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Antibody-independent activation of the classical complement pathway by cytomegalovirus-infected fibroblasts
1Department of Medical Biochemistry, University of Wales College of Medicine, Cardiff, UK. SpillerB@Cardiff.ac.uk
Abstract:
Human fibroblasts weakly activated the alternative complement pathway, as assessed by C3b deposition, while 4- to 5-fold more C3b was observed 4 days after infection on cytomegalovirus (CMV)-infected fibroblasts when incubated with human serum. CMV-infected fibroblasts activated via the classical complement pathway independent of specific anti-CMV antibody and incubation of CMV-infected fibroblasts with serum deficient in complement components revealed that C1q, but not mannan-binding lectin, was required for complement activation. The enhanced complement activation by CMV-infected cells was observed as early as 4 h after infection and required the active transcription of CMV genes. No difference in the complement activation by CMV-infected cells was observed with the use of CMV-seropositive or -seronegative serum as a complement source, suggesting that CMV infection induces or up-regulates a protein that binds directly to C1q in a complement-activating conformation.
Insights
Cytomegalovirus (CMV) infection enhances complement activation on human fibroblasts via the classical pathway, independent of antibodies. This process requires active CMV gene transcription and involves C1q binding.
Area of Science:
- Immunology
- Virology
- Cell Biology
Background:
- Human fibroblasts exhibit weak activation of the alternative complement pathway.
- Cytomegalovirus (CMV) is a common human virus with significant clinical implications.
Purpose of the Study:
- To investigate the effect of CMV infection on complement activation by human fibroblasts.
- To elucidate the specific complement pathway and components involved in CMV-induced activation.
Main Methods:
- Assessed C3b deposition on CMV-infected and uninfected human fibroblasts incubated with human serum.
- Utilized serum deficient in specific complement components (C1q, mannan-binding lectin) to determine pathway requirements.
- Investigated the role of CMV gene transcription and antibody-independence in complement activation.
Main Results:
- CMV-infected fibroblasts showed a 4- to 5-fold increase in C3b deposition compared to uninfected cells.
- Complement activation occurred via the classical pathway, independent of anti-CMV antibodies.
- C1q was essential for this enhanced activation, while mannan-binding lectin was not required.
- Enhanced complement activation was observed as early as 4 hours post-infection and depended on active CMV gene transcription.
Conclusions:
- CMV infection induces or up-regulates a protein on fibroblasts that directly binds C1q, activating the classical complement pathway.
- This antibody-independent mechanism suggests a direct interaction between CMV-infected cells and the complement system.