SARS Coronavirus Fusion Peptide-Derived Sequence Suppresses Collagen-Induced Arthritis in DBA/1J Mice

Shen, Zu T.; Sigalov, Alexander B.

Multichain immune recognition receptors (MIRRs) play an important role in the host immune response (reviewed in [11] [12] [13] . In MIRRs, the extracellular ligand recognition domains and intracellular signaling sequences containing immunoreceptor tyrosine-based activation motifs (ITAMs) are located on separate protein chains (subunits) bound together by noncovalent transmembrane (TM) interactions 11, 12 . Structurally, T cell receptor (TCR) is a member of the MIRR family and has the α and β antigen-binding subunits that are bound by electrostatic TM interactions with three signaling homo-and heterodimers: ζ ζ , CD3ε δ , and CD3ε γ (Fig. 1a) . Short synthetic TM peptides capable of inhibiting TCR-mediated cell activation are known since 1997 14 when TCR-targeted immunomodulatory activity was first reported for the TCR core peptide (CP), a synthetic peptide corresponding to the sequence of the TCRα TM domain (TMD) known to interact with the TMDs of CD3ε δ and ζ 15, 16 . Similar activity was later reported for HIV FP found in the N terminus of the HIV envelope glycoprotein 41 (gp41) 17, 18 . Intriguingly, the patterns of TCR-targeted inhibitory activity of TCR CP and HIV gp41 FP were very similar: both peptides inhibit antigen-but not anti-CD3-stimulated T cell activation 18, 19 . Both peptides were shown to reduce inflammation and ameliorate T cell-mediated autoimmune diseases such as arthritis in animal models 18,20,21 . However, despite extensive studies 14, 17, 18, [20] [21] [22] [23] [24] [25] , the mode of action of these clinically relevant peptides was enigmatic until a novel model of immune signaling, the Signaling Chain HOmoOLigomerization (SCHOOL) model, was first introduced and applied to this field 13, 26, 27 . Previously, using the SCHOOL model and comparative primary sequence analysis of proven and predicted immunomodulatory sequences of viral fusion protein regions, we not only suggested the specific molecular mechanisms of T cell activation inhibition by TCR CP and HIV gp41 FP [27] [28] [29] but also predicted similar immunomodulatory activity for other viral FPs such as SARS-CoV FP (Fig. 1b) 29 .