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Dengue Virus: Epidemiology, Pathogenesis, and Emerging Challenges, Study notes of Immunology

University of HyderabadImmunology

A comprehensive overview of the dengue virus (denv), including its classification, epidemiology, structure, pathogenesis, clinical manifestations, immune response, vaccine development, diagnostics, and treatment. It delves into the viral life cycle, immune evasion mechanisms, the role of the non-structural protein ns1, and the impact of host genetics on the immune response. The document also highlights emerging research topics, such as viral quasispecies, innate immune modulators, and therapeutic targets, as well as the challenges in vaccine development. Additionally, it touches on the global and public health perspectives, including epidemic prediction, response, and vector control innovations. This in-depth exploration of dengue virus can be valuable for students, researchers, and healthcare professionals interested in understanding the complexities of this significant global health concern.

Typology: Study notes

2023/2024

Available from 08/14/2024

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Immunology Topics - Dengue Virus
1. Introduction to Dengue Virus (DENV)
Classification:
oFamily: Flaviviridae
oGenus: Flavivirus
oFour serotypes: DENV-1, DENV-2, DENV-3, DENV-4
Epidemiology:
oTransmitted primarily by Aedes aegypti and Aedes albopictus mosquitoes.
oFound in tropical and subtropical regions around the world.
oApproximately 390 million infections annually, with 96 million manifesting
clinically.
2. Structure of Dengue Virus
Genome:
oPositive-sense single-stranded RNA (~10.7 kb).
oEncodes a single polyprotein, cleaved into three structural (C, prM/M, E) and
seven non-structural (NS) proteins.
Viral Proteins:
oCapsid (C): Forms the viral nucleocapsid.
oMembrane (prM/M): Protects the E protein during assembly.
oEnvelope (E): Major antigenic determinant; involved in viral attachment and
entry into host cells.
oNS Proteins: Key roles in replication (NS1, NS3, NS5) and immune evasion
(NS1, NS2A).
3. Pathogenesis of Dengue Virus
Viral Entry and Replication:
oDENV enters host cells via receptor-mediated endocytosis, primarily in
monocytes, dendritic cells, and endothelial cells.
oThe virus uncoats in the endosome, releasing RNA into the cytoplasm, where
translation and replication occur.
Immune Response:
oInnate Immunity: Activation of pattern recognition receptors (PRRs) like
TLR3, RIG-I, and MDA5, leading to the production of type I interferons.
oAdaptive Immunity: Involves both humoral (antibodies) and cellular (T-
cells) responses.
oAntibody-Dependent Enhancement (ADE): Non-neutralizing antibodies
from a previous infection can enhance viral entry and replication in Fc
receptor-bearing cells, leading to more severe disease.
pf3
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pf5

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Immunology Topics - Dengue Virus

1. Introduction to Dengue Virus (DENV)Classification : o Family: Flaviviridae o Genus: Flavivirus o Four serotypes: DENV-1, DENV-2, DENV-3, DENV-  Epidemiology : o Transmitted primarily by Aedes aegypti and Aedes albopictus mosquitoes. o Found in tropical and subtropical regions around the world. o Approximately 390 million infections annually, with 96 million manifesting clinically. 2. Structure of Dengue VirusGenome : o Positive-sense single-stranded RNA (~10.7 kb). o Encodes a single polyprotein, cleaved into three structural (C, prM/M, E) and seven non-structural (NS) proteins.  Viral Proteins : o Capsid (C) : Forms the viral nucleocapsid. o Membrane (prM/M) : Protects the E protein during assembly. o Envelope (E) : Major antigenic determinant; involved in viral attachment and entry into host cells. o NS Proteins : Key roles in replication (NS1, NS3, NS5) and immune evasion (NS1, NS2A). 3. Pathogenesis of Dengue VirusViral Entry and Replication : o DENV enters host cells via receptor-mediated endocytosis, primarily in monocytes, dendritic cells, and endothelial cells. o The virus uncoats in the endosome, releasing RNA into the cytoplasm, where translation and replication occur.  Immune Response : o Innate Immunity : Activation of pattern recognition receptors (PRRs) like TLR3, RIG-I, and MDA5, leading to the production of type I interferons. o Adaptive Immunity : Involves both humoral (antibodies) and cellular (T- cells) responses. o Antibody-Dependent Enhancement (ADE) : Non-neutralizing antibodies from a previous infection can enhance viral entry and replication in Fc receptor-bearing cells, leading to more severe disease.

4. Clinical ManifestationsDengue Fever (DF) : o Symptoms: High fever, severe headache, retro-orbital pain, myalgia, arthralgia, rash. o Typically self-limiting, but may progress to severe dengue.  Severe Dengue (Dengue Hemorrhagic Fever/Dengue Shock Syndrome) : o Characterized by plasma leakage, severe bleeding, and organ impairment. o Pathophysiology: Increased vascular permeability, leading to hemoconcentration and potentially shock. 5. ImmunopathogenesisCytokine Storm : Overproduction of pro-inflammatory cytokines (IL-6, TNF-α, IL- 10) leading to systemic inflammation.  Vascular Leakage : Mediated by immune complexes, complement activation, and inflammatory cytokines.  Thrombocytopenia : Decreased platelet production and increased destruction; immune-mediated mechanisms.  NS1 Protein : o Soluble NS1 contributes to endothelial dysfunction, complement activation, and vascular leakage. o Elicits a strong antibody response, but also involved in ADE and immune complex formation. 6. Host Immune ResponseInnate Immune Response : o Activation of PRRs, leading to IFN-α/β production and the antiviral state. o DENV evades immune detection by NS proteins interfering with signaling pathways (e.g., inhibition of IFN signaling by NS5).  Adaptive Immune Response : o B cells : Production of antibodies against E and NS1 proteins. Memory B cells play a role in secondary infections. o T cells : CD4+ T cells produce cytokines; CD8+ T cells kill infected cells. Cross-reactive memory T cells may contribute to immunopathology. 7. Vaccine DevelopmentChallenges : o Four serotypes: Immunity to one serotype increases the risk of severe disease upon subsequent infection with another serotype due to ADE. o Balancing immune responses across all serotypes is critical.  Current Vaccines : o Dengvaxia (CYD-TDV): First licensed vaccine; provides partial protection but may increase the risk of severe dengue in seronegative individuals. o Live-attenuated Vaccines : Under development, designed to induce balanced immunity to all four serotypes.

o The NS proteins, particularly NS3 (helicase/protease) and NS5 (RNA- dependent RNA polymerase), are crucial for viral RNA replication. o The viral RNA is replicated within the host cell's ER-derived membrane vesicles, forming double-stranded RNA intermediates.  Assembly and Release: o Newly synthesized viral RNA is packaged into nucleocapsids, which are then enveloped by a membrane containing prM and E proteins. o Immature virions bud into the ER and are transported through the Golgi apparatus, where furin cleavage of prM to M results in mature virions. o Mature virions are released from the cell via exocytosis, ready to infect new cells.

  1. Immune Evasion Mechanisms  Interference with Interferon Signaling: o DENV NS proteins, particularly NS2A, NS4A, NS4B, and NS5, interfere with the JAK-STAT signaling pathway, preventing the activation of antiviral genes by type I interferons. o NS5 mediates the degradation of STAT2, a critical transcription factor in the interferon signaling cascade.  Subversion of Antigen Presentation: o DENV infection can downregulate MHC class I and II molecules, impairing the ability of infected cells to present viral antigens to T cells. o This subversion delays the activation of the adaptive immune response, allowing the virus to replicate unhindered during the early stages of infection.  Modulation of Apoptosis: o DENV can manipulate apoptotic pathways to favor its replication. For instance, NS4A has been shown to inhibit apoptosis by interacting with mitochondrial pathways, promoting cell survival and prolonged viral production.
  2. Role of Non-Structural Protein 1 (NS1)  NS1 as a Diagnostic Marker: o NS1 is secreted into the bloodstream during the early stages of infection and can be detected as early as day one post-infection, making it a valuable diagnostic marker.  NS1 and Pathogenesis: o NS1 interacts with various components of the complement system, such as C4, leading to complement activation and contributing to the inflammatory response. o It also disrupts endothelial cell integrity, which is a critical factor in the vascular leakage observed in severe dengue cases.  NS1 in Vaccine Development: o As NS1 is a highly immunogenic protein, it is a candidate for vaccine development. However, its role in immune evasion and disease severity presents challenges.
  1. Antibody-Dependent Enhancement (ADE)  Mechanism: o During a secondary dengue infection with a different serotype, pre-existing antibodies from the primary infection may bind to the virus without neutralizing it. o These virus-antibody complexes can then interact with Fcγ receptors on monocytes and macrophages, facilitating viral entry and increasing viral load.  Impact on Disease Severity: o ADE is associated with the progression to severe dengue, including dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). o This phenomenon complicates vaccine development because a vaccine must provide balanced and effective immunity against all four serotypes to avoid enhancing disease.
  2. Host Genetics and Immune Response  Genetic Factors: o Certain HLA alleles are associated with susceptibility or resistance to severe dengue. For example, HLA-DR alleles can influence T-cell responses to DENV antigens. o Polymorphisms in genes related to the immune response, such as those encoding cytokines (e.g., TNF-α, IL-10) or pattern recognition receptors (e.g., TLRs), may affect the severity of the disease.  Immune Response Variability: o The immune response to DENV varies significantly between individuals, influenced by factors such as age, genetic background, and the presence of co- infections or comorbidities. o For instance, young children and elderly individuals are more susceptible to severe dengue due to their less robust immune responses.
  3. Emerging Research Topics  Viral Quasispecies: o DENV exists as a quasispecies within the host, with a population of closely related but genetically distinct variants. o The diversity within these viral populations can influence pathogenesis, immune evasion, and the response to vaccines or antiviral therapies.  Innate Immune Modulators: o Research is ongoing to identify host factors that modulate the innate immune response to DENV, such as interferon-stimulated genes (ISGs) that can either promote or inhibit viral replication.  Therapeutic Targets: o Novel therapeutic strategies are focusing on disrupting the interaction between DENV and host factors essential for viral replication, such as the use of small molecules targeting NS3 helicase or NS5 polymerase.