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Dissecting Innate Immune Signaling in Viral Evasion of Cytokine Production
Published on: March 2, 2014
Lethal monkeypox virus infection of CAST/EiJ mice is associated with a deficient gamma interferon response
Patricia L Earl1, Jeffrey L Americo, Bernard Moss
1Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. pearl@niaid.nih.gov
Abstract:
Monkeypox virus (MPXV) is endemic in Africa, where it causes disease in humans resembling smallpox. A recent importation of MPXV-infected animals into the United States raises the possibility of global spread. Rodents comprise the major reservoir of MPXV, and a variety of such animals, even those native to North America, are susceptible. In contrast, common inbred strains of mice, including BALB/c and C57BL/6, are greatly resistant to MPXV. However, several inbred strains of mice derived from wild mice, including CAST/EiJ, exhibit morbidity and mortality at relatively low inoculums of MPXV. Elucidating the basis for the susceptibility of CAST/EiJ mice could contribute to an understanding of MPXV pathogenicity and host defense mechanisms and enhance the value of this mouse strain as a model system for evaluation of therapeutics and vaccines. Here we compared virus dissemination and induced cytokine production in CAST/EiJ mice to those in the resistant BALB/c strain. Following intranasal infection, robust virus replication occurred in the lungs of both strains, although a relatively higher inoculum was required for BALB/c. However, while spread to other internal organs was rapid and efficient in CAST/EiJ mice, the virus was largely restricted to the lungs in BALB/c mice. Gamma interferon (IFN-γ) and CCL5 were induced in lungs of BALB/c mice concomitant with virus replication but not in CAST/EiJ mice. The importance of IFN-γ in protection against MPXV disease was demonstrated by the intranasal administration of the mouse cytokine to CAST/EiJ mice and the resulting protection against MPXV. Furthermore, C57BL/6 mice with inactivation of the IFN-γ gene or the IFN-γ receptor gene exhibited enhanced sensitivity to MPXV.
Insights
Susceptible CAST/EiJ mice infected with monkeypox virus (MPXV) showed widespread dissemination, unlike resistant BALB/c mice. Gamma interferon (IFN-γ) administration protected CAST/EiJ mice, highlighting its role in MPXV defense.
Area of Science:
- Virology
- Immunology
- Infectious Diseases
Background:
- Monkeypox virus (MPXV) is a zoonotic orthopoxvirus endemic in Africa.
- MPXV outbreaks have global implications, necessitating better understanding of host-pathogen interactions.
- Susceptibility to MPXV varies significantly across different mouse strains.
Purpose of the Study:
- To investigate the basis of MPXV susceptibility in CAST/EiJ mice compared to resistant BALB/c mice.
- To elucidate the role of cytokine responses, particularly gamma interferon (IFN-γ), in MPXV pathogenesis and host defense.
- To evaluate the potential of CAST/EiJ mice as a model for MPXV research.
Main Methods:
- Intranasal infection of CAST/EiJ and BALB/c mice with MPXV.
- Comparison of virus dissemination and replication in different organs.
- Measurement of cytokine production (IFN-γ, CCL5) in infected lungs.
- Therapeutic administration of IFN-γ to susceptible mice.
- Assessment of MPXV sensitivity in genetically modified C57BL/6 mice lacking IFN-γ signaling.
Main Results:
- MPXV replicated robustly in the lungs of both mouse strains, with higher inoculum needed for BALB/c mice.
- CAST/EiJ mice exhibited rapid and efficient systemic virus spread, while BALB/c mice showed lung-restricted infection.
- BALB/c mice induced IFN-γ and CCL5, which were absent in CAST/EiJ mice during infection.
- Intranasal IFN-γ treatment protected CAST/EiJ mice from MPXV.
- Mice lacking IFN-γ signaling (IFN-γ gene or receptor knockout) showed increased MPXV sensitivity.
Conclusions:
- IFN-γ is crucial for host defense against MPXV, mediating resistance in susceptible mouse strains.
- CAST/EiJ mice are a valuable model for studying MPXV pathogenesis and evaluating therapeutics due to their differential cytokine response.
- Understanding strain-specific immune responses can inform strategies for controlling MPXV spread and disease.
