Elsevier

Vitamins & Hormones

Volume 67, 2004, Pages 257-274
Vitamins & Hormones

TRAIL and Viral Infection

https://doi.org/10.1016/S0083-6729(04)67014-2Get rights and content

Abstract

Tumor necrosis factor (TNF)–related apoptosis-inducing ligand (TRAIL) is a member of the TNF family that can induce apoptosis when binding to either of two receptors bearing an intracellular death domain. The physiologic function of the TRAIL system, which also comprises three receptors not mediating a death signal has just begun to be elucidated. Expression of TRAIL, mostly upon stimulation by interferons, in different cytotoxic immune cells suggested it has a role as an important effector molecule in immune surveillance. In addition to its ability to induce apoptosis in transformed tumor cells, TRAIL has attracted attention for its possibly critical role in the defense against viral infection. Viruses may induce TRAIL expression in host and⧸or immune cells and sensitize host cells toward TRAIL-mediated apoptosis. On the other hand, viruses have evolved a variety of strategies to prevent TRAIL-mediated host cell death early in infection, which may contribute to allowing their replication and the spread of viral progeny. The knowledge of the molecular mechanisms leading to modification of TRAIL sensitivity in virus-host cell interactions may also impact upon future (virus-based) strategies to increase TRAIL sensitivity of tumor cells.

Introduction

Apoptosis, programmed cell death, is a fundamental biologic process which, in the developing organism, plays an important role in the formation and shaping of organs and tissues. In the adult, it has tremendous implications for the maintenance of tissue homeostasis. When apoptotic death rates overcome proliferation, this results in atrophy, whereas hyperplasia and neoplasia are consequences of mitotic activity surpassing cell death. Finally, apoptosis plays a pivotal role in inflammatory conditions where programmed cell death is an important way of cutting down immune responses, but, on the other hand, may also contribute to tissue damage. This is also true for viral infections in which apoptosis of host cells is, in most cases, the only way to destroy their deleterious load and terminate the infection. Cytotoxic immune cells are the main effectors which force host cells into apoptosis. It is, however, known from a variety of in situ experiments that virus-infected cells can also enter apoptosis in a cell-autonomous way (Tyler et al., 1995). Apoptosis of parenchymal cells, however, may contribute to infection-related organ failure, e.g., in fulminant viral hepatitis (Losser and Payen, 1996). On the other hand, viruses had to evolve strategies to delay or inhibit programmed death to enable their replication in host cells and the spread of viral progeny. These strategies may aim at avoiding recognition of infected cells by the immune system or activation of cytotoxic cells (for a recent review cf. Vossen et al., 2002), but most often also involve interference with the apoptosis signaling cascade in host cells.

In recent years, some members of the tumor necrosis factor (TNF) family of proteins have attracted particular attention due to their ability to induce apoptosis in a very direct way by ligation of so-called death receptors on target cells. The TNF-related apoptosis-inducing ligand, TRAIL, also called APO-2 ligand (APO-2L), is such a member of the TNF family. Together with its five known receptors, it constitutes a quite complex death-inducing system that has recently been implicated in viral infection-associated apoptosis induction. In this review, we will discuss what is known to date about the potential role of TRAIL and its receptors in viral infections.

Section snippets

Apoptosis as a process of degradation of host cell and viral constituents

The central signaling cascade of apoptosis involves a hierarchical system of proteases known as caspases. Caspases are preformed in the cell as proenzymes that are activated either autocatalytically or by activated upstream caspases. Once activated, they cleave a variety of cellular proteins bearing specific peptide motifs with an aspartic acid residue. However, it is quite conceivable that viral proteins may also be degraded during host cell apoptosis. Actually, adenoviral E1A protein has only

Death receptor⧸ligand systems

There are two main pathways by which cytotoxic cells involved in the elimination of virally infected cells induce apoptosis: the perforin-granzyme pathway and the death receptor pathway. Death receptors possess the unique property of directly activating the intracellular death signaling machinery upon ligation by their natural ligands or cross-linking antibody. All death receptors known so far are members of the TNF receptor (TNFR) superfamily, a group of type I transmembrane proteins with one

The Cytotoxic Activity of TRAIL Against Virus-Infected Cells

In contrast to most other death-inducing TNF family members, TRAIL is broadly expressed in a variety of different tissues (Wiley et al., 1995). Although this is also true for the apoptosis-inducing TRAIL-R1 and 2, normal cells are largely resistant to TRAIL-induced apoptosis. TRAIL-induced apoptosis may, therefore, be a rare event in the healthy organism. Actually, injection of soluble TRAIL into mice is well tolerated and does not seem to provoke significant apoptosis (Ashkenazi 1999, Walczak

Viral Strategies to Circumvent TRAIL-Induced Apoptosis

It is obvious that early death of host cells following viral infection would limit virus production and reduce or even eliminate the spread of progeny virus in the host. Viruses have therefore adapted a variety of different strategies to evade or delay apoptosis in an attempt to allow production of high yields of progeny virus. Receptor expression as well as different levels of the mitochondrion-dependent and -independent apoptosis signaling pathway may be affected. Due to homologies of the

TRAIL in Virus-Induced Immunosuppression

Once host cells have been rendered resistant to TRAIL-mediated apoptosis, viruses may even force immune cells to die by turning their weapons upon themselves. Two viruses have been shown to induce apoptosis in immune cells by TRAIL receptor ligation: the human immunodeficiency virus (HIV) and measles virus.

It is well known that HIV infection induces an acquired immunodeficiency syndrome (AIDS) with marked lymphopenia as the main reason for opportunistic infections and mortality in this disease.

Viruses and TRAIL in Malignant Disease

During recent years, TRAIL has attracted most attention in cancer research as a promising anticancer therapeutic. This is due to the fact that, in contrast to normal cells, many tumor cell lines undergo apoptosis upon TRAIL treatment in vitro (Griffith 1998, Pitti 1996, Wiley 1995) and, in contrast to FasL or TNF, its application in animal models does not show significant toxicity (Ashkenazi 1999, Walczak 1999). Moreover, tumor cells can be sensitized towards TRAIL by additional application of

Conclusions

We just begun to gain awareness of the potential role of the TRAIL system in viral infections. However, it remains to be seen whether TRAIL actually has the dominant role in host defense against viruses that recent in vitro studies suggest or whether it is just one way that virus-infected cells can be forced to apoptosis or to commit suicide. Redundancies in the repertoire of cytotoxic cells to induce apoptosis may be important in light of the multiple strategies viruses have developed to

Acknowledgements

This work was supported by grants from the Deutsche Krebshilfe to J. Sträter (10-1644-Str 2) and from the Deutsche Forschungsgemeinschaft (SFB518 TPA13) and the IZKF Ulm to P. Möller.

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