scholarly journals Effect of the phosphatidylinositol 3-kinase/Akt pathway on influenza A virus propagation

2007 ◽  
Vol 88 (3) ◽  
pp. 942-950 ◽  
Author(s):  
Yeun-Kyung Shin ◽  
Qiang Liu ◽  
Suresh K. Tikoo ◽  
Lorne A. Babiuk ◽  
Yan Zhou

The phosphatidylinositol 3-kinase (PI3K)/Akt signalling pathway has attracted much recent interest due to its central role in modulating diverse downstream signalling pathways associated with cell survival, proliferation, differentiation, morphology and apoptosis. An increasing amount of information has demonstrated that many viruses activate the PI3K/Akt pathway to augment their efficient replication. In this study, the effect of the PI3K/Akt signalling pathway on influenza virus propagation was investigated. It was found that Akt phosphorylation was elevated in the late phase of influenza A/PR/8/34 infection in human lung carcinoma cells (A549). The PI3K-specific inhibitor LY294002 could suppress Akt phosphorylation, suggesting that influenza A virus-induced Akt phosphorylation is PI3K-dependent. UV-irradiated influenza virus failed to induce Akt phosphorylation, indicating that viral attachment and entry were not sufficient to trigger PI3K/Akt pathway activation. Blockage of PI3K/Akt activation by LY294002 and overexpression of the general receptor for phosphoinositides-1 PH domain (Grp1-PH) led to a reduction in virus yield. Moreover, in the presence of LY294002, viral RNA synthesis and viral protein expression were suppressed and, possibly as a consequence of low NP and M1 protein level, viral RNP nuclear export was also suppressed. These data suggest that the PI3K/Akt signalling pathway plays a role in influenza virus propagation.

2007 ◽  
Vol 88 (1) ◽  
pp. 13-18 ◽  
Author(s):  
Yeun-Kyung Shin ◽  
Qiang Liu ◽  
Suresh K. Tikoo ◽  
Lorne A. Babiuk ◽  
Yan Zhou

Influenza A virus infection activates the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, but the mechanism is not clear. Here, it is reported that influenza A virus NS1 protein is responsible for PI3K/Akt pathway activation. It was demonstrated that the NS1 protein interacts with the p85 regulatory subunit of PI3K via direct binding to the SH3 and C-terminal SH2 domains of p85. Consensus binding motifs for SH3 and SH2 domains were found in influenza A virus NS1, namely an SH2-binding motif (YXXXM) at aa 89, SH3-binding motif 1 (PXXP) around aa 164 and SH3-binding motif 2 around aa 212. Mutant virus encoding NS1 protein with mutations in the SH-binding motifs failed to interact with SH domains of p85 and did not activate the PI3K/Akt pathway. The mutant virus is attenuated in Madin–Darby canine kidney cells. Our study has established a novel function of NS1: by interacting with p85 via the SH-binding motifs, NS1 can activate the PI3K/Akt pathway.


Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 808
Author(s):  
Stefanie Deinhardt-Emmer ◽  
Laura Jäckel ◽  
Clio Häring ◽  
Sarah Böttcher ◽  
Janine J. Wilden ◽  
...  

Influenza virus (IV) infections are considered to cause severe diseases of the respiratory tract. Beyond mild symptoms, the infection can lead to respiratory distress syndrome and multiple organ failure. Occurrence of resistant seasonal and pandemic strains against the currently licensed antiviral medications points to the urgent need for new and amply available anti-influenza drugs. Interestingly, the virus-supportive function of the cellular phosphatidylinositol 3-kinase (PI3K) suggests that this signaling module may be a potential target for antiviral intervention. In the sense of repurposing existing drugs for new indications, we used Pictilisib, a known PI3K inhibitor to investigate its effect on IV infection, in mono-cell-culture studies as well as in a human chip model. Our results indicate that Pictilisib is a potent inhibitor of IV propagation already at early stages of infection. In a murine model of IV pneumonia, the in vitro key findings were verified, showing reduced viral titers as well as inflammatory response in the lung after delivery of Pictilisib. Our data identified Pictilisib as a promising drug candidate for anti-IV therapies that warrant further studying. These results further led to the conclusion that the repurposing of previously approved substances represents a cost-effective and efficient way for development of novel antiviral strategies.


2009 ◽  
Vol 90 (11) ◽  
pp. 2751-2758 ◽  
Author(s):  
Junjie Zhang ◽  
Gang Li ◽  
Xiaoling Liu ◽  
Zengfu Wang ◽  
Wenjun Liu ◽  
...  

The matrix (M1) protein of influenza A virus is a conserved multifunctional protein that plays essential roles in regulating the viral life cycle. This study demonstrated that M1 is able to interact with complement C1qA and plays an important inhibitory function in the classical complement pathway. The N-terminal domain of M1 protein was required for its binding to the globular region of C1qA. As a consequence, M1 blocked the interaction between C1qA and heat-aggregated IgG in vitro and inhibited haemolysis. It was shown that M1 protein prevented the complement-mediated neutralization of influenza virus in vitro. In addition, studies on mice indicated that the administration of M1 could promote a higher virus propagation rate in lung and shortened survival of mice infected with the virus. Taken together, these results suggest strongly that the M1 protein plays a critical role in protecting influenza virus from the host innate immune system.


2010 ◽  
Vol 84 (18) ◽  
pp. 9439-9451 ◽  
Author(s):  
Sabine Eva Dudek ◽  
Christina Luig ◽  
Eva-Katharina Pauli ◽  
Ulrich Schubert ◽  
Stephan Ludwig

ABSTRACT Recently it has been shown that the proinflammatory NF-κB pathway promotes efficient influenza virus propagation. Based on these findings, it was suggested that NF-κB blockade may be a promising approach for antiviral intervention. The classical virus-induced activation of the NF-κB pathway requires proteasomal degradation of the inhibitor of NF-κB, IκB. Therefore, we hypothesized that inhibition of proteasomal IκB degradation should impair influenza A virus (IAV) replication. We chose the specific proteasome inhibitor PS-341, which is a clinically approved anticancer drug also known as Bortezomib or Velcade. As expected, PS-341 treatment of infected A549 cells in a concentration range that was not toxic resulted in a significant reduction of progeny virus titers. However, we could not observe the proposed suppression of NF-κB-signaling in vitro. Rather, PS-341 treatment resulted in an induction of IκB degradation and activation of NF-κB as well as the JNK/AP-1 pathway. This coincides with enhanced expression of antiviral genes, such as interleukin-6 and, most importantly, MxA, which is a strong interferon (IFN)-induced suppressor of influenza virus replication. This suggests that PS-341 may act as an antiviral agent via induction of the type I IFN response. Accordingly, PS-341 did not affect virus titers in Vero cells, which lack type I IFN genes, but strongly inhibited replication of vesicular stomatitis virus (VSV), a highly IFN-sensitive pathogen. Thus, we conclude that PS-341 blocks IAV and VSV replication by inducing an antiviral state mediated by the NF-κB-dependent expression of antivirus-acting gene products.


1999 ◽  
Vol 146 (5) ◽  
pp. 955-966 ◽  
Author(s):  
A.R. Vaillant ◽  
I. Mazzoni ◽  
C. Tudan ◽  
M. Boudreau ◽  
D.R. Kaplan ◽  
...  

In this report, we have examined the mechanisms whereby neurotrophins and neural activity coordinately regulate neuronal survival, focussing on sympathetic neurons, which require target-derived NGF and neural activity for survival during development. When sympathetic neurons were maintained in suboptimal concentrations of NGF, coincident depolarization with concentrations of KCl that on their own had no survival effect, synergistically enhanced survival. Biochemical analysis revealed that depolarization was sufficient to activate a Ras-phosphatidylinositol 3-kinase–Akt pathway (Ras–PI3-kinase–Akt), and function-blocking experiments using recombinant adenovirus indicated that this pathway was essential for ∼50% of depolarization-mediated neuronal survival. At concentrations of NGF and KCl that promoted synergistic survival, these two stimuli converged to promote increased PI3-kinase–dependent Akt phosphorylation. This convergent PI3-kinase–Akt pathway was essential for synergistic survival. In contrast, inhibition of calcium/calmodulin-dependent protein kinase II revealed that, while this molecule was essential for depolarization-induced survival, it had no role in KCl- induced Akt phosphorylation, nor was it important for synergistic survival by NGF and KCl. Thus, NGF and depolarization together mediate survival of sympathetic neurons via intracellular convergence on a Ras–PI3-kinase–Akt pathway. This convergent regulation of Akt may provide a general mechanism for coordinating the effects of growth factors and neural activity on neuronal survival throughout the nervous system.


Virology ◽  
2010 ◽  
Vol 396 (1) ◽  
pp. 94-105 ◽  
Author(s):  
David Jackson ◽  
Marian J. Killip ◽  
Caroline S. Galloway ◽  
Rupert J. Russell ◽  
Richard E. Randall

2006 ◽  
Vol 103 (38) ◽  
pp. 14194-14199 ◽  
Author(s):  
B. G. Hale ◽  
D. Jackson ◽  
Y.-H. Chen ◽  
R. A. Lamb ◽  
R. E. Randall

Viruses ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 156
Author(s):  
Jasmina M. Luczo ◽  
Sydney L. Ronzulli ◽  
Stephen M. Tompkins

Natural killer (NK) cells are part of the innate immunity repertoire, and function in the recognition and destruction of tumorigenic and pathogen-infected cells. Engagement of NK cell activating receptors can lead to functional activation of NK cells, resulting in lysis of target cells. NK cell activating receptors specific for non-major histocompatibility complex ligands are NKp46, NKp44, NKp30, NKG2D, and CD16 (also known as FcγRIII). The natural cytotoxicity receptors (NCRs), NKp46, NKp44, and NKp30, have been implicated in functional activation of NK cells following influenza virus infection via binding with influenza virus hemagglutinin (HA). In this review we describe NK cell and influenza A virus biology, and the interactions of influenza A virus HA and other pathogen lectins with NK cell natural cytotoxicity receptors (NCRs). We review concepts which intersect viral immunology, traditional virology and glycobiology to provide insights into the interactions between influenza virus HA and the NCRs. Furthermore, we provide expert opinion on future directions that would provide insights into currently unanswered questions.


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