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. 2016 Jun 28:6:28672.
doi: 10.1038/srep28672.

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

Zu T Shen  1 , Alexander B Sigalov  1
Affiliations

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

Zu T Shen et al. Sci Rep. .

Abstract

During the co-evolution of viruses and their hosts, the viruses have evolved numerous strategies to counter and evade host antiviral immune responses in order to establish a successful infection, replicate and persist in the host. Recently, based on our model of immune signaling, the Signaling Chain HOmoOLigomerization (SCHOOL) model, we suggested specific molecular mechanisms used by different viruses such as severe acute respiratory syndrome coronavirus (SARS-CoV) to modulate the host immune response mediated by members of the family of multichain immune recognition receptors (MIRRs). This family includes T cell receptor (TCR) that is critically involved in immune diseases such as autoimmune arthritis. In the present study, we provide compelling experimental in vivo evidence in support of our hypothesis. Using the SCHOOL approach and the SARS-CoV fusion peptide sequence, we rationally designed a novel immunomodulatory peptide that targets TCR. We showed that this peptide ameliorates collagen-induced arthritis in DBA/1J mice and protects against bone and cartilage damage. Incorporation of the peptide into self-assembling lipopeptide nanoparticles that mimic native human high density lipoproteins significantly increases peptide dosage efficacy. Together, our data further confirm that viral immune evasion strategies that target MIRRs can be transferred to therapeutic strategies that require similar functionalities.

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Conflict of interest statement

Alexander B. Sigalov and Zu T. Shen are employees of SignaBlok, Inc. The funders provided support in the form of salaries for authors [ABS and ZTS], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.

Figures

Figure 1
Figure 1. TCR assembly and SCHOOL inhibition mechanism.
(a) T cell receptor (TCR) assembly is depicted. The TCR α and β recognition subunits are shown in red and blue, respectively. The CD3ε, CD3δ, CD3γ and ζ signaling subunits are shown as purple, dark orange, light orange and green, respectively. Immunoreceptor tyrosine-based activation motifs (ITAMs) are shown as spheres and are colored accordingly by subunit. The recognition and signaling subunits are bound together by electrostatic transmembrane (TM) interactions. These TM interactions occur between basic and acidic amino acid residues. The TCRα transmembrane domain (TMD) contains two basic residues: a lysine, which interacts with two acidic residues of aspartic acid present in the TMDs of the CD3εδ heterodimer, and an arginine, which interacts with two aspartic acid residues present in the TMDs of the ζζ homodimer. The TCRβ TMD contains a lysine, which interacts with one aspartic acid residue and one acidic residue of glutamic acid present in the TMDs of the CD3εγ heterodimer. (b) TM-targeted SCHOOL peptides such as the SARS-CoV FP or the TCR CP disrupt TM electrostatic interactions between the TCRα subunit and both CD3εδ and ζζ by competing with TCRα for binding to CD3εδ and ζζ.
Figure 2
Figure 2. The SARS-CoV FP sequence MG11 strikingly ameliorates the clinical severity of collagen-induced arthritis.
(a) On day 24 post immunization, different groups of mice with collagen-induced arthritis (CIA) were intraperitoneally (i.p.) administered daily with either vehicle, control peptide MG11-2G (25 mg/kg), MG11 (25 mg/kg) or sHDL-bound MG11 (2.5 mg/kg) for 14 days. Development of arthritis was monitored daily and clinical arthritis was scored. (b) Mouse body weight (BW) was measured every other day from day 24 to day 38. (c) Percentage in BW change at day 38 compared with day 24. All results are expressed as the mean ± SEM (n = 10 mice per group). **P < 0.01; ***P < 0.005; and ****P < 0.001 versus vehicle.
Figure 3
Figure 3. Effects of treatment with the SARS-CoV FP sequence MG11 on joint inflammation, cartilage destruction, pannus formation, and bone resorption in collagen-induced arthritis.
(a,b) 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, control peptide MG11-2G (25 mg/kg), MG11 (25 mg/kg) or sHDL-bound MG11 (2.5 mg/kg) were euthanized and evaluated for histopathology. (A) Individual paw and knee joints were scored for inflammation (I), pannus (P), cartilage damage (CD), bone resorption (BR), and periosteal new bone formation (PBF). (b) A summed histopathology score, which is the sum of all five histopathological parameters was calculated. All results are expressed as the mean ± SEM (n = 10 mice per group). **P < 0.01; ***P < 0.005; and ****P < 0.001 versus vehicle.
Figure 4
Figure 4. Representative toluidine blue staining of the fore and hind paws and the ankle and knee joints of vehicle- and MG11-treated mice with collagen-induced arthritis.
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.
Figure 5
Figure 5. Effects of treatment with the SARS-CoV FP sequence MG11 on cytokine production in collagen-induced arthritis.
Serum was collected at the end of treatment on day 38 from different groups of mice with collagen-induced arthritis (CIA) intraperitoneally (i.p.) administered daily with either vehicle, control peptide MG11-2G (25 mg/kg), MG11 (25 mg/kg) or sHDL-bound MG11 (2.5 mg/kg). Serum samples were analyzed for concentrations of granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-γ (IFNγ), interleukin-1β (IL-1β), IL-2, IL-6, IL-17, macrophage colony-stimulating factor (M-CSF) and tumor necrosis factor-α (TNFα). Results are expressed as the mean ± SEM (n = 5 mice per group). *P < 0.05; **P < 0.01.
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