Characterization of a murine model of non-lethal, symptomatic dengue virus infection

Vanessa V Sarathy,Mellodee White,Gregg N Milligan,Jaclyn A Kaiser,Gerald A Campbell,Nigel Bourne,Alan D T Barrett,Li Li

doi:10.1038/s41598-018-22618-w

Vanessa V Sarathy, Mellodee White + Show 6 more

Open Access

https://doi.org/10.1038/s41598-018-22618-w

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Journal: Scientific Reports	Publication Date: Mar 20, 2018
Citations: 24	License type: open-access

Affiliation: Galveston College, John Sealy Hospital

Abstract

The mosquito-borne disease dengue is caused by four serologically- and genetically-related viruses, termed DENV-1 to DENV-4. Historical setbacks due to lack of human-like mouse models of dengue were partially remedied with characterization of lethal DENV-2 infection in immunocompromised AG129 mice (deficient in IFN-α/β/γ receptors). Recently, our group established lethal AG129 mouse infection models of DENV-1, DENV-3, and DENV-4 using human isolates. Here we compare a non-lethal, disseminated model of DENV-3 infection using strain D83-144 to that of the lethal outcome following infection by strain C0360/94. Both strains belong to DENV-3 genotype II and differ by only 13 amino acids. Intraperitoneal inoculation of AG129 mice with strain D83-144 led to clinical signs of dengue infection, such as cytokine induction, thrombocytopenia, and systemic infection. However, C0360/94 infection led to features of severe human dengue, including coagulopathy and lethal outcome, whereas D83-144 infection does not. This study is the first to investigate a low passage, non-mouse lethal strain in AG129 mice and demonstrates that D83-144 infection induces milder features of human dengue than those induced by lethal C0360/94 infection. The results suggest that the AG129 mouse model has applications to investigate factors associated with mild or severe disease.

Highlights

Dengue is a mosquito-borne disease that is endemic in most tropical countries and that causes at least 100 million clinical infections each year, including 2.1 million cases of severe dengue fever and 500,000 cases of dengue hemorrhagic fever (DHF)[1]
Viremia was either undetected or present at lower levels in animals infected with 10-fold less inoculum than in animals infected with lethal-doses of DENV-3 C0360/94, DENV-4 703-4 and DENV-4 TVP-37612–14
D83-144 was prepared as the other DENV strains used in AG129 mouse models, by amplification in C6/36 mosquito cells

Summary

Introduction

Dengue is a mosquito-borne disease that is endemic in most tropical countries and that causes at least 100 million clinical infections each year, including 2.1 million cases of severe dengue fever and 500,000 cases of dengue hemorrhagic fever (DHF)[1]. We established a lethal infection model in AG129 mice utilizing the DENV-3 strain C0360/94, a 1994 Thai clinical isolate that is low-passage and non-mouse adapted[11,12]. DENV-2 D2S10 and DENV-1 WP/74 infection with 10-fold lower doses did not cause systemic dengue disease, instead led to paralysis[9,15], indicating that the disease caused by the lower dose is uncharacteristic of dengue disease in humans One exception to this phenomenon is the D2Y98P model in AG129 mice, which shows lethality over a wide range of doses[10]. Strain D83-144 is non-lethal at 10-fold higher inoculum than C0360/94, and AG129 mice develop disseminated infection, accompanied by cytokine induction and thrombocytopenia, but the disease is less severe than that caused by C0360/94 infection, and mice recover fully. This study shows that the AG129 mouse model can be used to examine factors associated with mild or severe human dengue disease

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