subversion of early innate antiviral responses during antibody-dependent enhancement of dengue virus...
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Subversion of early innate antiviral responsesduring antibody-dependent enhancement of
Dengue virusinfection induces severe disease in
immunocompetent mice
Julia T. de Castro
MOST OF
THEM
UNIVERSIDADE FEDERAL DE MINAS GERAISIMMUNOFARMACOLOGY GROUP
Where is… I STUDY AND WORK!
Summary
• Introduction to Dengue• Antibody-Dependent Enhancement (ADE)• Methods• Results• Conclusion
Paper discussion
Dengue Fever• Tropical and subtropical disease• Transmitted by the bite of the female mosquito
Aedes aegypti • Female mosquitoes generally lay their eggs above
the water inside containers as tires, buckets, birdbaths, water storage jars, and flower pots.
dengue.org.br nature.com
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Dengue Map
Absent Improbable Probable Present
Dengue virus• DENV is a RNA virus• Four well-known serotypes (DENV1, DENV2,
DENV3 and DENV4)• A fifth type was discovered in 2013
Immune Response
• Infection of Langerhans cells• Innate immunity• Secretion of IFN• Infected cells go to lymph nodes• Adaptive immunity• Abs, complement, Cytotoxic T lymphocytes
Dengue fever
Severe Dengue
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How severe disease is developed?
Few hypotheses
Antibody-Dependent Enhancement (ADE)
Antibody-Dependent Enhancement (ADE)
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• Antibodies from the first infection are cross-reactive with other DENV serotypes
• But Abs are subneutralizing• FcγR recognizes Abs and internalizes immunocomplex • Evidences suggest that the mechanism is associated with both
increase in the number of infected cells, a phenomenon called “Extrinsic ADE,” and a subversion of the intracellular innate immune host responses through suppression of a the type I IFN and proinflammatory cytokines production—an event denominated as “Intrinsic ADE”
Let’s go to the paper…Methods
• ELISA• PCR• Immunohistochemistry• Plaque Assay• Plaque reduction neutralization test in Vero
Cells (PRNT)
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Results
Fig. 1
B cells are necessary for host resistance to primary Dengue infection
*B-cell-deficient mice (μMT−/−)
Conclusions
• B cells are protective to primary infection
Fig. 2
Preexisting immunity can exacerbate disease?
*Mice injected with anti-DENV3 serum and infected with DENV-2
Conclusions
• B cells are protective to primary infection• B-cell activation and antibody production can
exert a dual role
Fig. 3
To test whether the levels of Ab would directly impact on severe disease
*Commercial anti-DENV clone 4G2 (15 μg and 400 μg) at day −1, day +1 and day +3
Conclusions
• B cells are protective to primary infection• B-cell activation and antibody production can
exert a dual role• Presence of non-neutralizing or
subneutralizing levels of Ab can worsen disease (ADE)
Fig. 4
ADE-mediated severe disease resembles primary disease with high inoculum
*4G2 treated mice, sub lethal inoculum (100 PFU) and lethal (1000 PFU)
Fig. 5
Parameters of disease in day 7 (peak)
Conclusions
• B cells are protective to primary infection• B-cell activation and antibody production can
exert a dual role• Presence of non-neutralizing or subneutralizing
levels of Ab can worsen disease (ADE)• subneutralizing levels of anti-DENV antibodies
enhance viral replication to similar extents found in mice primarily infected with a higher DENV inoculum
Fig. 6
Involvement of FcγRs
*Mice treated with an FcγR-blocking Ab in the presence or not of 4G2
Conclusions
• B cells are protective to primary infection• B-cell activation and antibody production can exert a
dual role• Presence of non-neutralizing or subneutralizing
levels of Ab can worsen disease (ADE)• subneutralizing levels of anti-DENV antibodies
enhance viral replication to similar extents found in mice primarily infected with a higher DENV inoculum
• FcγRs play an essential role in disease
Fig. 7
Intrinsic ADE
Mice A129 -/- have more severe disease (supplementary figures)
Conclusions
• B cells are protective to primary infection• B-cell activation and antibody production can exert a dual
role• Presence of non-neutralizing or subneutralizing levels of Ab
can worsen disease (ADE)• subneutralizing levels of anti-DENV antibodies enhance
viral replication to similar extents found in mice primarily infected with a higher DENV inoculum
• FcγRs play an essential role in disease• Type I IFN play an essential role during primary and
secondary infections
Fig. 8
Passive intravenous immunoglobulin therapy (IVIG) containing subneutralizing titers of Ab
Conclusions
• B cells are protective to primary infection• B-cell activation and antibody production can exert a dual
role• Presence of non-neutralizing or subneutralizing levels of Ab
can worsen disease (ADE)• subneutralizing levels of anti-DENV antibodies enhance
viral replication to similar extents found in mice primarily infected with a higher DENV inoculum
• FcγRs play an essential role in disease• Type I IFN play an essential role during primary and
secondary infections
Conclusions
• Vaccines• Treatments
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