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.