Maternal Immunity and Vaccination Influence Disease Severity in Progeny in a Novel Mast Cell-Deficient Mouse Model of Severe Dengue.

Chinmay Kumar Mantri,Ashley L St John,Abhay P S Rathore,Gayathri Soundarajan,Sylvie Alonso,Wilfried A A Saron

doi:10.3390/v13050900

Abstract

Sub-neutralizing concentrations of antibodies in dengue infected patients is a major risk factor for the development of dengue hemorrhagic fever and dengue shock syndrome. Here, we describe a mouse model with a deficiency in mast cells (MCs) in addition to a deficiency in Type-I and II IFN receptors for studying dengue virus (DENV) infection. We used this model to understand the influence of MCs in a maternal antibody-dependent model of severe dengue, where offspring born to DENV-immune mothers are challenged with a heterologous DENV serotype. Mice lacking both MCs and IFN receptors were found susceptible to primary DENV infection and showed morbidity and mortality. When these mice were immunized, pups born to DENV-immune mothers were found to be protected for a longer duration from a heterologous DENV challenge. In the absence of MCs and type-I interferon signaling, IFN-γ was found to protect pups born to naïve mothers but had the opposite effect on pups born to DENV-immune mothers. Our results highlight the complex interactions between MCs and IFN-signaling in influencing the role of maternal antibodies in DENV-induced disease severity.

Highlights

Dengue is a mosquito-borne Flaviviral disease endemic in many countries within the tropical and subtropical regions of the world
DENV4 and were monitored for 14 days. This dose was selected as it was shown to be nonlethal in AG129 mice without antibody-dependent enhancement [39]
We first compared the clinical manifestations displayed by mast cells (MCs)-deficient KitW-sh/W-sh Ifnar1+/+ Ifngr1−/− mice lacking Type-II IFN receptors and MC-deficient KitW-sh/W-sh Ifnar1−/− Ifngr1+/+ mice lacking

Summary

Introduction

Dengue is a mosquito-borne Flaviviral disease endemic in many countries within the tropical and subtropical regions of the world. It can be caused by any one of the four serotypes of the dengue virus (DENV1-4) [1]. In some cases, DENV infection can manifest as a more severe form of disease with the possibilities of hemorrhaging and plasma leakage, which can lead to multiple organ failure. These severe forms of dengue disease have been referred to as dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS) [2,3]. In addition to vascular and respiratory dysfunction, dengue infection can rarely lead to neurological and neuromuscular complications such as Guillain–Barre syndrome and hypokalemic paralysis [4,5,6]

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