Pathogenesis and virulence of flavivirus infections

Abstract

The Flavivirus genus consists of >70 members including several that are considered significant human pathogens. Flaviviruses display a broad spectrum of diseases that can be roughly categorised into two phenotypes – systemic disease involving haemorrhage exemplified by dengue and yellow Fever virus, and neurological complications associated with the likes of West Nile and Zika viruses. Attempts to develop vaccines have been variably successful against some. Besides, mosquito-borne flaviviruses can be vertically transmitted in the arthropods, enabling long term persistence and the possibility of re-emergence. Therefore, developing strategies to combat disease is imperative even if vaccines become available. The cellular interactions of flaviviruses with their human hosts are key to establishing the viral lifecycle on the one hand, and activation of host immunity on the other. The latter should ideally eradicate infection, but often leads to immunopathological and neurological consequences. In this review, we use Dengue and Zika viruses to discuss what we have learned about the cellular and molecular determinants of the viral lifecycle and the accompanying immunopathology, while highlighting current knowledge gaps which need to be addressed in future studies.

ISG15 driven cellular responses to virus infection

“…Autophagy functions as a cell intrinsic pathway to dispose intracellular pathogens -a process often manipulated by viruses to their own advantage [45][46][47][48]. ISGylation has been reported to regulate autophagy in several different ways during virus infection.…”

The Japanese Encephalitis Antigenic Complex Viruses: From Structure to Immunity

“…Severe neurological disease is more likely to afflict the elderly and immune-compromised individuals. Studies aimed at understanding the molecular basis of pathogenesis and the host immune response in these diverse scenarios, using in vitro and in vivo murine models such as mice with single or double knock-outs of effector molecules, their receptors or other components, helped identify cellular components and biomarkers critical for viral restriction and the spread of infection in peripheral tissues as well as identify factors that may contribute to neuro-invasive disease, immunopathology or exacerbation of outcomes toward severe disease [ 105 , 131 , 132 ]. In addition to the three structural proteins (E, C and prM), the flavivirus polyprotein encodes seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5) [ 53 ].…”

“…Pattern recognition receptors (PRRs) on mammalian antigen-presenting cells, Langerhans, human primary keratinocytes and dermal dendritic cells in the skin detect pathogen-associated molecular patterns (PAMPs) such as double-strand viral RNA. Binding of viral components triggers a downstream signaling cascade, beginning with the activation of one or more of the three kinds of receptors: retinoic-acid inducible gene-I (RIG-I)-like receptors (RLRs); melanoma-differentiation-associated-gene 5 (MDA5) in the cytoplasm; and nucleotide oligomerization domain (Nod)-like receptors (NLRs) and Toll-like receptors (TLR; e.g., TLR3, TLR7 and TLR8) in endosomes [ 132 , 133 , 134 , 135 ]. Activation of downstream adapter molecules with kinase activity (e.g., NEMO, IKKα, IKKβ; TBK, IKKε) activates transcription factors (e.g., IRF3 and IRF7) and NF-κB in a cell-type-specific manner [ 132 , 133 ].…”

“…Binding of viral components triggers a downstream signaling cascade, beginning with the activation of one or more of the three kinds of receptors: retinoic-acid inducible gene-I (RIG-I)-like receptors (RLRs); melanoma-differentiation-associated-gene 5 (MDA5) in the cytoplasm; and nucleotide oligomerization domain (Nod)-like receptors (NLRs) and Toll-like receptors (TLR; e.g., TLR3, TLR7 and TLR8) in endosomes [ 132 , 133 , 134 , 135 ]. Activation of downstream adapter molecules with kinase activity (e.g., NEMO, IKKα, IKKβ; TBK, IKKε) activates transcription factors (e.g., IRF3 and IRF7) and NF-κB in a cell-type-specific manner [ 132 , 133 ]. IRF1, IRF3, IRF5 and IRF7 all restrict WNV replication; however, IRF5 plays a non-redundant, immunomodulatory role in shaping the early immune response events via production of pro-inflammatory cytokines in the lymphoid tissues, but not type I interferons, and also affects the trafficking and activation of immune cells entering the draining lymph node [ 136 ].…”

Validation of Flavivirus Infectious Clones Carrying Fluorescent Markers for Antiviral Drug Screening and Replication Studies

“…The situation with DENV is more difficult as it comprises four antigenically different serotypes. Development of vaccine for DENV has therefore been hampered by the existence of cross-reaction between antibodies against one serotype with viruses belonging to another serotype; in such case virus may escape neutralization which leads to an antibody dependent enhancement (ADE) believed to be responsible for establishment of severe forms of the DENV disease (13).…”