Apoptosis in pneumovirus infection

Abstract

Pneumovirus infections cause a wide spectrum of respiratory disease in humans and animals. The airway epithelium is the major site of pneumovirus replication. Apoptosis or regulated cell death, may contribute to the host anti-viral response by limiting viral replication. However, apoptosis of lung epithelial cells may also exacerbate lung injury, depending on the extent, the timing and specific location in the lungs. Differential apoptotic responses of epithelial cells versus innate immune cells (e.g., neutrophils, macrophages) during pneumovirus infection can further contribute to the complex and delicate balance between host defense and disease pathogenesis. The purpose of this manuscript is to give an overview of the role of apoptosis in pneumovirus infection. We will examine clinical and experimental data concerning the various pro-apoptotic stimuli and the roles of apoptotic epithelial and innate immune cells during pneumovirus disease. Finally, we will discuss potential therapeutic interventions targeting apoptosis in the lungs.

Figure 1

Schematic overview of three pathways of caspase-dependent apoptosis. First, the death receptor (extrinsic) pathway is activated upon tumor necrosis factor (TNF) death receptor family ligation by membrane-bound or soluble ligands, such as Fas ligand (FasL) and TNF-related apoptosis-inducing ligand (TRAIL), presented or secreted by local immune cells, including effector lymphocytes, neutrophils (PMN) and/or macrophages. Intracellular adaptor protein interactions through death domain modules follow the death receptor ligation and subsequently lead to activation of initiator caspase-8 and the downstream caspase cascade resulting in apoptosis. The inhibitor of apoptosis proteins (IAPs) can block several caspases, thereby inhibiting cell death. Second, granzymes delivered into the cytosol by effector lymphocytes can interact with several caspases and Bid to induce apoptosis. Third, members of the Bcl-2 family, including Bcl-2, Bax and Bcl-XL and p53, regulate cytochrome c release from the mitochondria (intrinsic pathway) in response to stimuli, such as DNA damage, infection and formation of reactive oxygen species (ROS). Cytochrome c in the cytosol assembles with apoptotic peptidase activating factor 1 (Apaf 1) to activate initiator caspase-9 with subsequent activation of the caspase-cascade and apoptosis. The mitochondrial and death receptor pathway can interact through BH3-interacting domain death agonist (Bid).

Figure 2

(A) Positive immunohistochemical staining for the apoptosis marker caspase-3 (brown) in bronchiolar epithelial cells in lung tissue from a child with fatal human pneumovirus respiratory syncytial virus (hRSV) disease. From Welliver et al. [24], by permission of Oxford University Press. (B) Positive immunohistochemical staining for caspase-3 (brown, arrows) in alveolar epithelial cells in lung tissue from a mouse (C57Bl/6 background) with severe pneumonia virus of mice (PVM) disease. From Bem et al. [25], Copyright 2010, The American Association of Immunologists, Inc.

Figure 3

Three theoretical scenarios regarding lung epithelial cell apoptosis during pneumovirus infection, which may co-exist. First (A), viral infection triggers the mitochondrial (intrinsic) apoptotic pathway via interaction with Bcl-2 family proteins. Second (B), death receptor ligands (either membrane-bound or soluble) presented or secreted by local immune cells activate the death receptor (extrinsic) apoptotic pathway in viral-infected cells. Similarly, granzymes released from effector lymphocytes into the cytosol of target cells induce apoptosis. Viral infection may modulate the susceptibility to death receptor ligands or granzymes by altering the expression of and interaction with the protein machinery, such as surface death receptors, involved in these pathways. Third (C), bystander (uninfected) epithelial cells undergo apoptosis as a result of extensive, non-specific signaling via the death receptor (extrinsic) and/or granzyme apoptotic pathway.