doi: 10.1128/JVI.03141-13. Epub 2013 Oct 30.
Exposure to mimivirus collagen promotes arthritis
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- PMID:24173233
- PMCID: PMC3911627
- DOI: 10.1128/JVI.03141-13
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Exposure to mimivirus collagen promotes arthritis
Nikunj Shah et al. J Virol.2014 Jan.
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Abstract
Collagens, the most abundant proteins in animals, also occur in some recently described nucleocytoplasmic large DNA viruses such as Mimiviridae, which replicate in amoebae. To clarify the impact of viral collagens on the immune response of animals exposed to Mimiviridae, we have investigated the localization of collagens in Acanthamoeba polyphaga mimivirus particles and the response of mice to immunization with mimivirus particles. Using protein biotinylation, we have first shown that viral collagen encoded by open reading frame L71 is present at the surface of mimivirus particles. Exposure to mimivirus collagens elicited the production of anti-collagen antibodies in DBA/1 mice immunized intradermally with mimivirus protein extracts. This antibody response also targeted mouse collagen type II and was accompanied by T-cell reactivity to collagen and joint inflammation, as observed in collagen-induced arthritis following immunization of mice with bovine collagen type II. The broad distribution of nucleocytoplasmic large DNA viruses in the environment suggests that humans are constantly exposed to such large virus particles. A survey of blood sera from healthy human subjects and from rheumatoid arthritis patients indeed demonstrated that 30% of healthy-subject and 36% of rheumatoid arthritis sera recognized the major mimivirus capsid protein L425. Moreover, whereas 6% of healthy-subject sera recognized the mimivirus collagen protein L71, 22% of rheumatoid arthritis sera were positive for mimivirus L71. Accordingly, our study shows that environmental exposure to mimivirus represents a risk factor in triggering autoimmunity to collagens.
Figures
Domain organization of mimivirus L71 protein. The four collagen domains of L71 are shown as gray boxes with the number of G-X-Y repeats given inside. The asterisk shows the position of the sequence motif similar to the epitope human collagen type II recognized as immunodominant in rheumatoid arthritis (24). The sequence of this human collagen type II (Hu CII) T-cell epitope encompassing amino acids 259 to 273 is shown aligned with the corresponding sequence of mimivirus L71 (Mi L71) amino acids 101 to 115.
Joint inflammation in DBA/1 mice immunized with mimivirus proteins. (A) Clinical severity of arthritic limbs in the groups of mice immunized with PBS (●), bovine collagen type II (■), recombinant L71 protein (▼), marseillevirus proteins (◆), and mimivirus proteins (▲) are shown as means ± standard errors of the means. The arrow shows the time point of booster immunization. Data represent three independent experiments with 10 to 21 mice per group. (B) Representative H&E-stained sections of hind limbs by day 75 after immunization showing cartilage damage and synovial hyperplasia in mice immunized with bovine collagen type II (BovCII) and mimivirus protein (MV). No signs of pathology were visible in PBS-immunized negative-control mice (Neg). Scale bar, 100 μm.
Anti-collagen type II IgG titers in DBA/1 mice immunized with mimivirus proteins. Levels of serum IgG measured by ELISA against endogenous mouse collagen type II (CII) in mice immunized with PBS (Neg), bovine collagen type II (BovCII), mimivirus proteins (MV), marseillevirus proteins (MsV), or recombinant L71 protein (L71). Data represent three independent experiments with 10 to 21 mice per group. Horizontal bars show means ± standard errors of the means (*,P < 0.01).
Autoreactive T-cell response in DBA/1 mice immunized with mimivirus proteins. (A) Recall responses in cells isolated from draining lymph nodes of mice immunized with PBS (Neg), bovine collagen type II (BovCII), or mimivirus proteins (MV) after stimulation with denatured mouse collagen type II. (B) Recall responses after stimulation with denatured bovine collagen type II. (C) Recall responses after stimulation with denatured fragmented recombinant mimivirus protein L71. Data represent means ± standard errors of the means of groups of 3 mice (*,P < 0.01).
Reactivity of human sera toward mimivirus proteins. Anti-mimivirus IgG titers in sera of 100 healthy subjects were measured by ELISA after dilution to 1:100 and expressed as a ratio to IgG titers measured in 1:1,000-diluted sera from rabbits previously immunized with mimivirus particles. Data represent means ± standard errors of the means from four analyses.
Recognition of mimivirus proteins by human sera. (A) Representative Western blots of sera from healthy subjects (HS) and rheumatoid arthritis (RA) patients recognizing mimivirus capsid protein L425. (B) Representative Western blots of sera from healthy subjects (HS) and rheumatoid arthritis (RA) patients recognizing mimivirus collagen L71. Sera were diluted 1:4,000. Positions of recombinant L425 and L71 proteins in the blots are shown at the left of each panel using an anti-His6 antibody (His6). A 15-kDa fragment of His6-tagged human GLT25D2 protein was used as a negative control (Neg).
Specific recognition of mimivirus collagen L71 by human sera. Representative Western blots of L71-positive sera from healthy subjects (HS) and rheumatoid arthritis (RA) patients recognizing mimivirus collagen L71 but not a fragment of human collagen type III containing 114 G-X-Y repeats (CIII). Sera were diluted 1:4,000. Positions of recombinant L71 and CIII proteins in the blots are shown at the left of the panel using an anti-His6 antibody (His6).
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