Role of host cellular proteases in the pathogenesis of influenza and influenza-induced multiple organ failure

Abstract

Influenza A virus (IAV) is one of the most common infectious pathogens in humans. Since the IVA genome does not have the processing protease for the viral hemagglutinin (HA) envelope glycoprotein precursors, entry of this virus into cells and infectious organ tropism of IAV are primarily determined by host cellular trypsin-type HA processing proteases. Several secretion-type HA processing proteases for seasonal IAV in the airway, and ubiquitously expressed furin and pro-protein convertases for highly pathogenic avian influenza (HPAI) virus, have been reported. Recently, other HA-processing proteases for seasonal IAV and HPAI have been identified in the membrane fraction. These proteases proteolytically activate viral multiplication at the time of viral entry and budding. In addition to the role of host cellular proteases in IAV pathogenicity, IAV infection results in marked upregulation of cellular trypsins and matrix metalloproteinase-9 in various organs and cells, particularly endothelial cells, through induced pro-inflammatory cytokines. These host cellular factors interact with each other as the influenza virus-cytokine-protease cycle, which is the major mechanism that induces vascular hyperpermeability and multiorgan failure in severe influenza. This mini-review discusses the roles of cellular proteases in the pathogenesis of IAV and highlights the molecular mechanisms of upregulation of trypsins as effective targets for the control of IAV infection. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.

Human H7N9 and H5N1 Influenza Viruses Differ in Induction of Cytokines and Tissue Tropism

“…Furthermore, H5N1 was able to spread efficiently to nonrespiratory tissues, such as the brain and kidney, while H7N9 was only transiently detected in these tissues, if at all. Highly pathogenic H5N1 viruses possess a multibasic cleavage site and are able to utilize ubiquitous cellular proteases such as furin, which accounts for an efficient spread throughout the alveolar space leading to the systemic spread seen with H5N1 viruses (27). However, H7N9 viruses were able to spread efficiently throughout the alveoli at later points in infection.…”

Endocytosis in Notch Signaling Activation

“…The impact of cleavage on signaling activation is a matter of open discussion: while it was seen by some laboratories to be a prerequisite for delivery of receptors to the cell surface [84,85], other groups have shown that Notch receptors which are defective for S1 cleavage are normally exposed to the cell surface, but fail in ligand-mediated activation of canonical Notch signaling [86,87]; these latter data support the hypothesis that dissociation of NECD from NTMD (by endocytosis, see later) may be a prerequisite for S2 proteolysis. Notably, S1 cleavage-defective Notch receptors exhibit little change in their crystal and NMR structure in comparison with wild-type receptors [88]; this is in contrast to what happens with some viruses (including avian influenza virus, HIV-1, measles and papilloma virus [89][90][91][92]) in which furin cleavage induces major conformational changes leading to protein activation (reviewed in [93]). …”

Clinicopathological Findings of Four Cases of Pure Influenza Virus A Pneumonia

“…The inflammatory response also affected cell adhesion, vascular permeability, apoptosis, and mitochondrial reactive oxygen species, which could progress to vascular dysfunction and multi-organ failure. Studies have shown that influenza virus infection significantly upregulates the expression of cellular trypsins and matrix metalloproteinase-9 in various organs and vascular endothelial cells (30). We propose that in addition to direct damage to alveolar epithelial cells, cytokine storm-induced endothelial cell damage and successive vascular hyperpermeability play major roles in the pathogenesis of severe influenza virus-induced pneumonia.…”

“…Influenza virus infection caused marked increases in the levels of pro-inflammatory cytokines, tumor necrosis factor-α, interleukin (IL)-6, and IL-1β (cytokine storm) (30). The inflammatory response also affected cell adhesion, vascular permeability, apoptosis, and mitochondrial reactive oxygen species, which could progress to vascular dysfunction and multi-organ failure.…”