Distinguishing host responses, extensive viral dissemination and long-term viral RNA persistence in domestic sheep experimentally infected with Crimean-Congo hemorrhagic fever virus Kosovo Hoti

Abstract

Crimean-Congo hemorrhagic fever orthonairovirus (CCHFV) is a tick-borne, biosafety level 4 pathogen often causing a fatal hemorrhagic disease in humans (CCHF). Although the virus is believed to be maintained in a tick-vertebrate-tick ecological cycle involving numerous wild and domestic animal species, the biology of CCHFV infection in these animals is far from clearly understood. Old experimental infection studies, remaining to be validated with modern laboratory methods, were largely based on CCHFV strains of unknown pathogenicity and limited to the observation of viremia. Here, domestic sheep are challenged with CCHFV Kosovo Hoti, a highly pathogenic clinical isolate increasingly utilized in current research. Despite a lack of prominent signs of disease, the infection demonstrates an acute viremia with coinciding viral shedding, high fever and makers for potential impairment in liver and kidney functions. The immune response is characterized by an early reduction of neutrophil recruitment and its chemoattractant, IL-8, in the blood stream, while neutrophil infiltration and elevated IL-8 are features of fatal CCHFV infections reported in immunodeficient mice and humans. Several inflammatory cytokines, which are predictive indicators of mortality in humans and have potential to cause vascular dysfunction, a primary hallmark of severe CCHF, are down-regulated or restricted from increase. Of particular interest, the detection of CCHFV RNA in a variety of organ tissues long after the acute phase of infection, while indicating a widespread viral dissemination in the host, suggests a potentially long-term persisting impact of CCHFV infection. Consistent with this, antibody responses exhibit features reminiscent of recurring antigenic boost, and a prolonged fever or late fever spike correlates with high levels of viral RNA persistence. These findings reveal previously unrecognized aspects of CCHFV biology in animals and highlight the need for extended experimental infection studies.