Respiratory syncytial virus infection exacerbates pneumococcal pneumonia via Gas6/Axl-mediated macrophage polarization

Shibata, Takehiko; Makino, Airi; Ogata, Ruiko; Nakamura, Shigeki; Ito, Toshihiro; Nagata, Kisaburo; Terauchi, Yoshihiko; Oishi, Taku; Fujieda, Mikiya; Takahashi, Yoshimasa; Ato, Manabu

doi:10.1172/jci125505

Cited by 48 publications

(39 citation statements)

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“…In other viral respiratory infections, GAS6 induction appears early after infection in animal models and its plasma concentration is maintained above the pre-infection concentration for weeks [ 17 ]. In this setting, as well as in many other models of inflammation/infection studied, GAS6/AXL represents a mechanism of control of the immune response in order to protect against organ damage resulting from the cytokine storm induced by intense inflammatory conditions.…”

Section: Resultsmentioning

confidence: 99%

Growth Arrest-Specific Factor 6 (GAS6) Is Increased in COVID-19 Patients and Predicts Clinical Outcome

et al. 2021

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Background: Growth arrest-specific factor 6 (GAS6) and the Tyro3, AXL, and MERTK (TAM) receptors counterbalance pro-inflammatory responses. AXL is a candidate receptor for SARS-CoV-2, particularly in the respiratory system, and the GAS6/AXL axis is targeted in current clinical trials against COVID-19. However, GAS6 and TAMs have not been evaluated in COVID-19 patients at emergency admission. Methods: Plasma GAS6, AXL, and MERTK were analyzed in 132 patients consecutively admitted to the emergency ward during the first peak of COVID-19. Results: GAS6 levels were higher in the SARS-CoV-2-positive patients, increasing progressively with the severity of the disease. Patients with initial GAS6 at the highest quartile had the worst outcome, with a 3-month survival of 65%, compared to a 90% survival for the rest. Soluble AXL exhibited higher plasma concentration in deceased patients, without significant differences in MERTK among SARS-CoV-2-positive groups. GAS6 mRNA was mainly expressed in alveolar cells and AXL in airway macrophages. Remarkably, THP-1 human macrophage differentiation neatly induces AXL, and its inhibition (bemcentinib) reduced cytokine production in human macrophages after LPS challenge. Conclusions: Plasma GAS6 and AXL levels reflect COVID-19 severity and could be early markers of disease prognosis, supporting a relevant role of the GAS6/AXL system in the immune response in COVID-19.

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Section: Resultsmentioning

confidence: 99%

Growth Arrest-Specific Factor 6 (GAS6) Is Increased in COVID-19 Patients and Predicts Clinical Outcome

et al. 2021

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“…Bacterial coinfections are another aspect to take into account, which have a profound effect on COVID-19 associated mortality [ 112 ]. A recent publication using a RSV mouse model demonstrated that AXL was crucial for attenuating the immune response to pneumococci, while GAS6/AXL blockade restored antibacterial protection [ 113 ]. From these data, the GAS6/AXL axis appears as a mechanism evolved to provide efficient clearance of respiratory viral infections, while adapting the subsequent immune response in order to avoid excessive organ damage and dysfunction ( Figure 3 ).…”

Section: Viral Infectionmentioning

confidence: 99%

Role of Vitamin K-Dependent Factors Protein S and GAS6 and TAM Receptors in SARS-CoV-2 Infection and COVID-19-Associated Immunothrombosis

Tutusaus

Marı́

Ortiz-Pérez

et al. 2020

Cells

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The vitamin K-dependent factors protein S (PROS1) and growth-arrest-specific gene 6 (GAS6) and their tyrosine kinase receptors TYRO3, AXL, and MERTK, the TAM subfamily of receptor tyrosine kinases (RTK), are key regulators of inflammation and vascular response to damage. TAM signaling, which has largely studied in the immune system and in cancer, has been involved in coagulation-related pathologies. Because of these established biological functions, the GAS6-PROS1/TAM system is postulated to play an important role in SARS-CoV-2 infection and progression complications. The participation of the TAM system in vascular function and pathology has been previously reported. However, in the context of COVID-19, the role of TAMs could provide new clues in virus-host interplay with important consequences in the way that we understand this pathology. From the viral mimicry used by SARS-CoV-2 to infect cells, to the immunothrombosis that is associated with respiratory failure in COVID-19 patients, TAM signaling seems to be involved at different stages of the disease. TAM targeting is becoming an interesting biomedical strategy, which is useful for COVID-19 treatment now, but also for other viral and inflammatory diseases in the future.

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“…Various ligand-receptor interactions of MCs with other cells illustrated multiple functions. For instance, common interactions of MCs and non-parenchymal cells like monocytes, ECs, fibroblasts were consistent with potential functions of MCs, including immunoregulation and neuroregulation (Matsuda et al, 2009;Pantouris et al, 2018), cell migration and inflammatory processes (Wu et al, 2014;MacDonald et al, 2001;Shibata et al, 2020;Chou et al, 2013), vascular stability, and angiogenesis (Saban et al, 2008;Fantin et al, 2014). Tissue-specific interactions of MCs and parenchymal cells also reminded us of tissue-dependent potentials, like VSMC hyperplasia (Boucher et al, 2013), epithelial homeostasis in the alveolar (Jung et al, 2019).…”

Section: Discussionmentioning

confidence: 68%

Single-cell transcriptomics of murine mural cells reveals cellular heterogeneity

Guan

Roosan

et al. 2020

Sci. China Life Sci.

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Respiratory syncytial virus infection exacerbates pneumococcal pneumonia via Gas6/Axl-mediated macrophage polarization

Cited by 48 publications

References 50 publications

Growth Arrest-Specific Factor 6 (GAS6) Is Increased in COVID-19 Patients and Predicts Clinical Outcome

Growth Arrest-Specific Factor 6 (GAS6) Is Increased in COVID-19 Patients and Predicts Clinical Outcome

Role of Vitamin K-Dependent Factors Protein S and GAS6 and TAM Receptors in SARS-CoV-2 Infection and COVID-19-Associated Immunothrombosis

Single-cell transcriptomics of murine mural cells reveals cellular heterogeneity

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