ABSTRACT
The implementation of preparedness strategies to prevent and mitigate the impact of global health threats poses several challenges. It should promptly identify cross-cutting drivers of pandemic threats, assess context-specific risks, engage multiple stakeholders, and translate complex data from multiple sources into accessible information for action. This requires a coordinated, multidisciplinary and multisectoral effort engaging systems that, most of the time, work in isolation. The One Health (OH) approach promotes the collaboration and communication among different disciplines and sectors, and could be applied across the preparedness phases at national and international level. We discuss here gaps and needs in preparedness strategies, which can benefit from the OH approach, and a set of actionable recommendations, as shared with the G20-2021 with a dedicated Policy Brief. The discussion adds to the current debate about OH operationalization and promotes a paradigm shift towards coordinated prevention and preparedness strategies for early assessment and management of global health threats.
ABSTRACT
Background: Humoral innate immunity consists of a limited, but diverse, set of humoral fluid phase pattern recognition molecules (PRMs) that represent a first line of resistance against microbial invaders by promoting pathogen disposal by phagocytosis, complement activation and inflammation. These factors encompass complement, ficolin, collectin and pentraxin family of proteins. Methods: We have analyzed the activity of PRMs for their potential capacity of inhibiting SARS-CoV-2 entry and replication into epithelial cells by a microneutralization assay based on a lentiviral particles pseudotyped with the SARS-CoV-2 spike protein in HEK293T cells overexpressing the angiotensin converting enzyme 2 (ACE2). Either SARS-CoV-2 or target cells were incubated with Mannose Binding Lectin (MBL, concentration range: 1-50 μ g/ml) to further characterize its anti-viral activity for 1 h prior to infection in both human Calu-3 cells and air-liquid interface cultures of human bronchial epithelial cells (HBEC). Binding experiments were carried out with SARS-CoV-2 Spike protein and recombinant MBL to further investigate its antiviral action. Results: Among 12 PRMs tested, only MBL inhibited viral entry in the pseudotyped neutralization assay. Furthermore, MBL protein inhibited SARS-CoV-2 viral replication in Calu-3 and HBEC by ca. one log10 at the top concentration (10 μ g/ml and 50 μ g/ml, respectively). MBL antiviral activity was confirmed also against alpha, beta and gamma SARS-CoV-2 variants of concern. Binding experiments showed that MBL specifically interacts with the trimeric form of SARS-CoV-2 spike. Conclusion: MBL binds to the Spike protein in its active trimeric conformation leading to the inhibition of SARS-CoV-2 infection and replication in vitro. These results suggest that MBL possesses an antiviral activity against SARS-CoV-2 that could bear therapeutic potential.
ABSTRACT
Introduction and aims. Patients with coronavirus disease-2019 (COVID-19) and metabolic-dysfunction associated fatty liver disease (MAFLD) appear to be at higher risk for severe manifestations like acute respiratory distress syndrome, especially in the youngest decades. Our aim was to examine whether patients with imaging-defined MAFLD and/or with increased non-invasive liver fibrosis scores (FIB-4) are at higher risk for severe illness from COVID-19, using a machine learning model. Methods. In this retrospective cohort study, we included 672 patients admitted for SARS-CoV-2 pneumonia between February the 28th 2020 and May the 1st 2021. Hepatic steatosis was detected by ultrasound or computed tomography (CT), whereas FIB-4 score was used to define the risk of advanced liver fibrosis. We used a machine learning (ML) model to evaluate the risks of both in-hospital death and prolonged hospitalizations (>28 days), considering MAFLD, a set of blood tests (hepatic profile;HP), and the FIB-4 score, either separately and together. Results. Three hundred-thirty-three (49.6% of total) had imaging-defined MAFLD. The accuracy in predicting in-hospital death in the whole sample was 0.709 for the HP alone, and 0.721 for HP+FIB-4 combined together;in the 55-to-75 age subgroup, the accuracies were respectively 0.842 and 0.855 for HP alone and HP+FIB-4 together. In the MAFLD subgroup, the accuracy in predicting death was 0.739 considering HP alone, and 0.772 when considering HP+FIB-4 together;whereas in the MAFLD 55-to-75 years cohort, the accuracies were respectively 0.825 for HP and 0.833 for HP+FIB-4. Similar results were obtained both in the entire cohort and in MAFLD patients when considering the accuracy in predicting prolonged hospitalization (>28 days). Conclusions. In our cohort of COVID-19 patients, the presence of a worse HP and a higher FIB-4 correlated with a higher risk of death and prolonged hospitalization, regardless of the presence of MAFLD. These findings could improve the clinical risk stratification of patients diagnosed with SARS-CoV-2 pneumonia.
ABSTRACT
Inflammation is a manifestation of innate immunity and has emerged as a metanarrative of modern medicine (Mantovani et al., Immunity, 2019;Furman et al., Nature Medicine, 2019), a component of diverse disease ranging from cancer to COVID-19 (Mantovani et al., Nature 2008;Mantovani e Netea, New England Journal of Medicine, 2020 in press). Dissection of the diversity and complexity of regulatory pathways of innate immunity has taken advantage of hypothesis driven and nonhypothesis driven approaches. IL-1 is the prototypic member of a complex family of cytokines and receptors which play a central role in innate immunity and in the activation and regulation of adaptive immune responses (Mantovani et al. Immunity, 2019). Based on structure, we originally hypothesized that IL-1R2 should behave as a decoy receptor, a tenet confirmed by extensive experimental data. In the same line, we cloned IL-1R8 and focused on it based on the hypothesis that it would behave as a negative regulator. IL1R8 was then found to be a negative regulator of signaling downstream of members of the IL-1 and Toll like receptor (TLR) family and a component of the receptor complex recognized by the anti-inflammatory immunosuppression cytokine IL-37. As a result of a fishing expedition we originally cloned PTX3 as a gene induced by IL-1 (Garlanda et al., Physiol Rev, 2020). This distant relative of C reactive protein (CRP) was then found to represent an essential component of the humoral of innate immunity playing a role in antimicrobial resistance and in the regulation of inflammation. The latter includes selected solid tumors and hematological malignancies (Garlanda et al., Physiol Rev, 2020). We also cloned in silico PTX4, but its function remains to be defined. Interestingly, PTX3 was recently found to be highly expressed in monocytes and lung macrophages at population and single cell level in COVID-19 and to represent a candidate novel biomarker of disease severity (Brunetta et al., medRxiv, 2020). Stemming from our interest in macrophage diversity and polarization (Locati, Curtale, Mantovani, Ann Rev Pathol 2020;Mantovani et al., Nature Rev. Clin. Onc. 2017;Jaillon et al., Nature Rev Cancer 2020). We identified the tetraspan MS4A4A, a gene of unknown function, as a gene associated with M2-like macrophage polarization (Mattiola et al., Nat Immunol. 2019). We found that MS4A4A partner with Dectin-1 and is essential for full syk signalling downstream of this pattern recognition receptors. The examples discussed above, selected from our previous and ongoing research efforts, highlight the complexity of innate immunity and its regulation. The dissection of the daunting complexity and diversity of cellular and human innate immunity requires the use of unbiased non-hypothesisdriven approaches complemented by hypothesis-driven, biased experimental and clinical testing.