral effects against H1N1, H3N2, H6N2, and Influenza B viruses (Courtin et al., 2017). Recent findings indicate that IAV infection stimulates the release of exosomes that downregulate several genes involved in the inflammatory response, including the AnxA1 gene (Zabrodskaya et al., 2022). Additionally, in vitro studies have demonstrated that H1N1 infection upregulates the expression of FPR2 (Ampomah et al., 2018), likely as a strategy to promote disease progression. However, treatment with AnxA1 prior to IAV infection has been shown to expand the population of alveolar macrophages and increase the survival of mice, considering the well-known protective role of these cells against IAV (Schloer et al., 2019). Collectively, these results may appear contradictory, but they highlight that the effect of a particular protein can depend on the timing of treatment initiation. In the latter study, the immunomodulatory role of AnxA1 proved to be beneficial in the context of the infection, despite its known involvement in pathways that facilitate viral replication.
The role of AnxA1 in the context of COVID-19 remains elusive. Canacik and co-workers have demonstrated a decrease in systemic levels of AnxA1 in severe COVID-19 patients compared to healthy volunteers and the moderate disease group. In contrast, Ural and colleagues have shown that patients with severe disease exhibit increased levels of AnxA1 compared to mild COVID-19 individuals or healthy controls (Canacik et al., 2021; Ural et al., 2022). An integrative analysis of multi-platform omics has revealed AnxA1 as a potential therapeutic target against SARS-CoV-2 infection (Li et al., 2021). Indeed, this may reflect the host response during COVID-19, as the levels of AnxA1 were found to be up-regulated in circulating monocytes of convalescent patients (Wen et al., 2020). Future investigations will provide clarity on the potential utilization of AnxA1 or its mimetic peptides as therapeutic agents to mitigate inflammation and accelerate the resolution process in the context of COVID-19.
Recent studies conducted by our group have demonstrated that in murine models of Dengue virus (DENV) and Chikungunya (CHIKV) virus infection, mice lacking AnxA1 (AnxA1KO) and mice lacking the FPR2 receptor (FPR2KO) exhibited increased inflammation without significant differences in viral loads compared to wild-type (WT) mice. Importantly, treatment with Ac2-26 resulted in decreased production of pro-inflammatory cytokines and reduced tissue damage in both DENV and CHIKV infections, while viral titers remained unaffected (Costa et al., 2022; de Araújo et al., 2022). These findings suggest that AnxA1 may hold promise as a therapeutic target against these viruses by suppressing excessive inflammation. Finally, the combination of antiviral agents with AnxA1-based therapies holds great potential as an ideal synergistic strategy for treating these conditions.
Overall, these results demonstrate that the effects of AnxA1 can be either beneficial or detrimental depending on the specific viral type. The potential use of FPR2 inhibitors or AnxA1 monoclonal antibodies shows great promise in the treatment of certain viral infections, such as HSV and IAV. However, it is crucial to conduct clinical trials and human studies to determine whether the findings observed in mouse models can be replicated in human diseases. Additionally, stimulating the AnxA1/FPR2 axis may offer improved prognostic outcomes against certain infections, such as DENV and CHIKV infections.