Pathogenesis and Host Response in Syrian Hamsters following Intranasal Infection with Andes Virus

Hantavirus pulmonary syndrome (HPS), also referred to as hantavirus cardiopulmonary syndrome (HCPS), is a rare but frequently fatal disease caused by New World hantaviruses. In humans HPS is associated with severe pulmonary edema and cardiogenic shock; however, the pathogenesis of this disease remains unclear largely due to a lack of suitable animal models for the study of disease progression. In this study we monitored clinical, virological, pathophysiological parameters and host immunological responses to decipher pathological factors and events in the lethal Syrian hamster model of HPS following intranasal inoculation of Andes virus. Transcriptional profiling of the host gene responses demonstrated a suppression of innate immune responses in most organs analyzed during the early stage of infection, except for in the lung which had low level activation of several pro-inflammatory genes. During this phase Andes virus established a systemic infection in hamsters, with viral antigen readily detectable in the endothelium of the majority of tissues analyzed by 7–8 days post-inoculation. Despite wide-spread infection, histological analysis confirmed pathological abnormalities were almost exclusively found in the lungs. Immediately preceding clinical signs of disease, intense activation of pro-inflammatory and Th1/Th2 responses were observed in the lungs as well as the heart, but not in peripheral organs, suggesting that localized immune-modulations by infection is paramount to pathogenesis. Throughout the course of infection a strong suppression of regulatory T-cell responses was noted and is hypothesized to be the basis of the aberrant immune activations. The unique and comprehensive monitoring of host immune responses to hantavirus infection increases our understanding of the immuno-pathogenesis of HPS and will facilitate the development of treatment strategies targeting deleterious host immunological responses

Molecular Insights into Crimean-Congo Hemorrhagic Fever Virus

Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne pathogen that causes high morbidity and mortality. Efficacy of vaccines and antivirals to treat human CCHFV infections remains limited and controversial. Research into pathology and underlying molecular mechanisms of CCHFV and other nairoviruses is limited. Significant progress has been made in our understanding of CCHFV replication and pathogenesis in the past decade. Here we review the most recent molecular advances in CCHFV-related research, and provide perspectives on future research

Animal Models of Tick-Borne Hemorrhagic Fever Viruses

Tick-borne hemorrhagic fever viruses (TBHFV) are detected throughout the African and Eurasian continents and are an emerging or re-emerging threat to many nations. Due to the largely sporadic incidences of these severe diseases, information on human cases and research activities in general have been limited. In the past decade, however, novel TBHFVs have emerged and areas of endemicity have expanded. Therefore, the development of countermeasures is of utmost importance in combating TBHFV as elimination of vectors and interrupting enzootic cycles is all but impossible and ecologically questionable. As in vivo models are the only way to test efficacy and safety of countermeasures, understanding of the available animal models and the development and refinement of animal models is critical in negating the detrimental impact of TBHFVs on public and animal health

Animal Models of Tick-Borne Hemorrhagic Fever Viruses

pathogen

Molecular Insights into Crimean-Congo Hemorrhagic Fever Virus

Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne pathogen that causes high morbidity and mortality. Efficacy of vaccines and antivirals to treat human CCHFV infections remains limited and controversial. Research into pathology and underlying molecular mechanisms of CCHFV and other nairoviruses is limited. Significant progress has been made in our understanding of CCHFV replication and pathogenesis in the past decade. Here we review the most recent molecular advances in CCHFV-related research, and provide perspectives on future research

Nucleocapsid protein-based vaccine provides protection in mice against lethal Crimean-Congo hemorrhagic fever virus challenge

<div><p>Crimean-Congo hemorrhagic fever (CCHF) is an acute, often fatal viral disease characterized by rapid onset of febrile symptoms followed by hemorrhagic manifestations. The etiologic agent, CCHF orthonairovirus (CCHFV), can infect several mammals in nature but only seems to cause clinical disease in humans. Over the past two decades there has been an increase in total number of CCHF case reports, including imported CCHF patients, and an expansion of CCHF endemic areas. Despite its increased public health burden there are currently no licensed vaccines or treatments to prevent CCHF. We here report the development and assessment of the protective efficacy of an adenovirus (Ad)-based vaccine expressing the nucleocapsid protein (N) of CCHFV (Ad-N) in a lethal immunocompromised mouse model of CCHF. The results show that Ad-N can protect mice from CCHF mortality and that this platform should be considered for future CCHFV vaccine strategies.</p></div

Efficacy of single-dose and prime-boost vaccination.

<p>(A,B) Single-dose vaccination. IFNAR^-/- mice (n = 9 for Ad-N; n = 6 for Ad-wt) were vaccinated with recombinant adenoviruses (1.25×10⁷ ifu) 28 days prior to lethal CCHFV infection (1000 LD₅₀). The animals were monitored for weight as a group (A) and disease progression/survival (B) over 30 days. (C,D) Prime-boost vaccination. IFNAR^-/- mice (n = 9 for Ad-N; n = 3 for Ad-wt) were vaccinated with recombinant adenoviruses 56 (1.25×10⁷ IFU; intramuscular) and 28 (10⁸ IFU; intranasal) days prior to lethal CCHFV infection (1000 LD₅₀). The animals were monitored for weight (C) and disease progression/survival (D) over 30 days. Data is reported as the means. *** p<0.001, ****p<0.0001.</p

Liver histopathology and CCHFV antigen distribution in single-dose and prime-boost vaccinated and challenged mice.

<p>Groups of IFNAR^-/- mice were either single, (1.25×10⁷ IFU; intramuscular) or prime-boost (1.25×10⁷ IFU; intramuscular / 10⁸ IFU; intranasal) vaccinated with Ad-N or Ad-wt and challenged with 1000 LD₅₀ of CCHFV 28 days following final vaccination. Mice (n = 9 per group) were anesthetized, bleed and euthanized to harvest organ samples on day 3 post CCHFV challenge. Thin-sections of liver material were stained with hematoxylin and eosin (H&E) or with N₁₀₂₈ rabbit polyclonal serum (anti-CCHFV N serum) (IHC). (A) Liver H&E of control-vaccinated mice (Ad-wt), (B) Liver H&E of prime-vaccinated mice (Ad-N); (C) Liver H&E of prime-boost-vaccinated mice (Ad-N); (D) Liver IHC of control-vaccinated mice (Ad-wt); (E) Liver IHC of prime-vaccinated mice (Ad-N); (F) Liver IHC of prime-boost-vaccinated mice (Ad-N). Images are at a magnification of 10x with 500x insets.</p