The Multifaceted Role of Annexin A1 in Viral Infections

The COVID-19 pandemic highlighted the global threat posed by emerging and re-emerging viral diseases and the urgent need for novel therapies beyond pathogen-directed antivirals and vaccines. Excessive or unresolved inflammation drives morbidity and mortality in several viral infections, as exemplified by the benefit of glucocorticoids in severe COVID-19. Resolution of inflammation is an active, regulated process mediated by pro-resolving molecules, including Annexin A1 (AnxA1). AnxA1 promotes neutrophil apoptosis and efferocytosis, enhances pathogen and debris clearance, polarizes regulatory macrophages, and dampens leukocyte recruitment and cytokine production. However, its role during viral infection is context dependent; AnxA1 can be protective by resolving inflammation or be subverted by viruses to enhance their replication. This review synthesizes pre-clinical and clinical evidence on AnxA1/FPR2 signaling in respiratory and non-respiratory viral infections and discusses its host-directed therapeutic potential.

The review first outlines inflammation and the active resolution phase, detailing sensors (TLRs, RIG-I), cytokines, leukocyte trafficking, and the switch to pro-resolving mediators (SPMs, peptides such as AnxA1). It summarizes AnxA1 biology: expression in leukocytes (notably neutrophils), mobilization and secretion, knockout mouse phenotypes (exaggerated inflammation), and proteolytic cleavage into fragments (e.g., Ac2-26) that can variably promote pro-resolving or pro-inflammatory responses depending on context. Next, it details FPR2 as the principal GPCR for AnxA1, emphasizing its ligand promiscuity (pro-resolving: LxA4, RvD1/3; pro-inflammatory: SAA, LL-37, Aβ-42), structural features enabling diverse agonist binding, and downstream signaling (e.g., p38/MAPKAPK/HSP27, ERK, STAT3). The review compiles evidence across viruses: - Respiratory: In COVID-19, circulating AnxA1 levels correlate inconsistently with disease severity across cohorts; some studies show lower levels in severe cases, others show elevations associated with ICU admission and convalescence. In influenza A virus (IAV), AnxA1/FPR2 generally facilitates viral replication via ERK activation, endosomal export, and NS1 nuclear import; FPR2 antagonists (WRW4, BOC2) protect mice, while prophylactic recombinant AnxA1 expands alveolar macrophages and reduces titers without boosting type I IFN signaling, underscoring timing-dependent effects. - Non-respiratory: In arboviruses (CHIKV, DENV, ZIKV), AnxA1/FPR2 activation reduces inflammation and nociception without impairing viral control; low plasma AnxA1 correlates with severe dengue; Ac2-26 mitigates CHIKV-induced inflammation and edema. In HCV, AnxA1 negatively regulates RNA replication; chronic replication downregulates ANXA1. In HPV-associated cancers, AnxA1 is overexpressed in high-risk HPV-positive tumors and induced by E6/E6AP, supporting a role in carcinogenesis. In SIV, AnxA1 expression diverges between gut and blood over disease course, associated with immune dysregulation. In HSV-1, AnxA1 binds viral gE to enhance cell binding and infection; FPR2 antagonism or genetic absence reduces encephalitis lethality. HIV subtypes A/C can use FPR2 as a co-receptor independent of AnxA1. AnxA1 is also required for reovirus/measles syncytiogenesis via calcium-dependent pore expansion, and FMDV 3A disrupts AnxA1–TBK1 interaction to blunt IFN-β induction. Overall, prior studies reveal pathogen- and timing-specific roles of AnxA1/FPR2 in viral pathogenesis and resolution.

This is a narrative review article. The authors synthesize evidence from clinical studies (case-control, cohort analyses of patient blood and tissues), pre-clinical animal models (primarily mouse knockout and wild-type infection models), and in vitro systems (human and animal cell lines including A549, MDCK, hepatoma lines). They summarize mechanistic studies of AnxA1/FPR2 signaling, receptor structure–function, and viral life-cycle interactions, and compile findings into descriptive sections and a table categorizing respiratory and non-respiratory infections. No new experiments or meta-analytic statistical methods are reported.

• AnxA1/FPR2 is a key pro-resolving axis but exhibits dual roles in viral infections, either mitigating harmful inflammation or being hijacked to enhance replication. - COVID-19: Circulating AnxA1 levels show cohort-dependent patterns; some studies report lower levels in severe/critical cases, others report higher levels associated with ICU admission or convalescence. - IAV: AnxA1 facilitates replication via FPR2-dependent ERK signaling, enhanced endosomal export, and NS1 nuclear import; AnxA1-deficient mice show improved survival with lower lung titers but more lung inflammation. FPR2 antagonists (WRW4, BOC2) reduce replication and mortality in mice. Prophylactic recombinant AnxA1 expands alveolar macrophages via GM-CSF and reduces viral load without increasing type I IFN responses, indicating timing-dependent benefit. - CHIKV/DENV/ZIKV: Activation of AnxA1/FPR2 reduces inflammation, edema, pain, and thrombocytopenia/hemoconcentration (DENV model) without compromising viral control; low plasma or placental AnxA1 associates with worse disease (severe dengue; inflamed ZIKV placentas). - HCV: AnxA1 expression is downregulated with long-term replication; AnxA1 inhibits HCV RNA replication without affecting entry. - HPV: ANXA1 is overexpressed in high-risk HPV-positive tumors; HPV16 E6 via E6AP increases ANXA1, and ANXA1 silencing reduces HPV-transformed cell proliferation. - HSV-1: AnxA1 binds viral gE, enhancing cell binding and infection; blocking AnxA1/FPR2 reduces brain viral load and lethality in mice. - SIV/HIV: AnxA1 levels change with disease stage (SIV) and some HIV subtypes use FPR2 as a co-receptor; progression may be linked to alternative co-receptor usage. - Reovirus/Measles: AnxA1 is necessary for efficient pore expansion and syncytium formation in a Ca2+-dependent manner. - FMDV: Viral 3A protein binds ANXA1, preventing TBK1 interaction and dampening IFN-β induction, promoting replication. Therapeutic implications: FPR2 antagonists may benefit infections where AnxA1/FPR2 is pro-viral (e.g., IAV, HSV-1), whereas AnxA1 mimetics (Ac2-26) or FPR2 agonists may help hyperinflammatory diseases (e.g., CHIKV, DENV) or as prophylaxis to bolster alveolar macrophages (IAV).

The review addresses whether modulating the AnxA1/FPR2 axis can serve as a host-directed strategy to limit viral disease severity. Evidence indicates AnxA1 promotes resolution of inflammation by curbing neutrophil influx, inducing apoptosis and efferocytosis, and skewing macrophages, which can ameliorate immunopathology in arboviral infections without impairing viral control. Conversely, several well-adapted human viruses (IAV, HSV-1) exploit AnxA1/FPR2 to enhance replication and spread, suggesting that antagonizing FPR2 or limiting AnxA1–virus interactions may be protective. The net effect depends on the pathogen, host compartment, infection stage, and timing of intervention: prophylactic or early AnxA1 agonism can expand protective macrophage niches, whereas during active IAV/HSV-1 replication, FPR2 antagonism reduces viral egress and lethality. In COVID-19, conflicting AnxA1 levels across cohorts may reflect disease stage heterogeneity; elevations could represent a compensatory response and correlate with severity or convalescence, but therapeutic exploitation remains unproven. Collectively, tailoring AnxA1/FPR2 modulation to viral biology and disease phase is crucial for efficacy.

AnxA1/FPR2 is a central immunoregulatory pathway with context-dependent effects in viral infections. It can resolve detrimental inflammation (notably in arboviral diseases) yet be co-opted by certain viruses (IAV, HSV-1) to aid replication. Therapeutic strategies should be pathogen- and timing-specific: FPR2 antagonists for viruses that hijack the pathway, and AnxA1 mimetics or FPR2 agonists for hyperinflammatory diseases where resolution is beneficial. Further translational work is needed to define dosing, timing, and safety; validate biomarkers (e.g., plasma AnxA1) across disease stages; and test AnxA1-based agents or FPR2 modulators in controlled clinical trials.

As a narrative review, conclusions rely on heterogeneous studies across species, models, and clinical cohorts, limiting direct comparability. Human data are limited for several pathogens, and findings for COVID-19 AnxA1 levels are conflicting. Many mechanistic insights derive from in vitro systems or mouse models, which may not fully recapitulate human disease. Optimal timing, dosing, and safety of AnxA1 mimetics or FPR2 antagonists remain undefined, and randomized clinical trials are lacking.