Kallistatin Ameliorates Influenza Virus Pathogenesis by Inhibition of Kallikrein-Related Peptidase 1-Mediated Cleavage of Viral Hemagglutinin

Leu, Chia Hsing; Yang, Mei; Chung, Nai Hui; Huang, Yen Jang; Su, Yu; Chen, Yi Cheng; Lin, Chia Cheng; Shieh, Gia Shing; Chang, Meng-Wei; Wang, Shainn Wei; Chang, Yao; Chao, Julie; Chao, Lee; Wu, Chao‐Liang; Shiau, Ai‐Li

doi:10.1128/aac.00065-15

Cited by 20 publications

(12 citation statements)

References 64 publications

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“…Human KLK1 did not activate uninfectious H1N1 A/Puerto Rico/8/34 or H3N2 A/Scotland/20/74 virions. This contrasts with a previous report that rat Klk1 enhances virus production in MDCK cells infected with influenza A/WSN/33 (H1N1) virus particles (25). This may be because of differences in the substrate specificities of rat Klk1 and human KLK1 (26).…”

Section: Discussioncontrasting

confidence: 54%

Kallikrein-Related Peptidase 5 Contributes to H3N2 Influenza Virus Infection in Human Lungs

Magnen

Gueugnon

Guillon

et al. 2017

J Virol

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Hemagglutinin (HA) of influenza virus must be activated by proteolysis before the virus can become infectious. Previous studies indicated that HA cleavage is driven by membrane-bound or extracellular serine proteases in the respiratory tract. However, there is still uncertainty as to which proteases are critical for activating HAs of seasonal influenza A viruses (IAVs) in humans. This study focuses on human KLK1 and KLK5, 2 of the 15 serine proteases known as the kallikrein-related peptidases (KLKs). We find that their mRNA expression in primary human bronchial cells is stimulated by IAV infection. Both enzymes cleaved recombinant HA from several strains of the H1 and/or H3 virus subtype in vitro, but only KLK5 promoted the infectivity of A/Puerto Rico/8/34 (H1N1) and A/Scotland/20/74 (H3N2) virions in MDCK cells. We assessed the ability of treated viruses to initiate influenza in mice. The nasal instillation of only the KLK5-treated virus resulted in weight loss and lethal outcomes. The secretion of this protease in the human lower respiratory tract is enhanced during influenza. Moreover, we show that pretreatment of airway secretions with a KLK5-selective inhibitor significantly reduced the activation of influenza A/Scotland/20/74 virions, providing further evidence of its importance. Differently, increased KLK1 secretion appeared to be associated with the recruitment of inflammatory cells in human airways regardless of the origin of inflammation. Thus, our findings point to the involvement of KLK5 in the proteolytic activation and spread of seasonal influenza viruses in humans.IMPORTANCE Influenza A viruses (IAVs) cause acute infection of the respiratory tract that affects millions of people during seasonal outbreaks every year. Cleavage of the hemagglutinin precursor by host proteases is a critical step in the life cycle of these viruses. Consequently, host proteases that activate HA can be considered promising targets for the development of new antivirals. However, the specific proteases that activate seasonal influenza viruses, especially H3N2 viruses, in the human respiratory tract have remain undefined despite many years of work. Here we demonstrate that the secreted, extracellular protease KLK5 (kallikrein-related peptidase 5) is efficient in promoting the infectivity of H3N2 IAV in vitro and in vivo. Furthermore, we found that its secretion was selectively enhanced in the human lower respiratory tract during a seasonal outbreak dominated by an H3N2 virus. Collectively, our data support the clinical relevance of this protease in human influenza pathogenesis.

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Section: Discussioncontrasting

confidence: 54%

Kallikrein-Related Peptidase 5 Contributes to H3N2 Influenza Virus Infection in Human Lungs

Magnen

Gueugnon

Guillon

et al. 2017

J Virol

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“…Finally, tissue kallikrein processes hemagglutinin and thus enhances infection by the influenza virus, whereas kallistatin gene transfer protects against influenza infection in mice by inhibiting tissue kallikrein-mediated hemagglutinin cleavage. 87 This suggests a novel role of kallistatin in suppressing tissue kallikrein's effect on viral infection. These combined findings indicate that kallistatin modulates different biological actions mediated by tissue kallikrein.…”

Section: Kallistatin Regulates Tissue Kallikrein-mediated Biological mentioning

confidence: 99%

Protective Role of Kallistatin in Vascular and Organ Injury

2016

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Kallistatin is an endogenous protein that exerts pleiotropic effects, including vasodilation and inhibition of angiogenesis, inflammation, oxidative stress, apoptosis, fibrosis, and tumor progression. Through its two functional domains – an active site and a heparin-binding site – kallistatin regulates differential signaling pathways and a wide spectrum of biological functions. Kallistatin's active site is key for inhibiting tissue kallikrein activity, and stimulating the expression of endothelial nitric oxide synthase (eNOS), sirtuin 1 (SIRT1) and suppressor of cytokine signaling 3 (SOCS3). Kallistatin via its heparin-binding site blocks signaling pathways mediated by growth factors and cytokines, such as vascular endothelial growth factor (VEGF), tumor necrosis factor-α (TNF-α), high mobility group box-1 (HMGB1), Wnt, transforming growth factor-β (TGF-β), and epidermal growth factor (EGF). Kallistatin gene or protein delivery protects against the pathogenesis of hypertension, heart and kidney damage, arthritis, sepsis, influenza virus infection, tumor growth and metastasis in animal models. Conversely, depletion of endogenous kallistatin by neutralizing antibody injection exacerbates cardiovascular and renal injury in hypertensive rats. Kallistatin levels are markedly reduced in rodents with hypertension, sepsis, streptozotocin-induced diabetes, and cardiac and renal injury. Kallistatin levels are also diminished in patients with liver disease, septic syndrome, diabetic retinopathy, severe pneumonia, inflammatory bowel disease, and obesity, prostate and colon cancer. Therefore, circulating kallistatin levels may serve as a new biomarker for human diseases. This review summarizes kallistatin's protective roles and mechanisms in vascular and organ injury, and highlights the therapeutic potential of kallistatin for multiple disease states.

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“…This group also includes surfactant D and other collectins that bind to oligosaccharides on the HA molecules, hindering receptor binding ( Hartshorn et al, 2008 ). The second group of HA inhibitors include molecules that inhibit host proteolytic enzymes (e.g., kallikrein-peptidases) necessary for cleavage-activation of the HA protein or molecules that inhibit V-ATPase dependent endosomal acidification necessary for the HA fusion-activation step ( Chen et al, 2013 ; Leu et al, 2015 ).…”

Section: Other Influenza Virus Inhibitorsmentioning

confidence: 99%

Peramivir: A Novel Intravenous Neuraminidase Inhibitor for Treatment of Acute Influenza Infections

2016

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Peramivir is a novel cyclopentane neuraminidase inhibitor of influenza virus. It was approved by the Food and Drug Administration in December 2014 for treatment of acute uncomplicated influenza in patients 18 years and older. For several months prior to approval, the drug was made clinically available under Emergency Use authorization during the 2009 H1N1 influenza pandemic. Peramivir is highly effective against human influenza A and B isolates as well as emerging influenza virus strains with pandemic potential. Clinical trials demonstrated that the drug is well-tolerated in adult and pediatric populations. Adverse events are generally mild to moderate and similar in frequency to patients receiving placebo. Common side effects include gastrointestinal disorders and decreased neutrophil counts but are self-limiting. Peramivir is administered as a single-dose via the intravenous route providing a valuable therapeutic alternative for critically ill patients or those unable to tolerate other administration routes. Successful clinical trials and post-marketing data in pediatric populations in Japan support the safety and efficacy of peramivir in this population where administration of other antivirals might not be feasible.

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Kallistatin Ameliorates Influenza Virus Pathogenesis by Inhibition of Kallikrein-Related Peptidase 1-Mediated Cleavage of Viral Hemagglutinin

Cited by 20 publications

References 64 publications

Kallikrein-Related Peptidase 5 Contributes to H3N2 Influenza Virus Infection in Human Lungs

Kallikrein-Related Peptidase 5 Contributes to H3N2 Influenza Virus Infection in Human Lungs

Protective Role of Kallistatin in Vascular and Organ Injury

Peramivir: A Novel Intravenous Neuraminidase Inhibitor for Treatment of Acute Influenza Infections

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