ABSTRACT
Background : Markers of both inflammation and coagulation are linked to clinical outcome in coronavirus disease 2019 (COVID-19). Binding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to the angiotensin-converting enzyme 2 receptor, which is involved in kinin breakdown, interferes with the kallikreinkinin pathway. This could result in increased vascular permeability, fluid excess in the lungs and pulmonary edema. Furthermore, the kallikrein-kinin pathway links coagulation and inflammation through its interactions with the contact activation pathway of coagulation via factor XII and with neutrophil extracellular traps (NETs). These insights could help to explain the clinical presentation of COVID-19 pneumonia with pulmonary coagulopathy and the high incidence of thromboembolic complications in COVID-19. Aims : Given the lack of clinical evidence to support this hypothesis, we studied the kallikrein-kinin system in bronchoalveolar lavage (BAL) fluid. Methods : In BAL fluid samples from patients with or without COVID-19, we performed in-depth analyses of kinin peptides (bradykinin, Lys-bradykinin, Lys-bradykinin-(1-8), bradykinin-(1-8), bradykinin-(1-7), and bradykinin-(1-5)) using a liquid chromatography with tandem mass spectrometry assay, along with measurements of plasma and tissue kallikrein hydrolytic activity and myeloperoxidase (MPO)-DNA complexes as a biomarker for NETs. Informed consent and ethical approval were obtained. Results : We observed higher levels of the most downstream kinin peptide bradykinin-(1-5) (Figure 1), higher tissue kallikrein activity (Figure 2), and higher levels of MPO-DNA complexes (699.0 ng/mL [66.0-142621.0], median [range], n = 21 vs 70.5 [9.9-960.0], n = 19;P < 0.001) in BAL fluid from patients with COVID-19 compared to those in BAL fluid from patients without COVID-19. Conclusions : Our data support the hypothesis that SARS-CoV-2 induces dysregulation of the kallikrein-kinin system, which contributes to thromboinflammation in COVID-19. These findings encourage the investigation of drugs that target the kallikrein-kinin system as a potential treatment option for patients with COVID-19.
ABSTRACT
Connecting basic data about bats and other potential hosts of SARS-CoV-2 with their ecological context is crucial to the understanding of the emergence and spread of the virus. However, when lockdowns in many countries started in March, 2020, the world's bat experts were locked out of their research laboratories, which in turn impeded access to large volumes of offline ecological and taxonomic data. Pandemic lockdowns have brought to attention the longstanding problem of so-called biological dark data: data that are published, but disconnected from digital knowledge resources and thus unavailable for high-throughput analysis. Knowledge of host-to-virus ecological interactions will be biased until this challenge is addressed. In this Viewpoint, we outline two viable solutions: first, in the short term, to interconnect published data about host organisms, viruses, and other pathogens;and second, to shift the publishing framework beyond unstructured text (the so-called PDF prison) to labelled networks of digital knowledge. As the indexing system for biodiversity data, biological taxonomy is foundational to both solutions. Building digitally connected knowledge graphs of host-pathogen interactions will establish the agility needed to quickly identify reservoir hosts of novel zoonoses, allow for more robust predictions of emergence, and thereby strengthen human and planetary health systems.