Potential Pathways and Pathophysiological Implications of Viral Infection-Driven Activation of Kallikrein-Kinin System (KKS)

Abstract

Microcirculatory and coagulation disturbances commonly occur as pathological manifestations of systemic viral infections. Research exploring the role of the kallikrein-kinin system (KKS) in flavivirus infections has recently linked microvascular dysfunctions to bradykinin (BK)-induced signaling of B2R, a G protein-coupled receptor (GPCR) constitutively expressed by endothelial cells. The relevance of KKS activation as an innate response to viral infections has gained increasing attention, particularly after the reports regarding thrombogenic events during COVID-19. BK receptor (B2R and B1R) signal transduction results in vascular permeability, edema formation, angiogenesis, and pain. Recent findings unveiling the role of KKS in viral pathogenesis include evidence of increased activation of KKS with elevated levels of BK and its metabolites in both intravascular and tissue milieu, as well as reports demonstrating that virus replication stimulates BKR expression. In this review, we will discuss the mechanisms triggered by virus replication and by virus-induced inflammatory responses that may stimulate KKS. We also explore how KKS activation and BK signaling may impact virus pathogenesis and further discuss the potential therapeutic application of BKR antagonists in the treatment of hemorrhagic and respiratory diseases.

Keywords: SARS-CoV-2; bradykinin; dengue; factor XII; hantavirus; kininogen.

Figure 1

Endothelial cell death and tissue lesion expose potential FXII activators. Inflammatory mediators released by infected circulating cells and by infection of endothelial cells may induce cell death by necroptosis or pyroptosis (1), promoting the release of negatively charged intracellular nucleic acids, which are potential FXII activators (2). Endothelial injury allows the exposure of subendothelial matrix proteins (3), which are also FXII activators. The activation of FXII by these events leads to release of FXIIa (4) and initiation of KKS proteolytic cascade, culminating in the release of BK. In addition, endothelial cell infection may induce apoptosis (5), leading to the exposure of membrane phosphatidylserine, which binds to kininogen, creating a platform that facilitates its cleavage by PKa and fuels BK formation. Increased BK via any of these mechanisms leads to plasma leakage and release of KKS components into the tissues (6). In addition, BKR may be upregulated in infected endothelial cells, amplifying these events (7). Created with BioRender.com (https://help.biorender.com/en/articles/3619405-how-do-i-cite-biorender, accessed on 8 December 2023).

Figure 2

Interplay between innate immune cell stimulation and KKS activation. Virus interaction with platelets (1) and mast cells (2) may trigger cellular activation, leading to increased expression and release of polyphosphates (polyP) (3), which are deposited on endothelial cell surfaces, resulting in the activation and autocleavage of factor XII and release of FXIIa (4). Neutrophil infection and virus sensing (5) also induce the release of granules and NETs (6a, 6b (amplification of the circle)), which contain proteases and negatively charged molecules, such as DNA, RNA, and histones. All these elements are also potential activators of FXII (4). FXIIa activates prekallikrein (PK), generating plasma kallikrein (PKa), which then cleaves its cofactor, kininogen (HK), resulting in the release of bradykinin (BK) (7). BK or des-Arg-BK act through their G-coupled receptors, B1R and B2R, contributing to increased vascular permeability, with cellular and plasma infiltration into tissues (8). Also, infection of endothelial cells may upregulate BKR and contribute to these effects (9). Created with BioRender.com.

Figure 3

Proposed mechanisms of KKS activation by SARS-CoV-2 leading to increased vascular permeability and thrombogenesis. The upper left panel represents the microcirculation surrounding the alveoli and summarizes the potential mechanisms associated with intravascular activation of KKS, promoting thrombus formation and increased vascular permeability. These mechanisms are detailed in panels 1–3. (Panel 1.) Interaction of SARS-CoV-2 with neutrophils and mast cells may induce the release of proteases and polyP; these activate FXII, triggering intrinsic coagulation pathway and KKS.BK and des-Arg-BK signal through B2R and B1R GPCR, respectively (arrows) (Panel 2.) ACE2 normally cleaves des-Arg-BK (arrows), controlling its function (left). However, in the context of SARS-CoV-2 infection (right), virus binding to the receptor induces its internalization and reduces its surface expression. ACE2 downregulation leads to increased availability of des-Arg-BK, which signals through B1R, promoting vascular permeability. (Panel 3.) Activation of FXII/contact pathway induces thrombus formation and vascular obstruction, contributing to local and systemic vascular syndromes. Also, FXII/HK activation ultimately leads to BK/des-Arg-BK generation, promoting vascular permeability through B2R/B1R signaling (arrows). This figure was created with BioRender.com.