Innate Recognition of Alphaherpesvirus DNA

Stefanie Luecke*; Søren R. Paludan†,‡,1    * Graduate School of Life Sciences, Universiteit Utrecht, Utrecht, The Netherlands
† Department of Biomedicine, Aarhus University, Aarhus, Denmark
‡ Aarhus Research Center for Innate Immunology, Aarhus University, Aarhus, Denmark
1 Corresponding author: email address: srp@biomed.au.dk

1 Introduction

1.1 Alphaherpesviruses

The Herpesviridae family comprises more than 130 virus species, which infect mammals, birds, and reptiles. Herpesviruses are enveloped, double-stranded DNA viruses (Fig. 1A), which usually lyse productively infected cells and establish latent infections in their hosts. Eight herpesviruses are known to cause disease in humans, most notably in children and immunocompromised individuals. The family is divided into three subfamilies, alpha-, beta-, and gamma-herpesviruses. This division was originally based on biological similarities and later confirmed by genome sequencing (Pellett & Roizman, 2013).

Alphaherpesviruses are characterized by a relatively broad host range and fast reproduction during lytic infection compared to other herpesviruses (Pellett & Roizman, 2013). They contain three virus species pathogenic to humans (herpes simplex virus type 1 (HSV-1, also called human herpesvirus 1), herpes simplex virus type 2 (HSV-2, also called human herpesvirus 2), and varicella zoster virus (VZV, also called human herpesvirus 3)) and many pathogens of veterinary importance, notably Marek's disease virus (MDV, also called gallid herpesvirus 2) and pseudorabies virus (PRV, also called suid herpesvirus 1).

Herpes simplex viruses are ubiquitous human pathogens, which lytically infect epithelial cells of mucosal surfaces and the skin and afterward establish latency in the cell bodies of peripheral sensory neurons innervating the infected area. During latency, the viral genome persists in the nucleus of the host while the majority of viral genes are silenced. It can be maintained for the lifetime of the host organism. Reactivation from latency can be induced by a number of factors, including tissue damage, UV radiation, immune status changes, and stress, but can also occur spontaneously. In reactivation, virus particles produced in the neuronal cell body are transported along the axons by anterograde transport and infect epithelial cells again. HSV-1 usually causes recurrent cold sores at the lips (herpes labialis), while HSV-2 is often responsible for genital herpes infections (herpes genitalis). HSV may also spread to the central nervous system, leading to herpes encephalitis, cause disseminating herpes infections in neonates and immunocompromised individuals, and infect the eyes, often leading to blindness (Roizman, Knipe, & Whitley, 2013).

VZV is the causal agent of chicken pox after primary infection and of shingles (herpes zoster) upon reactivation. In primary infection, the virus usually infects epithelial cells in the upper respiratory tract followed by infection of T cells in lymphoid tissues. This allows for transport of the virus to skin areas over the whole body, where viral replications result in the characteristic rash. VZV then establishes latency in peripheral sensory neurons. The virus can reactivate to cause shingles, which may be associated with serious neurological complications (Arvin & Gilden, 2013).

PRV first infects epithelial cells of the respiratory tract and then establishes latency in sensory neurons. The natural hosts for this virus are pigs, but it can also infect many other mammals such as cattle, sheep, and dogs. It is the causative agent of Aujeszky's disease, which is characterized by symptoms ranging from high mortality and severe central nervous system defects in suckling piglets, via abortions and stillbirths in pregnant sows, to fever and respiratory symptoms in adult pigs (Pomeranz, Reynolds, & Hengartner, 2005). MDV establishes latency in and causes oncogenic transformation of immune cells, especially CD4+ T cells, and lytically infects epithelial cells of inner organs and the skin in chickens, leading to a variety of clinical symptoms including chronic polyneuritis and visceral lymphoma (Osterrieder, Kamil, Schumacher, Tischer, & Trapp, 2006).

Herpesviruses enter their host cells by fusion of the viral lipid envelope with the plasma or endosomal membrane, which is initiated by interaction of viral glycoproteins in the virion envelope with cell surface receptors. Upon viral entry, the tegument proteins, located between the viral envelope and the capsid, are released into the cytoplasm and interact with host factors to create a favorable environment for the virus. In permissive cells, i.e., cells that allow productive replication of the virus, the icosahedral capsid containing the viral dsDNA genome moves along the microtubule network toward the nucleus, where the viral DNA is translocated through the nuclear pores. In the nucleus, the viral genome circularizes (Fig. 1). Silencing of viral gene expression can lead to the establishment of latent infection. During lytic infection, expression of viral genes takes place in three stages, immediate-early (responsible for subsequent viral gene expression and immune evasion), early (replication of viral DNA), and late (formation and release of progeny virions), and eventually leads to multiplication of the viral genome and to assembly and release of new virus particles (Arvin & Gilden, 2013; Roizman et al., 2013). However, some cells, such as macrophages in case of HSV-1, are nonpermissive for the virus, i.e., productive replication does not take place. Even in permissive cells, not all viral particles lead to productive infection. It is suspected that this is partly due to the early innate antiviral response of the cells (Paludan, Bowie, Horan, & Fitzgerald, 2011).

1.2 Immunity to alphaherpesviruses

As with most infectious diseases, immunity to alphaherpesviruses relies on innate and adaptive immune responses. One of the first responses upon detection of a herpesvirus in an infected cell is the production and secretion of interferons (IFNs), especially type I (IFNα and IFNβ), but also type III (e.g., IFNλ), and other proinflammatory cytokines and chemokines (Ank et al., 2008; Egan, Wu, Wigdahl, & Jennings, 2013). By paracrine and autocrine signaling, IFNs mediate a number of antiviral activities in infected and neighboring cells by the induction and expression of a variety of genes (interferon-stimulated genes, ISGs)...