Increased Mosquito Midgut Infection by Dengue Virus Recruitment of Plasmin Is Blocked by an Endogenous Kazal-type Inhibitor.

Karthik Ramesh,Dorothée Missé,Yu Keung Mok,Benjamin Wong,Ahmed Mahmoud Mohammed Sayed,R Manjunatha Kini,Varsha A Walvekar,Julien Pompon

doi:10.1016/j.isci.2019.10.056

Abstract

SummaryDengue symptoms include alteration of blood coagulation and fibrinolysis, causing severe hemorrhage and death. Here, we demonstrate that higher concentration of plasmin, the human fibrinolytic factor, in blood meal enhances dengue virus (DENV) infection in mosquito midgut and dissemination in mosquitoes. We also show that mosquitoes express a plasmin-selective Kazal-type inhibitor (AaTI) in the midgut to inhibit plasmin proteolysis and revert the enhanced infection. Using bio-layer interferometry, we show that DENV, plasmin, and AaTI interact to form a tripartite complex. Eventually, plasmin increases midgut internalization of dextran molecules and this is reverted by AaTI. Our study demonstrates that (1) DENV recruits plasmin to increase local proteolytic activity in the midgut, thus degrading the glycocalyx and enhancing DENV internalization and (2) AaTI can act as a transmission-blocking agent by inhibiting plasmin proteolysis. Our results indicate that dengue pathogenesis enhances DENV fitness by increasing its infectivity to mosquitoes.

Highlights

Pathogens alter host physiology in various ways
At the intersection between pathogenesis and vector competence, our study suggests that a human blood component related to dengue symptomatology increases dengue virus (DENV) fitness by enhancing mosquito infection
Plasmin Enhances Dengue Virus Infection of Mosquito Midgut To test whether plasmin increases DENV infectivity, we orally infected female Ae. aegypti with pig blood supplemented with human plasmin

Summary

Introduction

Vector-borne pathogens often influence three-way interactions involving host, vector, and pathogen (Mauck et al, 2012; Ewald, 1995; Hurd, 2003). Those alterations that maximize transmission success get fixated through natural selection (Ewald, 1995; Anderson and Robert, 1992). Deciphering how host alterations influence transmission is critical to understand virulence evolution This knowledge can contribute toward developing strategies to tackle important public health problems caused by vector-borne diseases. Only a small proportion of ingested DENV initiates midgut infection, creating a barrier that determines mosquito transmission (Franz et al, 2015). Previous reports have shown that DENV can alter host blood factors (Chuang et al, 2013), little is known about how these factors present in the ingested blood influence midgut infection

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