Host Inflammatory Response to Mosquito Bites Enhances the Severity of Arbovirus Infection

Summary

Aedes aegypti mosquitoes are responsible for transmitting many medically important viruses such as those that cause Zika and dengue. The inoculation of viruses into mosquito bite sites is an important and common stage of all mosquito-borne virus infections. We show, using Semliki Forest virus and Bunyamwera virus, that these viruses use this inflammatory niche to aid their replication and dissemination in vivo. Mosquito bites were characterized by an edema that retained virus at the inoculation site and an inflammatory influx of neutrophils that coordinated a localized innate immune program that inadvertently facilitated virus infection by encouraging the entry and infection of virus-permissive myeloid cells. Neutrophil depletion and therapeutic blockade of inflammasome activity suppressed inflammation and abrogated the ability of the bite to promote infection. This study identifies facets of mosquito bite inflammation that are important determinants of the subsequent systemic course and clinical outcome of virus infection.

Graphical Abstract

Highlights

• •

  Mosquito bites enhance virus replication and dissemination and increase host mortality

• •

  Neutrophil-driven inflammation retains virus in skin to drive macrophage recruitment

• •

  Recruited and resident myeloid cells become infected and replicate virus

• •

  Blocking leukocyte recruitment to bite site inhibits viral infection

Abstract

The inoculation of viruses into mosquito bite sites is an important and common stage of arbovirus infections. McKimmie and colleagues show that inflammation at bite sites aids viral replication and dissemination in vivo, resulting in more severe infection. These findings define additional targets for post-exposure prophylactic intervention.