Vascular leak ensues a vigorous proinflammatory cytokine response to Tacaribe arenavirus infection in AG129 mice

Virology Journal

Brian B Gowen²  Stewart W Schneller³  Arnaud J Van Wettere¹  Brett L Hurst⁴  Deanna P Larson⁴  Min-Hui Wong⁴  Eric J Sefing⁴ 

[1] Utah Veterinary Diagnostic Laboratory, Utah State University, Logan, Utah, USA;School of Veterinary Medicine, Utah State University, Logan, Utah, USA;Molette Laboratory for Drug Discovery Research, Chemistry and Biochemistry Department, Auburn University, Auburn, Alabama, USA;Institute for Antiviral Research, Utah State University, Logan, Utah, USA

关键词: Vascular leak;    Cytokines;    Animal model;    Arenavirus;    Tacaribe virus;   

Others  :  1130959
DOI  :  10.1186/1743-422X-10-221

 received in 2013-03-29, accepted in 2013-06-25,  发布年份 2013

【 摘 要 】

Background

Tacaribe virus (TCRV) is a less biohazardous relative of the highly pathogenic clade B New World arenaviruses that cause viral hemorrhagic fever syndromes and require handling in maximum containment facilities not readily available to most researchers. AG129 type I and II interferon receptor knockout mice have been shown to be susceptible to TCRV infection, but the pathogenic mechanisms contributing to the lethal disease are unclear.

Methods

To gain insights into the pathogenesis of TCRV infection in AG129 mice, we assessed hematologic and cytokine responses during the course of infection, as well as changes in the permeability of the vascular endothelium. We also treated TCRV-challenged mice with MY-24, a compound that prevents mortality without affecting viral loads during the acute infection, and measured serum and tissue viral titers out to 40 days post-infection to determine whether the virus is ultimately cleared in recovering mice.

Results

We found that the development of viremia and splenomegaly precedes an elevation in white blood cells and the detection of high levels of proinflammatory mediators known to destabilize the endothelial barrier, which likely contributes to the increased vascular permeability and weight loss that was observed several days prior to when the mice generally succumb to TCRV challenge. In surviving mice treated with MY-24, viremia and liver virus titers were not cleared until 2–3 weeks post-infection, after which the mice began to recover lost weight. Remarkably, substantial viral loads were still present in the lung, spleen, brain and kidney tissues at the conclusion of the study.

Conclusions

Our findings suggest that vascular leak may be a contributing factor in the demise of TCRV-infected mice, as histopathologic findings are generally mild to moderate in nature, and as evidenced with MY-24 treatment, animals can survive in the face of high viral loads.

【 授权许可】

   
2013 Sefing et al.; licensee BioMed Central Ltd.

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