Viral Innate Immune Evasion and the Pathogenesis of Emerging RNA Virus Infections

Abstract

Positive-sense single-stranded RNA (+ssRNA) viruses comprise many (re-)emerging human pathogens that pose a public health problem. Our innate immune system and, in particular, the interferon response form the important first line of defence against these viruses. Given their genetic flexibility, these viruses have therefore developed multiple strategies to evade the innate immune response in order to optimize their replication capacity. Already many molecular mechanisms of innate immune evasion by +ssRNA viruses have been identified. However, research addressing the effect of host innate immune evasion on the pathology caused by viral infections is less prevalent in the literature, though very relevant and interesting. Since interferons have been implicated in inflammatory diseases and immunopathology in addition to their protective role in infection, antagonizing the immune response may have an ambiguous effect on the clinical outcome of the viral disease. Therefore, this review discusses what is currently known about the role of interferons and host immune evasion in the pathogenesis of emerging coronaviruses, alphaviruses and flaviviruses.

Keywords: innate immune evasion; positive-sense single-stranded RNA viruses; type I and III interferons; viral pathogenesis.

Figure 1

Innate immune response to positive-stranded RNA viruses and interferon (IFN) signalling. (A) IFN production is induced when single-stranded RNA (ssRNA) (TLR7, RIG-I) or double-stranded RNA (dsRNA) (TLR3, RIG-I, MDA5) is detected in the cell. Signalling through these pattern recognition receptors (PRRs) will ultimately result in the translocation of NF-κB, IRF3 and IRF7 to the nucleus. These transcription factors then initiate production of IFNs and pro-inflammatory cytokines. (B) Type I IFNs bind to a receptor composed of IFNAR1 and IFNAR2, while type III IFNs signal through IFNLR1 and IL10RB. The two types of signalling pathways then converge and result in the expression of interferon-stimulated genes (ISGs).

Figure 2

Genome organization of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome-CoV (MERS-CoV). The genomes encode two large open reading frames (ORF1a and ORF1b), which contain 16 nonstructural proteins (1 to 16). ORF1b is transcribed after a −1 ribosomal frameshift (gray dot). The structural proteins (S, spike; E, envelope; M, membrane; N, nucleocapsid) and accessory proteins are expressed from subgenomic RNAs. Blue, green and yellow indicate the nonstructural, structural and accessory proteins, respectively.

Figure 3

Genome organization of alphaviruses. The genome encodes two ORFs, which contain the four nonstructural proteins (nsP) and the structural proteins (C, capsid; E, envelope). The structural proteins are expressed from a subgenomic promoter (SGP). Blue and green indicate the nonstructural and structural proteins, respectively.

Figure 4

Genome organization of flaviviruses. The genome encodes one ORF, which contains the seven nonstructural proteins (NS) and the structural proteins (C, capsid; prM, premembrane; E, envelope). Blue and green indicate the nonstructural and structural proteins, respectively.