The host inflammatory response contributes to disease severity in Crimean-Congo hemorrhagic fever virus infected mice

Abstract

Crimean-Congo hemorrhagic fever virus (CCHFV) is an important human pathogen. In cell culture, CCHFV is sensed by the cytoplasmic RNA sensor retinoic acid-inducible gene I (RIG-I) molecule and its adaptor molecule mitochondrial antiviral signaling (MAVS) protein. MAVS initiates both type I interferon (IFN-I) and proinflammatory responses. Here, we studied the role MAVS plays in CCHFV infection in mice in both the presence and absence of IFN-I activity. MAVS-deficient mice were not susceptible to CCHFV infection when IFN-I signaling was active and showed no signs of disease. When IFN-I signaling was blocked by antibody, MAVS-deficient mice lost significant weight, but were uniformly protected from lethal disease, whereas all control mice succumbed to infection. Cytokine activity in the infected MAVS-deficient mice was markedly blunted. Subsequent investigation revealed that CCHFV infected mice lacking TNF-α receptor signaling (TNFA-R-deficient), but not IL-6 or IL-1 activity, had more limited liver injury and were largely protected from lethal outcomes. Treatment of mice with an anti-TNF-α neutralizing antibody also conferred partial protection in a post-virus exposure setting. Additionally, we found that a disease causing, but non-lethal strain of CCHFV produced more blunted inflammatory cytokine responses compared to a lethal strain in mice. Our work reveals that MAVS activation and cytokine production both contribute to CCHFV pathogenesis, potentially identifying new therapeutic targets to treat this disease.

Comparative characterization of Crimean-Congo hemorrhagic fever virus cell culture systems with application to propagation and titration methods

“…For representative examples, in one study the entire viral propagation method was described as “CCHFV (strain IbAr10200) was propagated in Vero E6 cells”, with no specific details or reference to the literature [ 42 ]. A similar case was found, where the viral stock was amplified in HuH-7 cells [ 17 ]. In another study, the methods of viral propagation in SW-13 cells and plaque assay titration methods were referred to a Master’s thesis, which was not found by our search on the internet [ 43 ].…”

“…We performed a comprehensive search for research papers describing CCHFV cell culture, which covered all-time literature in the PubMed and identified four cell lines of considerable popularity, Vero (E6) [ 4 , 13 , 14 , 16 – 27 ], SW-13 [ 8 , 17 – 21 , 24 , 26 , 28 – 41 ], HuH-7 [ 17 , 20 , 21 , 31 , 33 , 39 , 56 , 57 ] and BSR-T7/5 [ 4 , 57 – 59 ] (Fig. 1 and Additional file 2 ).…”

“…A number of cell lines were found to be permissive to CCHFV replication [ 4 , 15 ]. Among these, Vero cell lines, primarily Vero E6 [ 4 , 13 , 14 , 16 – 27 ], and SW-13 [ 8 , 17 – 21 , 24 , 26 , 28 – 41 ] appear to be the most frequently used in CCHFV culture experiments. However, significant variations and a lack of specific details can be found across methods of in-house derived culture conditions in different laboratories.…”

Reduced phosphorylated Foxp3 levels in Crimean Congo haemorrhagic fever

“…Therefore, future studies are recommended to investigate the potential use of kinase-targeting therapies (Bhullar et al, 2018) and dephosphorylation inhibitors such as TNF-b-specific inhibitor (Nie et al, 2013) as promising therapy strategies against CCHF. The latter approach was also proposed in a recent study by Golden et al, which demonstrated the protective effects of anti-TNF-b neutralizing antibodies in mice exposed to CCHF (Golden et al, 2022).…”

In silico formulation of a next-generation multiepitope vaccine for use as a prophylactic candidate against Crimean-Congo hemorrhagic fever

“…Mainly four TLRs (TLR-3,4,7, and 8) broadly act as viral antigenic receptors and play a crucial role against viral infections [ 102 ] whereas TLR-1,2,5,6,9–12 primarily work against bacterial infection [ 102 ]. TLR3, which senses viral dsRNA and structured RNA, is associated with acute CCHF, and enhances the activity of the protein, can stimulate innate immune responses [ 103 – 106 ]. Therefore, the activity of these receptors with the desired vaccine candidate has been observed in this study.…”