Host response transcriptomic analysis of Crimean-Congo hemorrhagic fever pathogenesis in the cynomolgus macaque model

Catherine E Arnold,Charles J Shoemaker,Candace D Blancett,Darci R Smith,Amanda S Graham,Timothy D Minogue,Christina E Douglas

doi:10.1038/s41598-021-99130-1

Abstract

Crimean-Congo hemorrhagic fever virus (CCHFV) is a highly pathogenic tick-borne RNA virus prevalent in Asia, Europe, and Africa, and can cause a hemorrhagic disease (CCHF) in humans with mortality rates as high as 60%. A general lack of both effective medical countermeasures and a comprehensive understanding of disease pathogenesis is partly driven by an historical lack of viable CCHF animal models. Recently, a cynomolgous macaque model of CCHF disease was developed. Here, we document the targeted transcriptomic response of non-human primates (NHP) to two different CCHFV strains; Afghan09-2990 and Kosova Hoti that both yielded a mild CCHF disease state. We utilized a targeted gene panel to elucidate the transcriptomic changes occurring in NHP whole blood during CCHFV infection; a first for any primate species. We show numerous upregulated genes starting at 1 day post-challenge through 14 days post-challenge. Early gene changes fell predominantly in the interferon stimulated gene family with later gene changes coinciding with an adaptive immune response to the virus. There are subtle differences between viral strains, namely duration of the differentially expressed gene response and biological pathways enriched. After recovery, NHPs showed no lasting transcriptomic changes at the end of sample collection.

Highlights

Crimean-Congo hemorrhagic fever virus (CCHFV) is a highly pathogenic tick-borne RNA virus prevalent in Asia, Europe, and Africa, and can cause a hemorrhagic disease (CCHF) in humans with mortality rates as high as 60%
The study concluded on day 28, and non-human primates (NHP) showed no signs of residual illness
Histopathological analysis revealed that a subset of the NHPs (4/6 in Afg[09] group, 2/6 in Hoti group) had latent tuberculosis (TB) in the form of lung and liver granulomas; TB-positive NHPs showed no significant differences in any clinical parameter relative to TB negative NHPs

Summary

Introduction

Crimean-Congo hemorrhagic fever virus (CCHFV) is a highly pathogenic tick-borne RNA virus prevalent in Asia, Europe, and Africa, and can cause a hemorrhagic disease (CCHF) in humans with mortality rates as high as 60%. We document the targeted transcriptomic response of non-human primates (NHP) to two different CCHFV strains; Afghan09-2990 and Kosova Hoti that both yielded a mild CCHF disease state. Human infection show strong cytokine production, including IL-6, IL-8, IL-12, TNF-α, CSF2, IFN-γ, IL-10, CCL2, CCL3, CCL4, and CCL714–16. It is worth noting, that most of the extant human data is limited to cytokine protein detection and not changes in the host transcriptome

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Results

Conclusion