Evaluation of Macaca radiata as a non-human primate model of Dengue virus infection

Fumihiro Kato,Akihiko Kawakami,Tomoyuki Miura,Yuki Ishida,Takayuki Hishiki,Masayuki Saijo,Tomohiko Takasaki

doi:10.1038/s41598-018-21582-9

Abstract

Dengue virus (DENV) causes a wide range of illnesses in humans, including dengue fever and dengue haemorrhagic fever. Current animal models of DENV infection are limited for understanding infectious diseases in humans. Bonnet monkeys (Macaca radiata), a type of Old World monkey, have been used to study experimental and natural infections by flaviviruses, but Old World monkeys have not yet been used as DENV infection models. In this study, the replication levels of several DENV strains were evaluated using peripheral blood mononuclear cells. Our findings indicated that DENV-4 09-48 strain, isolated from a traveller returning from India in 2009, was a highly replicative virus. Three bonnet monkeys were infected with 09-48 strain and antibody responses were assessed. DENV nonstructural protein 1 antigen was detected and high viraemia was observed. These results indicated that bonnet monkeys and 09-48 strain could be used as a reliable primate model for the study of DENV.

Highlights

Dengue virus (DENV), which is transmitted to humans by Aedes mosquitoes, is the aetiological agent of dengue fever (DF) and dengue haemorrhagic fever (DHF), a self-limited febrile illness[1]
To investigate whether clinically isolated DENV strains were capable of efficient replication in primary cells derived from M. radiata, equal multiplicity of infection (MOI) of DENV strains were infected and titres of progeny viruses from peripheral blood mononuclear cells (PBMCs) at 2 dpi were measured by plaque assays
DENV-4 (09-48 strain) belonged to a cluster of strains isolated from Indonesia in 2004 and 2008 and was divergent from sylvatic strains

Summary

Introduction

Dengue virus (DENV), which is transmitted to humans by Aedes mosquitoes, is the aetiological agent of dengue fever (DF) and dengue haemorrhagic fever (DHF), a self-limited febrile illness[1]. Some mouse and non-human primate (NHP) models have been developed for the study of DENV9–11. These animal models have limits for pathological and virologic analyses and are genetically differentiated from humans[12]. An immunological response was not observed using immunocompromised mice and mouse models are not sufficient for studies of human disease[13]. The common marmoset has been used as an animal model of DENV and high viraemia and immune responses corresponding to those in humans have been observed[10,14]. Kyasanur forest disease virus (KFDV), tick-borne encephalitis virus (TBEV), Japanese encephalitis virus (JEV) and West Nile virus (WNV) have been inoculated into bonnet monkeys, resulting in high viraemia[23,24,25]. The experimental inoculation of DENV using bonnet monkeys has not yet been reported

Methods

Results

Conclusion