Trypsin promotes efficient influenza vaccine production in MDCK cells by interfering with the antiviral host response

Seitz, C.; Isken, Britta; Heynisch, B.; Rettkowski, Maria; Frensing, Timo; Reichl, Udo

doi:10.1007/s00253-011-3569-8

Cited by 33 publications

(26 citation statements)

References 57 publications

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“…Aprotinin reduced trypsin-mediated signaling and viral replication in a model of influenza A myocarditis [67,68]. Trypsin stimulation of cells inhibited IFN responses after influenza A infection [69], which may be via PAR-2 activation. In addition, trypsin may increase the infectivity of influenza A via the cleavage of the hemagglutinin protein [70].…”

Section: Serine Proteases In Viral Myocarditismentioning

confidence: 99%

Coagulation, Protease-Activated Receptors, and Viral Myocarditis

Antoniak

Mackman

2013

J. of Cardiovasc. Trans. Res.

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The coagulation protease cascade plays an essential role in hemostasis. In addition, a clot contributes to host defense by limiting the spread of pathogens. Coagulation proteases induce intracellular signaling by cleavage of cell surface receptors called protease-activated receptors (PARs). These receptors allow cells to sense changes in the extracellular environment, such as infection. Viruses activate the coagulation cascade by inducing tissue factor expression and by disrupting the endothelium. Virus infection of the heart can cause myocarditis, cardiac remodeling and heart failure. Recent studies using a mouse model have shown that tissue factor, thrombin and PAR-1 signaling all positively regulate the innate immune during viral myocarditis. In contrast, PAR-2 signaling was found to inhibit interferon-β expression and the innate immune response. These observations suggest that anticoagulants may impair the innate immune response to viral infection and that inhibition of PAR-2 may be a new target to reduce viral myocarditis..

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Section: Serine Proteases In Viral Myocarditismentioning

confidence: 99%

Coagulation, Protease-Activated Receptors, and Viral Myocarditis

Antoniak

Mackman

2013

J. of Cardiovasc. Trans. Res.

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“…For instance, IAV propagated in eggs may exhibit a higher virulence due to hemagglutinin cleavage by ectopic expressed FX-like proteases, which are not expressed by MadinDarby canine kidney cells. 75,76 Role of PAR1 in influenza infection in mice…”

Section: Role Of Par2 In Iav Infection In Micementioning

confidence: 99%

Multiple roles of the coagulation protease cascade during virus infection

Antoniak

Mackman

2014

Blood

194

205

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The coagulation cascade is activated during viral infections. This response may be part of the host defense system to limit spread of the pathogen. However, excessive activation of the coagulation cascade can be deleterious. In fact, inhibition of the tissue factor/factor VIIa complex reduced mortality in a monkey model of Ebola hemorrhagic fever. Other studies showed that incorporation of tissue factor into the envelope of herpes simplex virus increases infection of endothelial cells and mice. Furthermore, binding of factor X to adenovirus serotype 5 enhances infection of hepatocytes but also increases the activation of the innate immune response to the virus. Coagulation proteases activate protease-activated receptors (PARs). Interestingly, we and others found that PAR1 and PAR2 modulate the immune response to viral infection. For instance, PAR1 positively regulates TLR3-dependent expression of the antiviral protein interferon β, whereas PAR2 negatively regulates expression during coxsackievirus group B infection. These studies indicate that the coagulation cascade plays multiple roles during viral infections.

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“…These results thus indicate that IFN induction may not be the only cause of limited delNS1 virus replication in MDCK cells. Several recent studies already suggest that IFN has a minor effect on influenza virus replication in MDCK cells because canine myxovirus resistance proteins lack anti-influenza activity (38) and secreted IFN is proteolytically degraded by trypsin, which is normally present during influenza virus production on MDCK cells (39). Furthermore, delNS1 virus titers could be increased by recombinant NS1 expression, without lowering IFN induction (46), indicating that IFN induction in MDCK may play a less important role than generally assumed.…”

Section: Discussionmentioning

confidence: 80%

Mutations in the M-Gene Segment Can Substantially Increase Replication Efficiency of NS1 Deletion Influenza A Virus in MDCK Cells

Wielink

Harmsen

Martens

et al. 2012

J Virol

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bInfluenza viruses unable to express NS1 protein (delNS1) replicate poorly and induce large amounts of interferon (IFN). They are therefore considered candidate viruses for live-attenuated influenza vaccines. Their attenuated replication is generally assumed to result from the inability to counter the antiviral host response, as delNS1 viruses replicate efficiently in Vero cells, which lack IFN expression. In this study, delNS1 virus was parallel passaged on IFN-competent MDCK cells, which resulted in two strains that were able to replicate to high virus titers in MDCK cells due to adaptive mutations especially in the M-gene segment but also in the NP and NS gene segments. Most notable were clustered U-to-C mutations in the M segment of both strains and clustered A-to-G mutations in the NS segment of one strain, which presumably resulted from host cell-mediated RNA editing. The M segment mutations in both strains changed the ratio of M1 to M2 expression, probably by affecting splicing efficiency. In one virus, 2 amino acid substitutions in M1 additionally enhanced virus replication, possibly through changes in the M1 distribution between the nucleus and the cytoplasm. Both adapted viruses induced levels of IFN equal to that of the original delNS1 virus. These results show that the increased replication of the adapted viruses is not primarily due to altered IFN induction but rather is related to changes in M1 expression or localization. The mutations identified in this paper may be used to enhance delNS1 virus replication for vaccine production.

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Trypsin promotes efficient influenza vaccine production in MDCK cells by interfering with the antiviral host response

Cited by 33 publications

References 57 publications

Coagulation, Protease-Activated Receptors, and Viral Myocarditis

Coagulation, Protease-Activated Receptors, and Viral Myocarditis

Multiple roles of the coagulation protease cascade during virus infection

Mutations in the M-Gene Segment Can Substantially Increase Replication Efficiency of NS1 Deletion Influenza A Virus in MDCK Cells

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