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Front Immunol ; 12: 664209, 2021.
Article in English | MEDLINE | ID: covidwho-1247863


Rationale: Systemic activation of procoagulant and inflammatory mechanisms has been implicated in the pathogenesis of COVID-19. Knowledge of activation of these host response pathways in the lung compartment of COVID-19 patients is limited. Objectives: To evaluate local and systemic activation of coagulation and interconnected inflammatory responses in critically ill COVID-19 patients with persistent acute respiratory distress syndrome. Methods: Paired bronchoalveolar lavage fluid and plasma samples were obtained from 17 patients with COVID-19 related persistent acute respiratory distress syndrome (mechanical ventilation > 7 days) 1 and 2 weeks after start mechanical ventilation and compared with 8 healthy controls. Thirty-four host response biomarkers stratified into five functional domains (coagulation, complement system, cytokines, chemokines and growth factors) were measured. Measurements and Main Results: In all patients, all functional domains were activated, especially in the bronchoalveolar compartment, with significantly increased levels of D-dimers, thrombin-antithrombin complexes, soluble tissue factor, C1-inhibitor antigen and activity levels, tissue type plasminogen activator, plasminogen activator inhibitor type I, soluble CD40 ligand and soluble P-selectin (coagulation), next to activation of C3bc and C4bc (complement) and multiple interrelated cytokines, chemokines and growth factors. In 10 patients in whom follow-up samples were obtained between 3 and 4 weeks after start mechanical ventilation many bronchoalveolar and plasma host response biomarkers had declined. Conclusions: Critically ill, ventilated patients with COVID-19 show strong responses relating to coagulation, the complement system, cytokines, chemokines and growth factors in the bronchoalveolar compartment. These results suggest a local pulmonary rather than a systemic procoagulant and inflammatory "storm" in severe COVID-19.

COVID-19/immunology , Critical Illness , Lung/metabolism , Respiratory Distress Syndrome/immunology , SARS-CoV-2/physiology , Thromboplastin/metabolism , Aged , Blood Coagulation , Cohort Studies , Female , Fibrin Fibrinogen Degradation Products/metabolism , Follow-Up Studies , Humans , Immunity, Innate , Lung/pathology , Male , Middle Aged , Respiration, Artificial
mBio ; 12(2)2021 03 23.
Article in English | MEDLINE | ID: covidwho-1148106


Complement, contact activation, coagulation, and fibrinolysis are serum protein cascades that need strict regulation to maintain human health. Serum glycoprotein, a C1 inhibitor (C1-INH), is a key regulator (inhibitor) of serine proteases of all the above-mentioned pathways. Recently, an autotransporter protein, virulence-associated gene 8 (Vag8), produced by the whooping cough pathogen, Bordetella pertussis, was shown to bind to C1-INH and interfere with its function. Here, we present the structure of the Vag8-C1-INH complex determined using cryo-electron microscopy at a 3.6-Å resolution. The structure shows a unique mechanism of C1-INH inhibition not employed by other pathogens, where Vag8 sequesters the reactive center loop of C1-INH, preventing its interaction with the target proteases.IMPORTANCE The structure of a 10-kDa protein complex is one of the smallest to be determined using cryo-electron microscopy at high resolution. The structure reveals that C1-INH is sequestered in an inactivated state by burial of the reactive center loop in Vag8. By so doing, the bacterium is able to simultaneously perturb the many pathways regulated by C1-INH. Virulence mechanisms such as the one described here assume more importance given the emerging evidence about dysregulation of contact activation, coagulation, and fibrinolysis leading to COVID-19 pneumonia.

Bacterial Proteins/metabolism , Bordetella pertussis/pathogenicity , Complement C1 Inhibitor Protein/metabolism , Immune Evasion , Bacterial Proteins/chemistry , Bacterial Proteins/genetics , Binding Sites , Blood Coagulation , Bordetella pertussis/chemistry , Bordetella pertussis/metabolism , Complement C1 Inhibitor Protein/chemistry , Complement System Proteins/metabolism , Cryoelectron Microscopy , Fibrinolysis , Models, Molecular , Mutation , Protein Binding , Protein Domains , Type V Secretion Systems/genetics , Type V Secretion Systems/metabolism , Virulence , Virulence Factors, Bordetella