Abstract
Arenaviruses merit interest both as tractable experimental model systems to study acute and persistent viral infections, and as clinically-important human pathogens. Several arenaviruses cause hemorrhagic fever (HF) disease in humans. In addition, evidence indicates that the globally-distributed prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) is a human pathogen of clinical significance in congenital infections, and also poses a great danger to immunosuppressed individuals. Arenavirus persistence and pathogenesis are facilitated by their ability to overcome the host innate immune response. Mammalian hosts have developed both membrane toll-like receptors (TLR) and cytoplasmic pattern recognition receptors (PRRs) that recognize specific pathogen-associated molecular patterns (PAMPs), resulting in activation of the transcription factors IRF3 or IRF7, or both, which together with NF-κB and ATF-2/c-JUN induce production of type I interferon (IFN-I). IFN-I plays a key role in host anti-microbial defense by mediating direct antiviral effects via up-regulation of IFN-I stimulated genes (ISGs), activating dendritic cells (DCs) and natural killer (NK) cells, and promoting the induction of adaptive responses. Accordingly, viruses have developed a plethora of strategies to disrupt the IFN-I mediated antiviral defenses of the host, and the viral gene products responsible for these disruptions are often major virulence determinants. IRF3- and IRF7-dependent induction of host innate immune responses is frequently targeted by viruses. Thus, the arenavirus nucleoprotein (NP) was shown to inhibit the IFN-I response by interfering with the activation of IRF3. This NP anti-IFN activity, together with alterations in the number and function of DCs observed in mice chronically infected with LCMV, likely play an important role in LCMV persistence in its murine host. In this review we will discuss current knowledge about the cellular and molecular mechanisms by which arenaviruses can subvert the host innate immune response and their implications for understanding HF arenaviral disease as well as arenavirus persistence in their natural hosts.
Highlights
The ability to rescue infectious arenaviruses including lymphocytic choriomeningitis virus (LCMV) [41,42], Junin virus (JUNV) [43] and Pichinde virus (PICV) [44] entirely from cloned complementary DNAs has provided investigators with new avenues to start examining the relationship between predetermined mutations within the virus genome and specific phenotypes, which in the case of LCMV can be assessed in the context of virus infection of its natural host the mouse
pathogen-associated molecular patterns (PAMPs) recognition by toll-like receptors (TLR), C-type lectin receptors, RLRs and cytoplasmic DNA sensors leads to the activation of signaling pathways that culminate in the activation of transcription factors such as interferon regulatory factor (IRF), nuclear factor (NF)- B and activating transcription factor (ATF) 2/cJun that translocate into the nucleus and activate the transcription of inflammatory cytokines or IFN-I, or both [57,96,97,99,100,101,102,103,104]
Viruses have evolved a variety of strategies aimed at impairing IFN-I production. These can be grouped as follows: (1) reducing the number of specialized IFN-producing cells or impairing their functional capacity; (2) limiting access of viral PAMPs to pattern recognition receptors (PRRs) involved in IFN-I induction; (3) disrupting the intracellular signaling pathways involved in IFN-I induction following PRR ligation; and (4) blocking the positive feedback loop involved in amplification of IFN-I production
Summary
Studies using the prototypic arenavirus LCMV have uncovered many key concepts in virology and immunology that have been found subsequently to apply universally to other viral infections of humans, including virus-induced immunopathological disease, T cell-mediated killing of virus-infected cells and major histocompatibility complex (MHC) restriction of T cell responses [1,2]. The outcome of LCMV infection of its natural host, the mouse, varies dramatically depending on the strain, age, immunocompetence and genetic background of the host, as well as the route of infection and the strain and dose of infecting virus [1,2,3]. This feature of murine LCMV infection provides investigators with a unique model system in which to investigate parameters that critically influence many aspects of virus-host interaction, including those responsible for the heterogeneity of phenotypic manifestations often seen during infections with the same virus
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