Influenza Virus Induction of Apoptosis by Intrinsic and Extrinsic Mechanisms

Abstract

It is now firmly established that apoptosis is an important mechanism of influenza virus-induced cell death both in vivo and in vitro. Data are predominantly from experiments with influenza A virus and in vitro experimental systems. Multiple influenza virus factors have been identified that can activate intrinsic or extrinsic apoptotic induction pathways. Currently there is no evidence for influenza virus directly accessing the apoptosis execution factors. The best-studied influenza virus inducers of apoptosis are dsRNA, NS1, NA, and a newly described gene product PB1-F2. PB1-F2 is the only influenza virus factor to date identified to act intrinsically by localization and interaction with the mitochondrial-dependent apoptotic pathway. Both dsRNA and NA have been shown to act via an extrinsic mechanism involving proapoptotic host-defense molecules: PKR by induction of Fas-Fas ligand and NA by activation of TGF-beta. PKR is capable of controlling several important cell-signaling pathways and therefore may have multiple effects; a predominant one is increased interferon (IFN) production and activity. NS1 has been shown to be both proapoptotic and antiapoptotic. Use of influenza virus NS1 deletion mutants has provided evidence for NS1 interference with apoptosis, IFN induction, and related cell-signaling pathways. Influenza virus also has important exocrine paracrine effects, which are likely mediated via TNF family ligands and oxygen, free radicals capable of inducing apoptosis. Little is known about activation of inhibitors of apoptosis such as inhibitory apoptotic proteins. Whether all these factors always have a role in influenza virus-induced apoptosis is unknown. The kinetics of synthesis of influenza virus factors affecting apoptosis during the replication cycle may be an important aspect of apoptosis induction.

Detection of Influenza Virus Induced Ultrastructural Changes and DNA Damage

“…The virus predominantly infects and damage epithelial cells of respiratory tract and often results in cell death with apoptotic characteristics. Infection of epithelial cells and lymphocytes has been shown to induce apoptosis in vitro [6,14,17,24]. Infection with virulent influenza (H5N1) virus was also shown to induce lymphopenia and lymphocyte apoptosis in vivo [8,25,26].…”

“…Apoptotic cells undergo several complex morphological changes, including development of fragmented nuclei, extensive chromatin condensation and loss of cell volume. Recent studies have indicated that many viruses carry genes, like NS1 and NA, which directly influence the apoptotic ability of their host cell thus changing the view about significance of apoptosis in determining the outcome of virus infections [14].…”

Effects of human T‐cell leukemia virus type 1 (HTLV‐1) p13 on mitochondrial K+ permeability: A new member of the viroporin family?

“…Fig. 1 shows the amino acid sequence (Panel A) and in silico analysis of p13's structure (Panel B, ProtScale software, [5]) indicating that the N-terminus of the protein includes an amphipathic a-helix (residues 20-35) and a transmembrane region (residues [30][31][32][33][34][35][36][37][38][39][40]. These predictions are supported by circular dichroism analysis of a synthetic peptide corresponding to residues 9-41 (p13 ) which folds into an a-helix when exposed to membrane-like environments (e.g.…”

“…Segments A-D of the protein represent, respectively, the amphipathic a-helical domain, the transmembrane domain, the hinge region and the C-terminal beta sheet hairpin. Panel C also shows a more detailed helical wheel model of the amphipathic a-helical domain of p13 (amino acids [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35]. Panel C does not indicate the matrix and intermembrane space faces of the inner membrane, as the topology of p13 has not been defined.…”

“…Immuno-electron microscopy and sub-mitochondrial fractionation experiments demonstrated that the majority of p13 is inserted as an integral membrane protein in the inner mitochondrial membrane [6]. The mitochondrial targeting of p13 is directed by an atypical mitochondrial targeting sequence (MTS) formed by 10 amino-proximal residues (amino acids [21][22][23][24][25][26][27][28][29][30] that are contained within the a-helix described above [7], with four arginines in the MTS conferring amphipathic properties to the helix. In contrast to canonic MTSs, the targeting signal of p13 is not cleaved upon import into mitochondria [7].…”