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C5a peptidase interactions with human Type II and Type III interferons and their potential role in inflammatory disease
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Date
2025-12
Abstract
Autoimmune inflammatory diseases such as psoriasis and inflammatory bowel disease IBD involve complex immune pathways driven by factors including IFN IL17 and C5a. Current therapies for moderate to severe disease primarily rely on monoclonal antibodies targeting proinflammatory cytokines but their high cost and limited accessibility remain major limitations. In contrast therapeutics targeting the complement system have been less explored with only a few approved drugs. However, interest in complement inhibition has recently increased with several anti C3, C5 and C5a products seeking FDA approval.
Proteases have emerged as promising alternatives to antibody-based therapies due to their catalytic efficiency, substrate specificity and potential for lower dosing. One such enzyme, C5a peptidase, also known as ScpA, is a surface associated serine protease from Streptococcus pyogenes that contributes to streptococcus virulence by cleaving complement components C5a, C3 and C3a. While ScpA’s interactions with complement proteins are well characterized its potential activity toward other immune mediators remains unexplored.
This study systematically examined ScpA’s ability to cleave a panel of 23 human pro-inflammatory cytokines, revealing previously unreported enzymatic activity towards IFNγ, IFNλ1, IFNλ2, C5, IL-37. Biochemical characterization using mass spectrometry and surface plasmon resonance, revealed cleavage sites and relative affinities showing that ScpA binds and cleaves IFNγ, IFNλ1 and IFNλ2 with lower efficiency than C5a. Additionally, molecular dynamics simulations further characterized ScpA interactions with IFNγ, IFNλ1 and C5a providing structural insight into substrate recognition.
Functional assays using hTERT-RPE1 and HEKn cell lines demonstrated that ScpA mediated cleavage of IFNγ effectively suppresses IFN induced JAK/STAT signaling and additionally, ScpA was shown to restore health in IFNγ induced psoriatic epidermis models. Altogether, the data presented in this study demonstrates that ScpA has a role in Streptococcus pyogenes infection beyond complement modulation and highlights ScpA’s potential use as an anti-inflammatory therapeutic.
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An article has been redacted from 'Appendix D – Published Manuscripts'. This article can be consulted at: https://doi.org/10.1016/j.cyto.2025.156994
Publisher
University of Limerick
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Duarte_2025_C5.pdf
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