Dengue remains the most prevalent arthropod-borne viral disease in humans. While probing for blood vessels, Aedes aegypti and Ae. albopictus mosquitoes transmit the four serotypes of dengue virus (DENV1-4) by injecting virus-containing saliva into the skin. Even though arthropod saliva is known to facilitate transmission and modulate host responses to other pathogens, the full impact of mosquito saliva on dengue pathogenesis is still not well understood. Inoculating mice lacking the interferon-α/β receptor intradermally with DENV revealed that mosquito salivary gland extract (SGE) exacerbates dengue pathogenesis specifically in the presence of enhancing serotype-cross-reactive antibodies—when individuals already carry an increased risk for severe disease. We further establish that SGE increases viral titers in the skin, boosts antibody-enhanced DENV infection of dendritic cells and macrophages in the dermis, and amplifies dendritic cell migration to skin-draining lymph nodes. We demonstrate that SGE directly disrupts endothelial barrier function in vitro and induces endothelial permeability in vivo in the skin. Finally, we show that surgically removing the site of DENV transmission in the skin after 4 hours rescued mice from disease in the absence of SGE, but no longer prevented lethal antibody-enhanced disease when SGE was present. These results indicate that SGE accelerates the dynamics of dengue pathogenesis after virus transmission in the skin and induces severe antibody-enhanced disease systemically. Our study reveals novel aspects of dengue pathogenesis and suggests that animal models of dengue and pre-clinical testing of dengue vaccines should consider mosquito-derived factors as well as enhancing antibodies.
Inventory of data repository
Schmid et al. – Inventory of data repository
Schmid Inventory data repository SGE.pdf
01 - Dermis steady state
File type: The repository includes representative FSC 3.0 files that were exported from Diva software (BD Biosciences) and can be opened with FlowJo software (TreeStar). Fluorescent channels also indicate the specifically stained markers. Compensations values between fluorescence channels are included within FCS files.
01_Dermis_steady state.fcs
02 - Dermis 14h PBS
File type: The repository includes representative FSC 3.0 files that were exported from Diva software (BD Biosciences) and can be opened with FlowJo software (TreeStar). Fluorescent channels also indicate the specifically stained markers. Compensations values between fluorescence channels are included within FCS files.
02_Dermis_14h_PBS.fcs
03 - Dermis 14h SGE
File type: The repository includes representative FSC 3.0 files that were exported from Diva software (BD Biosciences) and can be opened with FlowJo software (TreeStar). Fluorescent channels also indicate the specifically stained markers. Compensations values between fluorescence channels are included within FCS files.
03_Dermis_14h_SGE.fcs
04 - Dermis 14h primary DENV
File type: The repository includes representative FSC 3.0 files that were exported from Diva software (BD Biosciences) and can be opened with FlowJo software (TreeStar). Fluorescent channels also indicate the specifically stained markers. Compensations values between fluorescence channels are included within FCS files.
04_Dermis_14h_primary_DENV.fcs
05 - Dermis 14h primary DENV+SGE
File type: The repository includes representative FSC 3.0 files that were exported from Diva software (BD Biosciences) and can be opened with FlowJo software (TreeStar). Fluorescent channels also indicate the specifically stained markers. Compensations values between fluorescence channels are included within FCS files.
05_Dermis_14h_primary_DENV+SGE.fcs
06 - Dermis 14h ADE DENV
File type: The repository includes representative FSC 3.0 files that were exported from Diva software (BD Biosciences) and can be opened with FlowJo software (TreeStar). Fluorescent channels also indicate the specifically stained markers. Compensations values between fluorescence channels are included within FCS files.
06_Dermis_14h_ADE_DENV.fcs
07 - Dermis 14h ADE DENV+SGE.fcs
File type: The repository includes representative FSC 3.0 files that were exported from Diva software (BD Biosciences) and can be opened with FlowJo software (TreeStar). Fluorescent channels also indicate the specifically stained markers. Compensations values between fluorescence channels are included within FCS files.
07_Dermis_14h_ADE_DENV+SGE.fcs
08 - LNs steady state
File type: The repository includes representative FSC 3.0 files that were exported from Diva software (BD Biosciences) and can be opened with FlowJo software (TreeStar). Fluorescent channels also indicate the specifically stained markers. Compensations values between fluorescence channels are included within FCS files.
08_LNs_steady state.fcs
09 - LNs 14h PBS
File type: The repository includes representative FSC 3.0 files that were exported from Diva software (BD Biosciences) and can be opened with FlowJo software (TreeStar). Fluorescent channels also indicate the specifically stained markers. Compensations values between fluorescence channels are included within FCS files.
09_LNs_14h_PBS.fcs
10 - LNs 14h SGE
File type: The repository includes representative FSC 3.0 files that were exported from Diva software (BD Biosciences) and can be opened with FlowJo software (TreeStar). Fluorescent channels also indicate the specifically stained markers. Compensations values between fluorescence channels are included within FCS files.
10_LNs_14h_SGE.fcs
11 - LNs 14h primary DENV
File type: The repository includes representative FSC 3.0 files that were exported from Diva software (BD Biosciences) and can be opened with FlowJo software (TreeStar). Fluorescent channels also indicate the specifically stained markers. Compensations values between fluorescence channels are included within FCS files.
11_LNs_14h_primary_DENV.fcs
12 - LNs 14h primary DENV+SGE
File type: The repository includes representative FSC 3.0 files that were exported from Diva software (BD Biosciences) and can be opened with FlowJo software (TreeStar). Fluorescent channels also indicate the specifically stained markers. Compensations values between fluorescence channels are included within FCS files.
12_LNs_14h_primary_DENV+SGE.fcs
13 - LNs 14h ADE DENV
File type: The repository includes representative FSC 3.0 files that were exported from Diva software (BD Biosciences) and can be opened with FlowJo software (TreeStar). Fluorescent channels also indicate the specifically stained markers. Compensations values between fluorescence channels are included within FCS files.
13_LNs_14h_ADE_DENV.fcs
14 - LNs 14h ADE DENV+SGE
File type: The repository includes representative FSC 3.0 files that were exported from Diva software (BD Biosciences) and can be opened with FlowJo software (TreeStar). Fluorescent channels also indicate the specifically stained markers. Compensations values between fluorescence channels are included within FCS files.
14_LNs_14h_ADE_DENV+SGE.fcs