Targeting cytokine signaling in mice infected with bunyaviruses provides protection from severe disease and death
Introduction: Crimean-Congo hemorrhagic fever virus (CCHFV) is an important human pathogen in the Bunyavirales order. CCHFV causes a spectrum of disease in humans that can range from minimally symptomatic to a catastrophic and lethal infection. Factors dictating why some develop mild illness and oth...
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Elsevier
2025-03-01
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| Series: | International Journal of Infectious Diseases |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1201971224004909 |
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| author | Dr Joseph Golden Dr. Xiankun Zeng LTC Curtis Cline Dr. Charles Shoemaker Dr. Jun Liu Mr. Collin Fitzpatrick Dr Christopher Stefan Dr. Aura Garrison Dr. Brian Carey |
| author_facet | Dr Joseph Golden Dr. Xiankun Zeng LTC Curtis Cline Dr. Charles Shoemaker Dr. Jun Liu Mr. Collin Fitzpatrick Dr Christopher Stefan Dr. Aura Garrison Dr. Brian Carey |
| author_sort | Dr Joseph Golden |
| collection | DOAJ |
| description | Introduction: Crimean-Congo hemorrhagic fever virus (CCHFV) is an important human pathogen in the Bunyavirales order. CCHFV causes a spectrum of disease in humans that can range from minimally symptomatic to a catastrophic and lethal infection. Factors dictating why some develop mild illness and others succumb to disease are unclear. The cytoplasmic RNA sensor, retinoic acid-inducible gene I (RIG-I), has been shown to sense CCHFV in cell culture. When recognized by RIG-I an adaptor molecule, mitochondrial antiviral signaling (MAVS), induces pro-inflammatory responses as well as type I interferon (IFN-I). Methods: We used a mouse model of CCFHV infection in various pathogen sensing and cytokine deficient animals to examine their role in the disease process. We also used antibodies targeting cytokines to show their importance in the disease process. Results: We found that MAVS-deficient mice are not susceptible to CCHFV infection and show no signs of disease when IFN-I signaling was active. However, in an antibody mediated IFN-I suppressed mouse model, mice were uniformly protected from lethal disease (albeit with significant weight loss) and showed significantly blunted cytokine signaling, specifically TNF-α. All control mice succumbed to infection and displayed high cytokine levels. Additionally, we found that a disease causing but non-murine lethal strain of CCHFV (Kosova Hoti) produced more blunted inflammatory cytokine responses compared to a lethal strain (Afg09-2990) in mice. Subsequent investigation revealed that CCHFV infected mice lacking TNF-α receptor signaling (TNFA-R-deficient) had reduced liver pathology and were largely protected from lethal outcomes. Further, treatment of mice with an anti-TNF-α neutralizing antibody conferred partial protection in a post-virus exposure setting. Finally, interleukins 1 and 6 (IL-1, IL-6) were shown to be significantly downregulated in MAVS and TNFA-R deficient mice, which led us to explore their potential protective activity in CCHFV infected mice. We are also exploring the effects of suppression of IL-6 and IL-1 in mice infected with other bunyaviruses. Discussion: Our work suggests specific pathogen sensing pathways or important inflammatory cytokine signaling pathways contribute to severe viral disease. We also found that a strain of CCHFV that does not cause lethal disease in mice does not induce as potent of an inflammatory cytokine response compared to lethal strains, despite similar levels of replication. This work highlights the host inflammatory pathway induced by viral infection as a component of the pathological process and should be consider important targets for medical intervention. Furthermore, CCHFV strains attenuated in the host failed to activate inflammatory pathway to a high degree, further implicating them in the severe disease process. Conclusions: Our work reveals that induction of interferon and increased cytokine production both contribute to CCHFV pathogenesis, potentially identifying new therapeutic targets to treat this disease. |
| format | Article |
| id | doaj-art-89e2184bd5444a839080c33977460a34 |
| institution | OA Journals |
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| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
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| series | International Journal of Infectious Diseases |
| spelling | doaj-art-89e2184bd5444a839080c33977460a342025-08-20T02:11:00ZengElsevierInternational Journal of Infectious Diseases1201-97122025-03-0115210741510.1016/j.ijid.2024.107415Targeting cytokine signaling in mice infected with bunyaviruses provides protection from severe disease and deathDr Joseph Golden0Dr. Xiankun Zeng1LTC Curtis Cline2Dr. Charles Shoemaker3Dr. Jun Liu4Mr. Collin Fitzpatrick5Dr Christopher Stefan6Dr. Aura Garrison7Dr. Brian Carey8USAMRIID, Frederick, United StatesUSAMRIID, Frederick, United StatesUSAMRIID, Frederick, United StatesUSAMRIID, Frederick, United StatesUSAMRIID, Frederick, United StatesUSAMRIID, Frederick, United StatesUSAMRIID, Frederick, United StatesUSAMRIID, Frederick, United StatesUSAMRIID, Frederick, United StatesIntroduction: Crimean-Congo hemorrhagic fever virus (CCHFV) is an important human pathogen in the Bunyavirales order. CCHFV causes a spectrum of disease in humans that can range from minimally symptomatic to a catastrophic and lethal infection. Factors dictating why some develop mild illness and others succumb to disease are unclear. The cytoplasmic RNA sensor, retinoic acid-inducible gene I (RIG-I), has been shown to sense CCHFV in cell culture. When recognized by RIG-I an adaptor molecule, mitochondrial antiviral signaling (MAVS), induces pro-inflammatory responses as well as type I interferon (IFN-I). Methods: We used a mouse model of CCFHV infection in various pathogen sensing and cytokine deficient animals to examine their role in the disease process. We also used antibodies targeting cytokines to show their importance in the disease process. Results: We found that MAVS-deficient mice are not susceptible to CCHFV infection and show no signs of disease when IFN-I signaling was active. However, in an antibody mediated IFN-I suppressed mouse model, mice were uniformly protected from lethal disease (albeit with significant weight loss) and showed significantly blunted cytokine signaling, specifically TNF-α. All control mice succumbed to infection and displayed high cytokine levels. Additionally, we found that a disease causing but non-murine lethal strain of CCHFV (Kosova Hoti) produced more blunted inflammatory cytokine responses compared to a lethal strain (Afg09-2990) in mice. Subsequent investigation revealed that CCHFV infected mice lacking TNF-α receptor signaling (TNFA-R-deficient) had reduced liver pathology and were largely protected from lethal outcomes. Further, treatment of mice with an anti-TNF-α neutralizing antibody conferred partial protection in a post-virus exposure setting. Finally, interleukins 1 and 6 (IL-1, IL-6) were shown to be significantly downregulated in MAVS and TNFA-R deficient mice, which led us to explore their potential protective activity in CCHFV infected mice. We are also exploring the effects of suppression of IL-6 and IL-1 in mice infected with other bunyaviruses. Discussion: Our work suggests specific pathogen sensing pathways or important inflammatory cytokine signaling pathways contribute to severe viral disease. We also found that a strain of CCHFV that does not cause lethal disease in mice does not induce as potent of an inflammatory cytokine response compared to lethal strains, despite similar levels of replication. This work highlights the host inflammatory pathway induced by viral infection as a component of the pathological process and should be consider important targets for medical intervention. Furthermore, CCHFV strains attenuated in the host failed to activate inflammatory pathway to a high degree, further implicating them in the severe disease process. Conclusions: Our work reveals that induction of interferon and increased cytokine production both contribute to CCHFV pathogenesis, potentially identifying new therapeutic targets to treat this disease.http://www.sciencedirect.com/science/article/pii/S1201971224004909 |
| spellingShingle | Dr Joseph Golden Dr. Xiankun Zeng LTC Curtis Cline Dr. Charles Shoemaker Dr. Jun Liu Mr. Collin Fitzpatrick Dr Christopher Stefan Dr. Aura Garrison Dr. Brian Carey Targeting cytokine signaling in mice infected with bunyaviruses provides protection from severe disease and death International Journal of Infectious Diseases |
| title | Targeting cytokine signaling in mice infected with bunyaviruses provides protection from severe disease and death |
| title_full | Targeting cytokine signaling in mice infected with bunyaviruses provides protection from severe disease and death |
| title_fullStr | Targeting cytokine signaling in mice infected with bunyaviruses provides protection from severe disease and death |
| title_full_unstemmed | Targeting cytokine signaling in mice infected with bunyaviruses provides protection from severe disease and death |
| title_short | Targeting cytokine signaling in mice infected with bunyaviruses provides protection from severe disease and death |
| title_sort | targeting cytokine signaling in mice infected with bunyaviruses provides protection from severe disease and death |
| url | http://www.sciencedirect.com/science/article/pii/S1201971224004909 |
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