Apoptosis and Pathogenesis of Avian Influenza A (H5N1) Virus in Humans

Uiprasertkul, Mongkol; Kitphati, Rungrueng; Puthavathana, Pilaipan; Kriwong, Romchat; Kongchanagul, Alita; Ungchusak, Kumnuan; Angkasekwinai, Suwimon; Chokephaibulkit, Kulkanya; Srisook, Kanittar; Vanprapar, Nirun; Auewarakul, Prasert

doi:10.3201/eid1305.060572

Cited by 147 publications

(171 citation statements)

References 20 publications

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“…ROS formation may result in caspase-dependent apoptosis and virus-induced apoptosis may be a major mechanism in the destruction of epithelial cells infected with H5N1 both in vitro and in vivo [8,25]. To investigate the influence of NAC on H5N1-induced apoptosis in A549 cells, cells were treated with or without NAC and infected with H5N1 at an MOI of 0.01.…”

Section: Influence Of Nac On H5n1-induced Caspase Activationmentioning

confidence: 99%

“…Human infections with highly pathogenic influenza A H5N1 viruses are associated with severe pneumonia, lymphopenia, high viral loads in the respiratory tract, and hyper-induction of cytokines and chemokines (cytokine storm) [7]. Pathological investigations revealed that induction of apoptosis may be a major mechanism in the destruction of alveolar epithelial cells in humans infected with H5N1 [8].…”

Section: Introductionmentioning

confidence: 99%

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N-acetyl-l-cysteine (NAC) inhibits virus replication and expression of pro-inflammatory molecules in A549 cells infected with highly pathogenic H5N1 influenza A virus

Geiler

Michaelis

Naczk

et al. 2010

Biochemical Pharmacology

182

149

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 The combination of BAY 11-7085 and SB203580 resulted in increased inhibitory effects on virus replication and production of pro-inflammatory molecules relative to either single treatment. NAC inhibits H5N1 replication and H5N1-induced production of proinflammatory molecules. Therefore, antioxidants like NAC represent a potential additional treatment option that could be considered in the case of an influenza A virus pandemic.

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Section: Influence Of Nac On H5n1-induced Caspase Activationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

N-acetyl-l-cysteine (NAC) inhibits virus replication and expression of pro-inflammatory molecules in A549 cells infected with highly pathogenic H5N1 influenza A virus

Geiler

Michaelis

Naczk

et al. 2010

Biochemical Pharmacology

182

149

View full text Add to dashboard Cite

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“…However, these molecules can also cause the host harm by a phenomenon known as cytokine storm. Cytokine storm has been convincingly documented both in experimental animals infected with the 1918/1919 and H5N1 influenza viruses (2,(10)(11)(12)(13) as well as in humans (14)(15)(16)(17)(18) succumbing to H5N1 infection. Although antiviral drugs can be used to treat the virus, a strategy to balance the resultant cytokine release and lung injury while maintaining benefits of the antiviral protective immune response is needed (19).…”

mentioning

confidence: 99%

A critical role for the sphingosine analog AAL-R in dampening the cytokine response during influenza virus infection

Marsolais

Hahm

Walsh

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

116

141

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Pulmonary tissue damage resulting from influenza virus infection is caused by both the cytolytic activity of the virus and the host immune response. Immune-mediated injury results from T cellmediated destruction of virus-infected cells and by release of cytokines and chemokines that attract polymorphonuclear leukocytes (PML) and macrophages to the infected site. The cytokines/ chemokines potentiate dendritic cell (DC) activation and T cell expansion, which further enhances local damage. Here we report that immune modulation by local administration to the respiratory tract of sphingosine analog AAL-R significantly dampens the release of cytokines and chemokines while maintaining protective neutralizing antibody and cytotoxic T cell responses. As a result there was a marked reduction of infiltrating PML and macrophages into the lung and resultant pulmonary tissue injury. DC maturation was suppressed, which limited proliferation of specific antiviral T cells in the lung and draining lymph nodes. Further, AAL-R was effective in controlling CD8 ؉ T cell accumulation in the lungs even when given 4 days after initiation of influenza virus infection. These data indicate that sphingosine analogs display useful potential for controlling the immunopathology caused by influenza virus.immunopathology ͉ dendritic cells ͉ cytokine storm ͉ T cells T he antiviral host response evolved to limit the spread of infection at the cost of causing tissue injury. There is a balance between the protective and injurious responses that leads either to the purging of infectious virus and host recovery or to severe disease and even death. Thus, strategies to balance the antiviral immune response in favor of host outcome need to be developed.T cell response elicited early in the course of infection recognizes, attacks and lyses virus-infected cells to eliminate potential factories of progeny viruses (1-5). The protective influenza antibody response is elicited later and plays a role in controlling re-infection (6, 7). The innate and adaptive immune systems release wide varieties of cytokines and chemokines that activate and attract inflammatory cells to the site of infection (2,8,9). However, these molecules can also cause the host harm by a phenomenon known as cytokine storm. Cytokine storm has been convincingly documented both in experimental animals infected with the 1918/1919 and H5N1 influenza viruses (2, 10-13) as well as in humans (14-18) succumbing to H5N1 infection. Although antiviral drugs can be used to treat the virus, a strategy to balance the resultant cytokine release and lung injury while maintaining benefits of the antiviral protective immune response is needed (19). Influenza virus replication is most often limited primarily to the respiratory tract but the systemic signs and symptoms of disease, e.g., fever, muscle pain and shakes, intestinal tract involvement, are related to cytokine effects (20, 21).We reported that intratracheal (i.t.) delivery of the sphingosine analog AAL-R or its phosphate ester inhibited virus-specifi...

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“…While lymphopenia, hypercytokinemia, and hemophagocytosis have been the most notable clinicopathological findings, the biological basis accounting for the severity of H5N1 infection in humans remains unknown (10,51). In a recent study, apoptosis among the alveolar epithelial cells of two patients who died of H5N1 infection was observed (53), suggesting that apoptosis may play a role in H5N1 pathogenesis in humans.…”

mentioning

confidence: 99%

Avian Influenza Virus A/HK/483/97(H5N1) NS1 Protein Induces Apoptosis in Human Airway Epithelial Cells

Lam

Tang²,

Yeung³

et al. 2008

J Virol

108

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Avian H5N1 influenza virus causes a remarkably severe disease in humans, with an overall case fatality rate of greater than 50%. Human influenza A viruses induce apoptosis in infected cells, which can lead to organ dysfunction. To verify the role of H5N1-encoded NS1 in inducing apoptosis, the NS1 gene was cloned and expressed in human airway epithelial cells (NCI-H292 cells). The apoptotic events posttransfection were examined by a terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick-end-labeling assay, flow cytometric measurement of propidium iodide, annexin V staining, and Western blot analyses with antibodies specific for proapoptotic and antiapoptotic proteins. We demonstrated that the expression of H5N1 NS1 protein in NCI-H292 cells was sufficient to induce apoptotic cell death. Western blot analyses also showed that there was prominent cleavage of poly(ADP-ribose) polymerase and activation of caspase-3, caspase-7, and caspase-8 during the NS1-induced apoptosis. The results of caspase inhibitor assays further confirmed the involvement of caspase-dependent pathways in the NS1-induced apoptosis. Interestingly, the ability of H5N1 NS1 protein to induce apoptosis was much enhanced in cells pretreated with Fas ligand (the time posttransfection required to reach >30% apoptosis was reduced from 24 to 6 h). Furthermore, 24 h posttransfection, an increase in Fas ligand mRNA expression of about 5.6-fold was detected in cells transfected with H5N1 NS1. In conclusion, we demonstrated that the NS1 protein encoded by avian influenza A virus H5N1 induced apoptosis in human lung epithelial cells, mainly via the caspase-dependent pathway, which encourages further investigation into the potential for the NS1 protein to be a novel therapeutic target.

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Apoptosis and Pathogenesis of Avian Influenza A (H5N1) Virus in Humans

Abstract: Apoptosis may play a crucial role in the pathogenesis of pneumonia and lymphopenia caused by this virus in humans.

Cited by 147 publications

References 20 publications

N-acetyl-l-cysteine (NAC) inhibits virus replication and expression of pro-inflammatory molecules in A549 cells infected with highly pathogenic H5N1 influenza A virus

N-acetyl-l-cysteine (NAC) inhibits virus replication and expression of pro-inflammatory molecules in A549 cells infected with highly pathogenic H5N1 influenza A virus

A critical role for the sphingosine analog AAL-R in dampening the cytokine response during influenza virus infection

Avian Influenza Virus A/HK/483/97(H5N1) NS1 Protein Induces Apoptosis in Human Airway Epithelial Cells

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