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Surviving mousepox infection requires the complement system
Elizabeth A Moulton1, John P Atkinson, R Mark L Buller
1Rheumatology Division, Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA.
Abstract:
Poxviruses subvert the host immune response by producing immunomodulatory proteins, including a complement regulatory protein. Ectromelia virus provides a mouse model for smallpox where the virus and the host's immune response have co-evolved. Using this model, our study investigated the role of the complement system during a poxvirus infection. By multiple inoculation routes, ectromelia virus caused increased mortality by 7 to 10 days post-infection in C57BL/6 mice that lack C3, the central component of the complement cascade. In C3(-/-) mice, ectromelia virus disseminated earlier to target organs and generated higher peak titers compared to the congenic controls. Also, increased hepatic inflammation and necrosis correlated with these higher tissue titers and likely contributed to the morbidity in the C3(-/-) mice. In vitro, the complement system in naïve C57BL/6 mouse sera neutralized ectromelia virus, primarily through the recognition of the virion by natural antibody and activation of the classical and alternative pathways. Sera deficient in classical or alternative pathway components or antibody had reduced ability to neutralize viral particles, which likely contributed to increased viral dissemination and disease severity in vivo. The increased mortality of C4(-/-) or Factor B(-/-) mice also indicates that these two pathways of complement activation are required for survival. In summary, the complement system acts in the first few minutes, hours, and days to control this poxviral infection until the adaptive immune response can react, and loss of this system results in lethal infection.
Insights
The complement system is crucial for controlling poxvirus infections. Loss of complement component C3 in mice led to increased mortality and viral spread, highlighting complement
Area of Science:
- Immunology
- Virology
- Infectious Diseases
Background:
- Poxviruses employ immunomodulatory proteins to evade host immunity.
- The ectromelia virus in mice serves as a model for studying poxvirus-host immune co-evolution.
- The complement system is a key component of innate immunity with known antiviral functions.
Purpose of the Study:
- To investigate the role of the complement system in poxvirus infection using the ectromelia virus mouse model.
- To determine the impact of complement deficiency on viral dissemination, pathogenesis, and mortality.
- To elucidate the specific complement pathways involved in antiviral defense against poxviruses.
Main Methods:
- Utilized C57BL/6 mice with targeted deficiencies in complement components (C3, C4, Factor B).
- Administered ectromelia virus via multiple inoculation routes to assess mortality and viral load.
- Performed in vitro neutralization assays using mouse sera with varying complement pathway activities.
- Analyzed viral dissemination, organ titers, hepatic inflammation, and necrosis.
Main Results:
- Mice lacking C3 exhibited significantly increased mortality (7-10 days post-infection) and earlier viral dissemination.
- Higher viral titers in target organs of C3-deficient mice correlated with increased hepatic inflammation and necrosis.
- In vitro studies demonstrated that complement activation via classical and alternative pathways, along with natural antibodies, neutralizes ectromelia virus.
- Deficiencies in C4 or Factor B also led to increased mortality, underscoring the importance of both pathways.
Conclusions:
- The complement system provides essential early control of poxviral infections, bridging the gap until adaptive immunity develops.
- Complement component C3 is critical for limiting viral replication and dissemination, thereby preventing lethal outcomes.
- Both the classical and alternative complement pathways are required for effective host survival during ectromelia virus infection.
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