Apoptosis in animal models of virus-induced disease

Abstract

Apoptosis is associated with virus-induced human diseases of the central nervous system, heart and liver, and causes substantial morbidity and mortality. Although virus-induced apoptosis is well characterized in individual cells in cell culture, virus-induced apoptosis in vivo and the role of apoptosis in virus-induced disease is not well established. This Review focuses on animal models of virus-induced diseases of the central nervous system, heart and liver that provide insights into the role of apoptosis in pathogenesis, the pathways involved and the potential therapeutic implications.Apoptosis plays an essential part in homeostasis, development and human disease by facilitating the removal of unwanted, damaged or infected cells. However, apoptosis may also have a pathogenic role by contributing to cell death and tissue injury. Apoptotic cell death occurs in a wide range of human viral infections, including infections of the central nervous system (CNS), heart and liver. For example, apoptosis can be detected in the brains of patients with virus-induced CNS disease, including patients with HIV-1-associated dementia 1 , herpes simplex virus (HSV) 2,3 and cytomegalovirus (CMV) 3 encephalitis. Furthermore, apoptotic cells can be observed in the diseased human heart during both active and chronic viral myocarditis 4 , and hepatocyte apoptosis is emerging as an important feature of liver injury in patients with hepatitis B virus (HBV) and hepatitis C virus (HCV) infections [5][6][7][8][9][10] .The morphological and nuclear changes associated with apoptosis are typically caused by the sequential activation of a family of aspartate-specific cysteine proteases called caspases [11][12][13] (BOX 1). Caspase 3, the main executioner caspase, can be activated by the initiator caspase, caspase 8, following activation of cell-surface death receptors in the extrinsic apoptotic pathway (BOX 1 ; FIG. 1). Alternatively, the intrinsic apoptotic pathway can activate caspase 3 following release of pro-apoptotic factors from the mitochondria and activation of the initiator caspase, caspase 9 (BOX 1 ; FIG. 1). In some cell types (type I cells), activation of caspase 8 is sufficient for apoptosis. However, in other cell types (type II cells), apoptosis requires intrinsic apoptotic signalling, which can be activated directly or through extrinsic apoptotic signalling through the caspase 8-dependent cleavage of BCL-2 interacting domain death agonist (BID), a member of the BH3-only B-cell lymphoma protein 2 family (BOX 2 ; FIG. Correspondence to P.C. Penny.Clarke@uchsc.edu. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript 1). Caspase 3 can also be activated by granzyme B, a serine protease found in cytotoxic T lymphocytes (CTLs) (FIG. 1). Granzyme B can also cleave BID, forming the truncated protein gtBID and resulting in the activation of intrinsic apoptotic signalling 14 . Granzyme B and extrinsic apoptotic signalling constitute the two major components of CTL-induced cell death. B...

Cloning and characterization of Bax1 and Bax2 genes of Ctenopharyngodon idellus and evaluation of transcript expression in response to grass carp reovirus infection

“…Apoptosis is an inherently programmed phenomenon of cell death that can be triggered or inhibited by various physiological and pathological stimuli (Kerr et al 1972;Groh et al 2011;Xu et al 2012). It plays an essential role in maintaining homeostasis and in case of diseases by removing damaged or infected cells (Ashkenazi and Dixit 1998;Clarke and Tyler 2009). There are two distinct pathways of apoptosis: extrinsic pathway and intrinsic pathway.…”

Death Receptor-Mediated Apoptotic Signaling Is Activated in the Brain following Infection with West Nile Virus in the Absence of a Peripheral Immune Response

“…euronal apoptosis is an important mechanism of virus-induced pathogenesis within the central nervous system (CNS) (1). During West Nile virus (WNV) encephalitis, the proapoptotic executioner caspase, caspase 3, is activated, and mice lacking caspase 3 have reduced neuronal death and tissue injury following West Nile virus infection (2).…”

Activation of Innate Immune Responses in the Central Nervous System during Reovirus Myelitis

“…Development of novel antiviral and neuroprotective therapies for myelitis requires a better understanding of the basic pathogenic mechanisms by which viruses infect and injure the spinal cord (SC). Reovirus infection of the central nervous system (CNS) provides a model for understanding the molecular pathogenesis of virus-induced CNS injury (16).…”