The Multifaceted Role of Annexin A1 in Viral Infections.

Dysregulated inflammatory responses are often correlated with disease severity during viral infections. Annexin A1 (AnxA1) is an endogenous pro-resolving protein that timely regulates inflammation by activating signaling pathways that culminate with the termination of response, clearance of pathogen and restoration of tissue homeostasis. Harnessing the pro-resolution actions of AnxA1 holds promise as a therapeutic strategy to control the severity of the clinical presentation of viral infections. In contrast, AnxA1 signaling might also be hijacked by viruses to promote pathogen survival and replication. Therefore, the role of AnxA1 during viral infections is complex and dynamic. In this review, we provide an in-depth view of the role of AnxA1 during viral infections, from pre-clinical to clinical studies. In addition, this review discusses the therapeutic potential for AnxA1 and AnxA1 mimetics in treating viral infections.

Annexin A1 as a potential prognostic biomarker for COVID-19 disease: Case-control study.

BACKGROUND: Annexin A1 (AnxA1) is an important endogenous glucocoticoid protein that contributes to the suppression of inflammation by limiting the production of neutrophil and pro-inflammatory cytokines. This study aims to determine the clinical predictivity value of blood AnxA1 levels in patients with mild and severe-critical pneumonia induced by COVID-19. METHODS: This study employed a prospective, case-control study design and was conducted at Ankara Training and Research hospital between 10 February 2021 and 15 March 2021. A total of 74 patients (42 of whom had moderate and 32 of whom had severe/critical cases of COVID-19 disease according to World Health Organization guidelines) and 50 nonsymptomatic healthy volunteers participated in the study. Blood samples were taken from patients at the time of hospital admission, after which serum was isolated. Following the isolation of serum, AnxA1 levels were evaluated using the enzyme-linked immunosorbent assay method. RESULTS: The serum AnxA1 levels were measured as 25.5 (18.6-38.6) ng/ml in the control group, 21.2 (14.7-32) ng/ml in the moderate disease group, and 14.8 (9.7-26.8) ng/ml in the severe/critical disease group. Serum AnxA1 levels were significantly lower in the severe/critical disease group compared with the control and moderate disease groups (P = .01 and P = .0001, respectively). Using receiver operating characteristic analysis, a larger area under the curve (AUC) for the serum AnxA1 levels of the control group (AUC = 0.715, 95% CI = 0.626-0.803; P = .0001) was calculated compared with the COVID-19 patient group for the diagnosis of COVID-19 disease. The AnxA1 level was found to be 80% sensitive and 54.1% specific at a cut-off level of 18.5 ng/ml for the diagnosis of COVID-19 disease. Moreover, the AnxA1 level was found to be 69.8% sensitive and 58.1% specific at a cut-off level of 17.2 ng/ml in predicting the need for intensive care unit (ICU) treatment. CONCLUSION: AnxA1 levels may be a beneficial biomarker in the diagnosis of COVID-19 pneumonia and in predicting the need for ICU treatment in patients with COVID-19 pneumonia at the time of admission to the emergency department.

Ac2-26 mimetic peptide of annexin A1 to treat severe COVID-19: A hypothesis.

The Coronavirus Diseases-2019 (COVID-19) pandemic leads many researchers around the world to study the SARS-CoV-s2 infection and pathology to find a treatment for it. This generates a massive production of papers including pre-clinical, clinical and revisions but till now no specific treatment were identified. Meanwhile, like other coronavirus infections, COVID-19 leads to the cytokine storm syndrome resulting in hyperinflammation, exacerbated immune response and multiple organ dysfunctions indicating that drugs that modulate this response, as glucocorticoids could be a treatment option. However glucocorticoids have several side effects or usage limitations. In this sense a drug with anti-inflammatory effects and capable to reduce inflammation but with less after-effects could be a powerful tool to combat COVID-19. Thus the Ac2-26 Mimetic Peptide of Annexin A1 emerges as a possible therapy. The peptide has many anti-inflammatory effects described including the reduction of interleukin (IL)-6, one of the main mediators of cytokine storm syndrome. Therefore the hypothesis to use the Ac2-26 peptide to treat severe COVID-19 will be highlighted in this paper.

Rationale for the Use of Radiation-Activated Mesenchymal Stromal/Stem Cells in Acute Respiratory Distress Syndrome.

We have previously shown that the combination of radiotherapy with human umbilical-cord-derived mesenchymal stromal/stem cells (MSCs) cell therapy significantly reduces the size of the xenotumors in mice, both in the directly irradiated tumor and in the distant nonirradiated tumor or its metastasis. We have also shown that exosomes secreted from MSCs preirradiated with 2 Gy are quantitatively, functionally and qualitatively different from the exosomes secreted from nonirradiated mesenchymal cells, and also that proteins, exosomes and microvesicles secreted by MSCs suffer a significant change when the cells are activated or nonactivated, with the amount of protein present in the exosomes of the preirradiated cells being 1.5 times greater compared to those from nonirradiated cells. This finding correlates with a dramatic increase in the antitumor activity of the radiotherapy when is combined with MSCs or with preirradiated mesenchymal stromal/stem cells (MSCs*). After the proteomic analysis of the load of the exosomes released from both irradiated and nonirradiated cells, we conclude that annexin A1 is the most important and significant difference between the exosomes released by the cells in either status. Knowing the role of annexin A1 in the control of hypoxia and inflammation that is characteristic of acute respiratory-distress syndrome (ARDS), we designed a hypothetical therapeutic strategy, based on the transplantation of mesenchymal stromal/stem cells stimulated with radiation, to alleviate the symptoms of patients who, due to pneumonia caused by SARS-CoV-2, require to be admitted to an intensive care unit for patients with life-threatening conditions. With this hypothesis, we seek to improve the patients' respiratory capacity and increase the expectations of their cure.

Harnessing inflammation resolving-based therapeutic agents to treat pulmonary viral infections: What can the future offer to COVID-19?

Inflammation is generally accepted as a component of the host defence system and a protective response in the context of infectious diseases. However, altered inflammatory responses can contribute to disease in infected individuals. Many endogenous mediators that drive the resolution of inflammation are now known. Overall, mediators of resolution tend to decrease inflammatory responses and provide normal or greater ability of the host to deal with infection. In the lung, it seems that pro-resolution molecules, or strategies that promote their increase, tend to suppress inflammation and lung injury and facilitate control of bacterial or viral burden. Here, we argue that the demonstrated anti-inflammatory, pro-resolving, anti-thrombogenic and anti-microbial effects of such endogenous mediators of resolution may be useful in the treatment of the late stages of the disease in patients with COVID-19.