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Review
. 2017 Sep 28:8:1220.
doi: 10.3389/fimmu.2017.01220. eCollection 2017.

Induction of Apoptosis and Subsequent Phagocytosis of Virus-Infected Cells As an Antiviral Mechanism

Firzan Nainu  1   2 , Akiko Shiratsuchi  2 , Yoshinobu Nakanishi  2
Affiliations
Review

"VSports手机版" Induction of Apoptosis and Subsequent Phagocytosis of Virus-Infected Cells As an Antiviral Mechanism

Firzan Nainu et al. Front Immunol. .

Abstract

Viruses are infectious entities that hijack host replication machineries to produce their progeny, resulting, in most cases, in disease and, sometimes, in death in infected host organisms. Hosts are equipped with an array of defense mechanisms that span from innate to adaptive as well as from humoral to cellular immune responses. We previously demonstrated that mouse cells underwent apoptosis in response to influenza virus infection VSports手机版. These apoptotic, virus-infected cells were then targeted for engulfment by macrophages and neutrophils. We more recently reported similar findings in the fruit fly Drosophila melanogaster, which lacks adaptive immunity, after an infection with Drosophila C virus. In these experiments, the inhibition of phagocytosis led to severe influenza pathologies in mice and early death in Drosophila. Therefore, the induction of apoptosis and subsequent phagocytosis of virus-infected cells appear to be an antiviral innate immune mechanism that is conserved among multicellular organisms. We herein discuss the underlying mechanisms and significance of the apoptosis-dependent phagocytosis of virus-infected cells. Investigations on the molecular and cellular features responsible for this underrepresented virus-host interaction may provide a promising avenue for the discovery of novel substances that are targeted in medical treatments against virus-induced intractable diseases. .

Keywords: antiviral mechanism; apoptosis; innate immunity; phagocytosis; viral infection. V体育安卓版.

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Figures

Figure 1
Figure 1
Similarity in apoptosis-inducing pathways in three model animals. Pathways for the induction of apoptosis in mammals, Drosophila melanogaster, and Caenorhabditis elegans are shown. Not all signal mediators are indicated. In the activation of initiator caspases, the mitochondrion is involved in mammals, probably involved in Drosophila, and not involved in C. elegans. Initiator caspases are caspase-9 in mammals, caspase-9-like Dronc in Drosophila, and absent in C. elegans, while effector caspases are caspase-3 and caspase-7 in mammals, caspase-3-like DrICE and Dcp-1 in Drosophila, and caspase-9-like CED-3 in C. elegans. Effector caspases, once activated by initiator caspases, degrade a number of cellular proteins, leading to structural and functional features that are typical of apoptosis. In mammals, two different modes of apoptosis-inducing pathways exist, and the so-called intrinsic pathway that involves the action of mitochondria is shown. The other one, the extrinsic pathway, which is initiated by extracellular death factors and their receptors independent of mitochondrial actions, is not shown (see Figure 4). CED, cell death abnormal; Dcp-1, death caspase-1; DrICE, Drosophila interleukin-1 β-converting enzyme; Dronc, Drosophila Nedd2-like caspase; Egl-1, egg-laying defective-1.
Figure 2
Figure 2
Processes of apoptosis-dependent phagocytosis. Cells undergoing apoptosis secrete substances that attract phagocytes (STEP 1), often called find-me signals, and simultaneously express eat-me signals on their surface (STEP 2). Phagocytes that come into close proximity to apoptotic cells recognize and bind eat-me signals using engulfment receptors (STEP 2), and activate signaling pathways for the induction of phagocytosis. The culmination of this signal transduction is the generation of pseudopodia that help phagocytes surround and incorporate apoptotic cells (STEP 3). Materials engulfed exist as phagosomes, which subsequently fuse with the lysosomes for degradation (STEP 4).
Figure 3
Figure 3
Similarity in signaling pathways for the induction of apoptotic cell clearance in three model animals. Molecules constituting two partly overlapping pathways for the induction of phagocytosis in the nematodes, insects, and mammals are shown. The names of eat-me signals, bridging molecules, engulfment receptors, and intracellular signal mediators of Caenorhabditis elegans, Drosophila melanogaster, and mammals are shown from left to right with slashes in between. All molecules in each individual category are counterparts to each other in three animal species. Refer to the text for explanation.
Figure 4
Figure 4
Fas and Fas ligand-induced apoptosis in influenza virus-infected cells. Upon infection with influenza virus, the production of the death receptor Fas and its ligand, the Fas ligand, is enhanced at the level of gene transcription. As a result, virus-infected cells have higher levels of Fas and the Fas ligand on their surface. When these cells associate with each other, the ligand-engaged receptor activates an intracellular signaling pathway for the induction of apoptosis. This mode of apoptosis induction is called the extrinsic pathway and does not involve mitochondria (see Figure 1).
Figure 5
Figure 5
PS-mediated and sugar residue-stimulated phagocytosis of influenza virus-infected cells. Influenza virus-infected cells are induced to undergo apoptosis and express PS and viral NA on their surfaces. When phagocytes, macrophages and neutrophils, bind to these cells through interactions between PS and a PS-recognizing engulfment receptor, NA enzymatically modifies sugar residues that exist on the surface of phagocytes. The PS-bound receptor activates a signaling pathway for the induction of phagocytosis, while modified sugar residues somehow stimulate phagocytosis. NA, neuraminidase; PS, phosphatidylserine.
Figure 6
Figure 6
Possible mechanism for the induction of apoptosis in Drosophila C virus-infected cells. The process for the propagation of the virus somehow increases pro-apoptotic proteins Reaper and Hid, which cause a decrease in the level of DIAP1. This leads to the liberation and, thus, activation of the initiator caspase Dronc that partially cleaves the effector caspases DrICE and Dcp-1 for activation. Activated DrICE and Dcp-1, in turn, cleave a number of cellular proteins for apoptotic changes. The brownish dot at the end of the viral genome indicates a viral protein called virion protein, genome-linked, which plays a role in the synthesis of viral RNA. Dcp-1, death caspase-1; DIAP1, Drosophila inhibitor of apoptosis protein 1; DrICE, Drosophila interleukin-1 β-converting enzyme; Dronc, Drosophila Nedd2-like caspase.
Figure 7
Figure 7
Orchestrated antiviral mechanisms initiated by the phagocytosis of virus-infected cells. Virus-infected cells are subjected to apoptosis-dependent phagocytosis, which results in the digestion of viruses together with host cells, Virus Removal. At the same time, phagocytes process incorporated viral proteins for the presentation of antigens toward CTLs for their activation, Antigen Presentation. Moreover, phagocytes change the pattern of gene expression at a transcriptional level, so that the repertoire of cytokines shifts to the mitigation of inflammation, Inflammation Resolution; the phagocytic activity of phagocytes is enhanced, Trained Immunity; and virus-specific RNAi is systemically induced, Trained Immunity. CTLs, cytotoxic T lymphocytes.
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