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

Shen, Zu T.; Sigalov, Alexander B.

To successfully infect, replicate and persist in the host, viruses have evolved numerous strategies to take control of multiple cellular processes including those that target transmembrane signal transduction mediated by immune receptors including MIRRs (reviewed in [42] [43] [44] ). For T lymphotropic viruses, this approach allows the virus to inhibit TCR signaling to disarm the receptor and successfully enter the cell while for other viruses it allows for evasion from T cell response towards the infected cells 42, 45, 46 . Recently reported TCR-targeted immunomodulatory activity mediated by HIV gp41 FP 17, 18 suggests that fusion peptides function not only to fuse the virion with the host cell 47,48 but also to silence the TCR signaling pathway. Interestingly, the characteristic pattern of TCR-targeted inhibitory activity of HIV gp41 FP is strikingly similar to that of TCR CP: both peptides colocalize with TCR in the cell membrane, inhibit antigen-but not anti-CD3-stimulated T cell activation in vitro, and suppress autoimmune arthritis in vivo [18] [19] [20] [21] 23, 25 . Both peptides were suggested for the treatment of T cell-mediated pathologies including inflammatory skin diseases and RA 18, [49] [50] [51] . In addition, TCR CP has been shown in human studies to be a proper treatment for human T cell-mediated dermatoses that can substitute for corticosteroids 52 . The molecular mechanisms of action for these clinically relevant peptides were first explained by the SCHOOL model 13, 27, 43, 53 . Later, based on the SCHOOL model and primary sequence analysis of a variety of viral FPs including SARS-CoV FP, we hypothesized that similar to HIV gp41 FP, these FPs may not only have fusogenic but also TCR-targeted immunomodulatory activity and that the SCHOOL model, together with the lessons learned from viral pathogenesis, can be used practically for rational drug design and the development of new therapies for immune disorders 29 . At the end of treatment on day 38, different groups of mice with collagen-induced arthritis (CIA) intraperitoneally (i.p.) administered daily with either vehicle, MG11 (25 mg/kg) or sHDL-bound MG11 (2.5 mg/kg) were euthanized and sections were prepared using fore paws, hind paws, knees and ankles. Individual joint photomicrographs from representative mice are shown for each group. For paws and ankles, arrows identify affected joints. For knees, large arrow identifies cartilage damage, small arrow identifies pannus, and arrowhead identifies bone resorption. W, wrist; S, synovium.