Intracellular antibody receptor TRIM21 prevents fatal viral infection - PubMed (original) (raw)

Intracellular antibody receptor TRIM21 prevents fatal viral infection

Marina Vaysburd et al. Proc Natl Acad Sci U S A. 2013.

Abstract

Host species have evolved mechanisms that can inhibit pathogen replication even after a cell has been successfully invaded. Here we show that tripartite-motif protein 21 (TRIM21), a ubiquitously expressed E3 ubiquitin ligase that targets viruses inside the cytosol, protects mice against fatal viral infection. Upon infection with mouse adenovirus-1, naive mice lacking TRIM21 succumb to encephalomyelitis within 7 d. In contrast, wild-type mice rapidly up-regulate TRIM21 and control viremia. Trim21 heterozygous mice have a haploinsufficiency phenotype in which reduced TRIM21 expression leads to a viral load that is higher than wild types but lower than knockouts. TRIM21 is a high-affinity antibody receptor that allows antibodies to operate inside an infected cell. In passive transfer experiments at high viral dose, antisera that fully protects wild-type mice fails to protect most Trim21 knockout animals. These results demonstrate that TRIM21 provides potent antiviral protection and forms an important part of the humoral immune response.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Fig. 1.

MAV-1 causes fatal infection in naive TRIM21−/− mice. (A) Change in body weight upon infection of T21+/+ (white circles) and T21−/− (black squares) mice with 360 TCID50 MAV-1. (B) Brain viral copies at day 7 postinfection in T21+/+ (n = 13) and T21−/− (n = 14). (C) Survival of T21+/+ (n = 48) and T21−/− (n = 47) mice.

Fig. 2.

Fig. 2.

Early immune response to MAV-1 infection. (A) Fold induction of TRIM21 (black squares) and IFN-γ (black circles) transcripts and viral copies (black triangles) in the brains of T21+/+ mice infected with MAV-1 during the first week of infection. (B) Fold induction of inflammatory cytokines in T21+/+ (white circles) and T21−/− (black squares) mice by day 9.

Fig. 3.

Fig. 3.

Protection by early MAV-1 antisera is dependent upon TRIM21 expression. (A) Survival of T21+/+ (white circles) and T21−/− mice (black squares) after infection with 3.6 × 103 TCID50 of MAV-1. (B) Survival of T21+/+ (n = 14) and T21−/− (n = 15) mice upon infection with 3.6 × 103 TCID50 MAV-1 in the presence of passively transferred early antisera. (C) Survival of T21+/+ (n = 14) and T21+/− (n = 16) mice (black triangles) upon infection with 3.6 × 103 TCID50 MAV-1 in the presence of passively transferred early antisera. (D) Brain viral copies in T21+/+, T21+/−, and T21−/− mice after infection with 3.6 × 103 TCID50 MAV-1 in the presence of early antisera. (E) Induction of TRIM21 in T21+/+ (white bar) or T21+/− (hatched bar) after challenge with 3.6 × 103 TCID50 MAV-1 and early antisera 7 d postinfection.

Fig. 4.

Fig. 4.

Late MAV-1 antisera reduces viremia and protects T21+/+ but not T21−/− mice. (A) Neutralizing titer of preimmune (PI), early antisera (ES), and late antisera (LS) produced by T21+/+ (circles) and T21−/− (squares) mice. (B_–_D) Survival upon infection with 3.6 × 103 TCID50 MAV-1 in the presence of passively transferred LS at dilutions of 1/1,280 (B), 1/2,560 (C), or 1/10,240 (D). n = 5 for each genotype except in C, where n = 12. (E) Brain viral copies in T21+/+ and T21−/− mice after infection with 3.6 × 103 TCID50 MAV-1 in the presence of PBS or LS. (F) Binding of pooled serum antibody (squares) or F(ab′)2 fragments (circles) to MAV-1 virus as detected by ELISA. (G and H) Survival upon infection with 3.6 × 103 TCID50 MAV-1 in the presence of passively transferred pooled serum antibody (G) or F(ab′)2 fragments (H) at 1 mg/mL or 0.1 mg/mL, respectively.

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