Mosquito Saliva Increases Endothelial Permeability in the Skin, Immune Cell Migration, and Dengue Pathogenesis during Antibody-Dependent Enhancement.
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.
Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, California, United States of America.
Michael A
MA
Schmid
Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, California, United States of America.
Dustin R
DR
Glasner
Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, California, United States of America.
Sanjana
S
Shah
Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, California, United States of America.
Daniela
D
Michlmayr
Wadsworth Center, New York State Department of Health, Albany, New York, United States of America.
Laura D
LD
Kramer
Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, California, United States of America.
Eva
E
Harris
D000818:Animals; D019067:Antibody-Dependent Enhancement / Q000276:immunology*; D002199:Capillary Permeability; D002465:Cell Movement; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D009033:Culicidae / Q000378:metabolism / Q000821:virology*; D003715:Dengue / Q000276:immunology / Q000635:transmission*; D003716:Dengue Virus / Q000276:immunology / Q000472:pathogenicity; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000276:immunology / Q000821:virology*; D005434:Flow Cytometry; D007303:Insect Vectors / Q000276:immunology / Q000472:pathogenicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012463:Saliva / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D012867:Skin / Q000098:blood supply / Q000276:immunology