L11 - Dengue virus immunity and vaccination part 1 ( Laura Rivino) Flashcards
• To describe the characteristics and global burden of dengue • To describe the host adaptive immune response to dengue virus • To describe the role of altered adaptive immune responses in dengue pathology (antibody-dependent enhancement and original antigenic sin)
What is dengue?
🦠 Dengue is a rapidly spreading viral infection caused by an arbovirus. It is transmitted by mosquitoes and is a major global health concern.
How common is dengue
📊 An estimated 390 million infections occur each year, but only 96 million cases show clinical symptoms.
How many severe cases of dengue occur annually?
⚠️ About 500,000 cases of severe dengue (Dengue Hemorrhagic Fever (DHF) and Dengue Shock Syndrome (DSS)) occur annually, leading to 20,000 deaths, mainly in children and young adults.
Where is dengue commonly found
🌍 Dengue is mainly found in tropical and subtropical regions but has been spreading geographically in recent years.
What type of virus is dengue?
🧬 Dengue is a single-stranded RNA virus belonging to the Orthoflavivirus family (previously Flavivirus).
What other viruses are related to dengue?
🦠 Dengue is related to:
Zika virus
Yellow fever virus
West Nile virus
How is dengue transmitted?
🦟 Dengue is transmitted through the bite of Aedes mosquitoes, primarily Aedes aegypti, but Aedes albopictus can also spread it.
How many serotypes of dengue exist?
🔬 There are four infectious serotypes of dengue: DENV-1, DENV-2, DENV-3, and DENV-4.
Why is it difficult to develop a dengue vaccine?
🧩 A vaccine must provide protection against all four serotypes to be effective, which makes it challenging to design.
Is there a specific treatment for dengue?
🚫 No. There is no antiviral treatment for dengue. Management includes fluids, pain relief (paracetamol), and supportive care.
Are there vaccines for dengue ( if so what are they?)
💉 Yes, there are two licensed vaccines:
Dengvaxia (Sanofi Pasteur)
Qdenga (Takeda Pharmaceuticals)
However, they are only partially protective and have some limitations.
What are the concerns with Dengvaxia?
⚠️ Dengvaxia can increase the risk of severe dengue in people who have never been previously infected with the virus.
How has dengue incidence changed over time?
📈 Dengue cases have steadily increased from the 1950s to the present, with 2023 recording the highest number of cases ever reported.
What are the mosquito species transmit dengue?
🦟 The primary mosquito vector is Aedes aegypti, but Aedes albopictus can also spread the virus.
Where is dengue now spreading to
🌍Dengue is now being reported in European countries, particularly in coastal areas of Italy, Spain, France, and Croatia during the summer months.
Why is dengue spreading in Europe?
🦟 The mosquito Aedes albopictus spreads via travelers who are infected in dengue-endemic regions bring the virus back. Local mosquitoes bite these infected travelers and then spread the virus.
Can dengue be transmitted locally in Europe ( example case study)
✅ In the summer of 2023, Italy recorded 42 local dengue infections in people who had never traveled to endemic regions, proving that local transmission is happening.
Why do dengue cases in Europe drop in the winter?
❄️ Winters are too cold for Aedes mosquitoes to survive, leading to a drop in cases. However, with climate change, this could change in the future.
How severe is the dengue outbreak in South America?
🌎 Central and South America have experienced very high dengue cases, making it one of the worst-hit regions.
What is the incubation period for dengue?
⏳ After being bitten by an infected mosquito, symptoms usually appear within 5 days.
What is viremia in dengue?
🩸 Viremia refers to the presence of dengue virus in the blood. It peaks during the first few days of infection and then declines.
When do symptoms of dengue appear?
🤒 Symptoms start around day 5 after infection, usually coinciding with the peak of viremia and fever.
What is the critical phase of dengue?
⚠️ The critical phase occurs around days 4–5, after the fever subsides. This is when patients are at highest risk of developing severe dengue.
Why is it challenging to predict severe dengue cases?
🔬 Severe dengue only becomes apparent after day 4, by which time the virus is no longer detectable in the blood, making early identification difficult.
What are the common symptoms of dengue fever?
🤕 Dengue fever symptoms include:
High fever
Severe headaches
Muscle and joint pain (“breakbone fever”)
Severe eye pain
Extreme fatigue
How does dengue affect recovery?
⚡ Even after recovery, dengue can leave patients debilitated for a long time, causing extreme fatigue.
What percentage of dengue cases become severe?
📉 Around 5–10% of dengue cases progress to severe dengue.
What are the case number of asymtomatic and/ or unreported cases of Dengue vs DHF and or / DSS (Nat Rev Immunology 2019)
Asymtomatic and / or unreported = 294 million
DHF and / or DSS = 96 million
How did the WHO classify severe dengue?
📚 The old WHO classification divided severe dengue into:
Dengue Hemorrhagic Fever (DHF)
Dengue Shock Syndrome (DSS)
While these terms are still used, the classification has been updated.
Why did WHO introduce the 2009 dengue classification?
✅ WHO introduced it to help with patient triaging by identifying patients at risk of developing severe dengue.
What are the two categories of non-severe dengue?
1️⃣ Dengue without warning signs
2️⃣ Dengue with warning signs (higher risk of progressing to severe dengue)
What are the general symptoms of probable dengue?
🤒 Fever plus two or more of the following:
Nausea/vomiting
Rash
Aches and pains
Leukopenia (low white blood cells)
Positive Tourniquet test
What are the warning signs of dengue?
⚠️ Warning signs (indicate risk of progression to severe dengue):
Persistent vomiting
Mucosal bleeding
Severe abdominal pain or tenderness
Liver enlargement (>2 cm)
Lethargy/restlessness
Fluid accumulation
Increased hematocrit with rapid platelet drop
What is severe dengue?
🛑 Severe dengue is a life-threatening form of the disease that involves:
Severe plasma leakage → Shock (DSS) or fluid accumulation → Respiratory distress
Severe hemorrhage
Severe organ impairment
What causes severe plasma leakage in dengue?
🩸 Increased vascular permeability allows plasma to leak out of blood vessels, leading to:
Fluid accumulation in tissues
Respiratory distress
Hypovolemic shock
What is Dengue Shock Syndrome (DSS)?
💥 DSS occurs when severe plasma leakage leads to hypovolemic shock, which can be fatal if untreated.
What causes severe bleeding in dengue?
🩸 Severe bleeding is caused by widespread blood vessel damage, which leads to:
Mucosal bleeding (e.g., gums, nosebleeds)
Internal hemorrhages
Organ bleeding
What organs can be affected in severe dengue?
🫀 Severe organ involvement can affect:
Liver (AST/ALT ≥ 1000)
CNS (impaired consciousness)
Heart and other organs
What is the role of the immune system in severe dengue?
⚠️ Severe dengue is associated with an immune-mediated “cytokine storm,” where the immune system overreacts and damages tissues.
Why is the mechanism of severe dengue still unclear?
🧐 Despite decades of research, the exact mechanisms of the cytokine storm and disease severity are not fully understood, though some studies suggest possible pathways.
What is the most well-characterized risk factor for severe dengue?
⚠️ Secondary dengue infection (infection with a different serotype) greatly increases the risk of severe disease.
what are 5 host risk factors for severe dengue
- Secondary dengue infection
- Age
- Co-morbidities (hypertension and diabetes)
- Obesity / overweight
- Genetic polymorphisms
How does a secondary dengue infection increase severity?
🦠 The immune response to the first dengue infection can worsen the second infection through a process called Antibody-Dependent Enhancement (ADE).
How does age influence the risk of severe dengue?
👶🧓 Extremes of age (young children and the elderly) are at higher risk of severe disease due to weaker immune responses and other physiological factors.
What common comorbidities increase the risk of severe dengue?
🩸 Hypertension and diabetes increase the risk due to:
Weakened immune response
Increased inflammation
Vascular damage
( dengue spreading more globally in countrues where we have these problems )
How does obesity affect dengue severity?
⚖️ Obesity and overweight increase the risk of severe dengue, likely due to:
Higher inflammation levels
Altered immune response
Increased vascular permeability
What genetic factors influence susceptibility to severe dengue?
🧬 Several genetic polymorphisms have been linked to increased risk:
1️⃣ MICB, PLCE1 (Genome-Wide Association Studies - GWAS)
2️⃣ TNF-α, IL-10 (Key inflammatory cytokines)
3️⃣ HLA Class I & II (Influences T-cell responses)
Why is the MICB gene important in dengue severity?
🧬 The MICB gene is involved in immune activation and its polymorphisms may affect how the immune system responds to dengue.
What role do cytokines like TNF-α and IL-10 play in severe dengue?
🦠 TNF-α and IL-10 regulate inflammation and immune responses, but their dysregulation can contribute to severe dengue and cytokine storm.
How do HLA Class I and II polymorphisms affect dengue severity?
⚠️ HLA molecules help present viral antigens to the immune system. Certain variations may lead to:
Weaker immune response
Increased viral replication
Higher risk of severe disease
What are the typical skin manifestations of dengue?
🩸 Skin rashes and petechiae (small red spots caused by minor bleeding) are common.
How does severe plasma leakage affect the lungs?
💨 Fluid accumulation in the lungs can cause respiratory distress and difficulty breathing.
What happens when a patient goes into dengue shock syndrome (DSS)?
🛑 In DSS, plasma leakage leads to hypovolemic shock, which can cause:
Low blood pressure
Organ failure
Death if untreated
What is the highest risk factor for severe dengue?
⚠️ Secondary heterologous infection (infection with a different dengue serotype) is the greatest risk factor for severe dengue.
How does the risk of severe dengue change with each infection?
1️⃣ First infection → Medium risk
2️⃣ Second (heterologous) infection → Highest risk
3️⃣ Third & fourth infections → Low risk
🦠 This suggests that subsequent infections may induce broader immunity.
What is the adaptive immune response?
🛡️ It’s a pathogen-specific defense system that develops immunological memory. It consists of:
1️⃣ B cells → Produce antibodies
2️⃣ T cells → Release cytokines & kill infected cells
What are the two main types of T cells in adaptive immunity?
🦠 CD8+ T cells (Cytotoxic T cells) → Recognize infected cells and kill them.
🦠 CD4+ T cells (Helper T cells) → Coordinate the immune response by activating B cells & CD8+ T cells.
How do T cells recognize dengue virus?
T cells recognize viral peptides presented on:
🧬 MHC Class I → CD8+ T cells (intracellular viral antigens)
🧬 MHC Class II → CD4+ T cells (extracellular/endocytosed viral antigens)
How does MHC Class I present dengue antigens?
🦠 Intracellular viral proteins are:
Intracellular dengue degraded by the proteasome of the cell
Transported via TAP molecules
Loaded onto MHC Class I in the ER
Presented to CD8+ T cells on the cell surface
How does MHC Class II present dengue antigens?
🦠 Extracellular/endocytosed viral proteins are:
Dengue endocytosed
Degraded in endosomes
Loaded onto MHC Class II
Presented to CD4+ T cells
Is there cross-presentation between MHC Class I and Class II?
🔄 Yes! Some endocytosed antigens (normally MHC Class II) can be cross-presented on MHC Class I, activating CD8+ T cells.
What are the 3 phases of a primary T cell response
- Expansion
- Contraction
- memory
What happens when a naïve T cell first encounters an antigen?
🔬 Activation Process:
1️⃣ Recognizes antigen via T-cell receptor (TCR) on an antigen-presenting cell (APC) (e.g., dendritic cell)
2️⃣ Proliferates extensively (10⁴–10⁵ fold expansion)
3️⃣ Undergoes transcriptional changes to differentiate into effector cells
What happens after T cell activation?
📉 Contraction phase: After clearing the infection, 90–95% of effector T cells die off, while 5–10% survive as memory T cells.
🛡️ Memory cells persist long-term and provide faster, stronger responses upon re-exposure.
What allows T cells to survive and become memory cells?
🧬 Expression of IL-7 receptor α chain (CD127)
⚡ IL-7 signaling helps memory T cells survive and proliferate in the absence of antigen.
What does a typical T cell response to an acute virus look like?
📊 Phases of response:
1️⃣ Viral load increases → Virus replicates
2️⃣ T cells get activated & proliferate → Slightly delayed peak compared to viremia
3️⃣ Contraction phase → Most T cells die, but some survive as memory cells
4️⃣ Memory cells persist for a lifetime → Faster response upon re-exposure
How rare is it for a naïve T cell to encounter its specific antigen?
🔎 Precursor frequency of antigen-specific naïve T cells: ~1 in 100,000 (similar in humans & mice).
🚀 Memory T cells have a much higher precursor frequency → Faster immune response to repeat infections.
What are the key characteristics of memory T cells?
🧬 Clonally expanded from naïve T cells
⚡ Low activation threshold → Faster & stronger response
🛡️ Immediate protection against reinfection
🕰️ Persist for a lifetime without antigen
🌍 Highly heterogeneous (different subsets with unique functions & migration patterns)
What happens during a primary dengue infection?
🦟 Mosquito bite → Incubation period → Viremia develops
📈 Viremia peaks early (~Day 2-3)
🔬 T cell response peaks later (~Day 8-9)
🛡️ B cell activation leads to IgM production (~Day 1) → IgG appears (~Day 5-6)
How does a secondary dengue infection differ from a primary infection?
🚀 Higher & more rapid viremia (due to pre-existing immunity)
🔄 Tighter viremia curve (cleared faster by antibodies)
⚠️ Increased risk of severe dengue (~Day 5) → Associated with vascular permeability increase
What is the “critical phase” in dengue?
⚠️ Occurs around Day 5 (as fever and viremia subside)
💧 Vascular permeability increases → Risk of shock & severe dengue
💀 Dangerous complications include plasma leakage, organ failure, and hemorrhage
How is severe dengue associated with viremia levels?
📈 Higher viremia early in illness → Greater risk of severe dengue
🔬 Studies confirm this across different serotypes and immune statuses
⚠️ Higher plasma viremia in the febrile phase predicts later severe dengue
What is the structure of the dengue virus genome?
🧬 RNA virus → Encodes one polyprotein
🔪 Polyprotein is cleaved into:
✅ 3 Structural proteins: Capsid (C), Membrane (M), Envelope (E)
✅ 7 Nonstructural (NS) proteins: NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5
What are + the function of the dengue virus nonstructural proteins?
🛠️ NS proteins help with viral replication & immune evasion
⚙️ NS5 = RNA polymerase (essential for viral replication)
🦠 NS1 = Immune evasion, endothelial dysfunction
⚡ NS3 = Protease + helicase (processes polyprotein)
How does the structure of mature vs. immature dengue virus differ?
🔘 Mature Dengue Virus:
Smooth surface → Formed by E protein dimers in an antiparallel arrangement
Infectious form of the virus
🔺 Immature Dengue Virus:
Spiky surface → Due to PRM precursor peptide
Must be cleaved to become infectious
How does dengue virus assemble & get released from the cell?
🏗️ Polyprotein synthesis at the ER membrane
🔪 Host & viral proteases cleave polyprotein into functional components
🚀 Virus assembly occurs, then virus exits the cell to infect new cells
Which dengue proteins do T cells target?
🎯 All dengue proteins are targeted to some extent
💪 Stronger responses to nonstructural proteins:
🔹 NS3 (most dominant)
🔹 NS5 (second most targeted)
How was T cell targeting studied in dengue patients?
- Patient Samples
Peripheral Blood Mononuclear Cells (PBMCs) were collected from dengue patients.
Samples were taken at different stages of infection:
Acute phase (after fever subsides, post-febrile stage)
Convalescent phase (3-4 months after infection) - Overlapping Peptide Library
The entire dengue viral genome was broken into short overlapping peptides.
These peptides covered:
Structural proteins (Capsid, Membrane, Envelope)
Nonstructural proteins (NS1, NS2A/B, NS3, NS4A/B, NS5)
Why? 🔍 To determine which parts of the virus triggered the strongest T cell response. - IFN-γ ELISpot Assay
PBMCs were stimulated with dengue virus peptides.
If a T cell recognized a peptide, it would release interferon-gamma (IFN-γ).
IFN-γ secretion was detected as spots in the ELISpot assay.
The more spots, the stronger the immune response
What are the strengths and limitations of ELISpot for studying T cell responses?
✅ Strengths:
🔹 High throughput
🔹 Detects antigen-specific T cell responses
🔹 Sensitive for measuring cytokine production
❌ Limitations:
🔸 Cannot differentiate between CD4+ & CD8+ T cells
🔸 Does not provide functional information on T cells
What is the significance of the dominant T cell response to NS3 & NS5?
🦠 NS proteins = Key for viral replication → Strong immune response
🛡️ NS3 & NS5 responses may be important for viral clearance
🧐 Possible targets for vaccine development
What technique was used to determine whether the dengue-specific T cell response was mediated by CD4 or CD8 T cells?
🧪🔬 Flow cytometry and intracellular cytokine staining were used to analyze the type of T cell response.
What did flow cytometry reveal about the dengue-specific T cell response?
The majority of the T cell response was mediated by CD8 T cells (🔵), but there was also a CD4 T cell response (🟢).
Which dengue virus proteins were predominantly targeted by CD8 T cells?
🦠🎯CD8 T cells mainly targeted non-structural proteins NS3 and NS5.
Which dengue virus proteins were predominantly targeted by CD4 T cells?
🏗🛡CD4 T cells mainly targeted structural proteins like capsid (C) and envelope (E), but some also recognized NS3.
What was observed regarding the magnitude of CD8 versus CD4 T cell responses?
📈🔥Dengue-specific CD8 T cell responses were stronger in magnitude compared to CD4 T cell responses.
What did Alex Sette’s study reveal about the breadth and focus of the T cell response?
🎯🧬Although the T cell response is broad, it is focused on specific immunodominant regions.
How did the study map the immunodominant regions of the dengue virus
Using IFN-γ ELISpot, they tested 11 donors and identified regions recognized by most patients. 🧫📊
What was a key finding about the distribution of T cell responses across antigenic regions?
50% of the total response was concentrated in just 25 antigenic regions, showing a focused but broad response. 🎯🦠
Why is identifying immunodominant regions important for vaccine design?
It helps in designing vaccines that target the most commonly recognized T cell epitopes, improving immune responses. 💉🛡
How does dengue virus enter the body, and what happens immediately after?
🦟🧑⚕️ Dengue virus enters through the skin via a mosquito bite. The viral antigens are picked up by local dendritic cells, such as Langerhans cells, which then migrate to the draining lymph nodes to present the antigens to T cells.
What happens when T cells recognize antigens presented by skin dendritic cells?
🩸🌿T cells develop a skin-homing phenotype, characterized by the expression of CLA (cutaneous lymphocyte antigen). These T cells are primed in the skin, enter the blood, and later migrate back to the skin.
What marker do dengue-specific T cells express in the blood during acute infection?
🏥🔬During acute infection, dengue-specific T cells in the blood express CLA, indicating skin homing.
What additional marker do dengue-specific T cells express as the infection progresses?
🏥🫀 Over time, they begin expressing CXCR6, a liver-homing molecule, as dengue virus spreads through the blood and infects the liver.
How does dengue spread after the initial infection?
🦠🩸The virus starts in the skin but later spreads systemically via the bloodstream, reaching organs like the liver.
Aside from T cells and antibodies, what other immune cells play a role in dengue infection?
⚔️🧪Mast cells in the skin recognize dengue and release granules containing inflammatory mediators. They also produce cytokines, which help recruit T cells and NK cells to the infection site.
How might mast cells contribute to severe dengue symptoms?
🩸⚠️They may play a role in vascular permeability, a key feature of severe dengue, by releasing inflammatory mediators that affect blood vessel integrity.
Why is secondary dengue infection a significant risk factor for severe disease?
🔄🦠 Secondary infection suggests a role for the adaptive immune response in dengue immunopathology. Pre-existing antibodies from a prior infection can either neutralize the virus or, if suboptimal, lead to antibody-dependent enhancement (ADE), increasing viral replication.
What is antibody-dependent enhancement (ADE) in dengue?
🛡️➡️🦠ADE occurs when suboptimal antibodies bind to dengue virus but fail to neutralize it. Instead, the Fc portion of the antibody interacts with Fc receptors on monocytes and macrophages, facilitating viral entry and increasing viral load.
Who first described antibody-dependent enhancement (ADE) in dengue?
Scott Halstead proposed ADE in 1973 based on epidemiological studies, identifying how pre-existing antibodies can either protect or worsen dengue infection.
How does the efficiency of ADE compare to neutralization in dengue infections?
📉⚠️ADE occurs at half the antibody concentration required for neutralization. This means that low-affinity, cross-reactive, or waning antibodies can enhance viral infection instead of preventing it.
What types of antibodies are most likely to cause ADE?
ADE is mediated by:
1️⃣ Cross-reactive, low-affinity antibodies from a previous infection.
2️⃣ Low antibody concentration due to waning immunity.
3️⃣ Antibodies targeting specific epitopes, such as prM (precursor membrane protein).
How does prM contribute to dengue infection through ADE?
🔗🦠Immature dengue virions contain prM, making them non-infectious initially. However, if antibodies bind to prM, the virus can enter cells via Fc receptor-mediated internalization, allowing it to replicate and cause infection.
What are extrinsic and intrinsic ADE in dengue?
🏡 Extrinsic ADE occurs when virus-bound antibodies enhance Fc receptor-mediated internalization into immune cells.
🛑Intrinsic ADE occurs when this process interferes with innate immune signaling, reducing type I interferon responses and antiviral defenses.
How does intrinsic ADE suppress the innate immune response?
The virus-bound antibodies allow suboptimal coating, leaving sites exposed for LILRB1 binding. This recruits SHP-1, which dephosphorylates SYK, blocking the expression of interferon-stimulated genes (ISGs) and weakening antiviral defenses.
What is the role of Fc receptors in ADE?
Fcγ receptors I, IIa, and III mediate dengue internalization. Though they are activating receptors, ADE paradoxically suppresses type I interferon responses, enabling higher viral replication. 🔗🦠
What did a 2017 study reveal about ADE in vivo?
A Nicaraguan pediatric cohort study tracked children over 12 years and found that those with mid-range antibody levels (1:21-1:80 dilution) had a higher risk of severe dengue (DHF/DSS). This provided strong evidence that ADE occurs in vivo. 📊🧪👶
How does antibody concentration affect the risk of severe dengue?
🪬 High antibody levels provide protection,
🤷🏻♀️ very low levels do not significantly impact risk.
📈 specific mid-range antibody concentration increases susceptibility to severe dengue, likely due to ADE
What is fucosylation
🍓Fructosylation is a post translational modification where a fructose sugar is added to IgG
what do afucosylated IgG have increased affinity for
afucosylated IgGs have increased affinity for Fcγ receptor III, which is associated with severe dengue and ADE.
What did a recent study show about afucosylated IgG levels in severe dengue?
📊🦠⚠️Patients with severe dengue had higher levels of afucosylated IgG, including antibodies targeting Dengue Envelope (E) and NS1 proteins. This suggests a link between IgG glycosylation and disease severity.
What is the potential cause of afucosylated IgG in dengue?
🧩🧪The cause is unclear, but dengue antigens or microRNAs might interfere with fucosyltransferase 8 (FUT8), the enzyme responsible for IgG fucosylation. More research is needed to understand this mechanism.
How does dengue severity correlate with IgG fucosylation
🏥Severe dengue (hospitalized cases) showed higher afucosylated IgG levels, especially in secondary infections. However, mild dengue cases did not exhibit this pattern.
What percentage of human circulating IgG is fucosylated
~94%
What is original antigenic sin in the context of dengue virus?
🔄 Original antigenic sin occurs when memory T cells from a primary infection (e.g., DENV-3) are preferentially activated during a secondary infection (e.g., DENV-2). This can lead to either an effective response or a suboptimal response, depending on how well the TCR recognizes the new serotype’s peptides.
How do memory T cells contribute to dengue severity in secondary infections?
🚀Memory T cells have a low activation threshold and respond faster than naïve T cells. However, if they weakly recognize the new dengue serotype, they may be suboptimally activated, leading to ineffective viral clearance and increased immunopathology.
What happens when memory T cells are efficiently triggered during a secondary dengue infection?
💥If memory T cells from the primary infection recognize the secondary serotype well, they will kill infected cells efficiently, producing IFN-γ, CD107a, and granzymes, which help control the infection.
What happens when memory T cells are suboptimally triggered during a secondary dengue infection?
❌🩸If memory T cells weakly recognize the new dengue serotype, their response is inefficient, leading to poor viral clearance and possible immune-mediated pathology, contributing to severe dengue.
Does original antigenic sin always cause severe dengue?
💪No. Only 5-10% of secondary dengue infections lead to severe disease. In most cases, pre-existing memory T cells provide a protective advantage by responding rapidly and effectively.
What is the controversy surrounding T cell responses in dengue?
🥊 There is debate over whether T cells are protective or pathogenic in dengue. Some studies (e.g., Gavin Screaton’s and Alan Rothman’s groups) suggest that T cells contribute to immunopathology, while others argue they are protective against severe disease.
How does the controversy over T cell responses in dengue compare to the antibody response?
🤔Similar to antibody-dependent enhancement (ADE), T cells are essential for protection, but suboptimal activation (e.g., low-affinity TCR interactions) may contribute to disease severity rather than protection.
Why is it difficult to determine whether T cells are protective or pathogenic in dengue?
🛡️💥The role of T cells is complex and context-dependent. While they are crucial for immune defense, an inefficient or excessive T cell response may lead to immune-mediated damage rather than protection.
What did Gavin Screaton’s group find about the magnitude of T cell responses in dengue?
📈🤒Patients with dengue hemorrhagic fever (DHF) had a higher magnitude T cell response to all dengue proteins, particularly NS3, compared to patients with dengue fever (DF).
What method did Screaton’s group use to analyze T cell responses in dengue patients?
They used polychromatic flow cytometry with intracellular cytokine staining to measure interferon-gamma (IFN-γ), TNF-α, and CD107a expression.
How did the cytokine response differ between dengue fever (DF) and dengue hemorrhagic fever (DHF) patients?
DHF patients showed higher IFN-γ and TNF-α production in both primary and secondary infections, but CD107a expression (cytotoxicity marker) was not significantly different
How was the quality of the T cell response skewed in severe dengue?
⚖️🔥In DHF, T cells were more cytokine-producing (IFN-γ, TNF-α) and less cytotoxic, indicating a shift towards inflammatory rather than antiviral functions.
What is the significance of impaired T cell cytotoxic function in severe dengue?
🦠❌💣Instead of killing infected cells, T cells in DHF patients mainly produce inflammatory cytokines, which may contribute to immune-mediated pathology.
what did the GWAS study identify regarding genetic risk for severe dengue
identified two loci, MCB and PLC, where certain SNPs are linked to an increased risk of developing severe dengue.
What is MCB and when is it expressed?
😧MCB (Macrophage Colony Stimulating Factor) is a ligand expressed by cells when they are stressed or infected with the dengue virus.
What does MCB bind to, and what effect does this have on immune cells?
MCB binds to NKG2D, a receptor on NK cells and CD8+ T cells, activating their cytotoxic functions and enhancing their ability to kill infected cells.
How does the MCB-NKG2D interaction impact T cell responses?
💥 The interaction enhances the cytotoxic functions of NK and CD8+ T cells, which are crucial for fighting the dengue infection.
What is suggested by studies on T cell responses in dengue?
🤔 Studies suggest that the quality of T cell responses could be altered in individuals with specific genetic risk factors, particularly their ability to kill infected cells.
