Simultaneous Neutralization and Innate Immune Detection of a Replicating Virus by TRIM21

Abstract

Tripartite motif-containing 21 (TRIM21) is a cytosolic immunoglobulin receptor that mediates antibody-dependent intracellular neutralization (ADIN). Here we show that TRIM21 potently inhibits the spreading infection of a replicating cytopathic virus and activates innate immunity. We used a quantitative PCR (qPCR)-based assay to measure in vitro replication of mouse adenovirus type 1 (MAV-1), a virus that causes dose-dependent hemorrhagic encephalitis in mice. Using this assay, we show that genetic ablation of TRIM21 or chemical inhibition of either the AAA ATPase p97/valosin-containing protein (VCP) or the proteasome results in a >1,000-fold increase in the relative level of infection in the presence of immune serum. Moreover, the TRIM21-mediated ability of antisera to block replication was a consistent feature of the humoral immune response in immunized mice. In the presence of immune sera and upon infection, TRIM21 also activates a proinflammatory response, resulting in secretion of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6). These results demonstrate that TRIM21 provides a potent block to spreading infection and induces an antiviral state.

Antibody- and TRIM21-dependent intracellular restriction ofSalmonella enterica

“…These would recognise damaged vesicles rather than the pathogen or the antibody itself (Randow et al ., ), (Paz et al ., ; Ray et al ., ; Thurston et al ., ) and recruit downstream defence complexes, among those possibly TRIM21. However, the recognition of antibodies by TRIM21 is required to trigger downstream effects like immune signalling (McEwan et al ., ) or ADIN in viruses (Watkinson et al ., ). In this respect, the microscopy images (Fig.…”

“…The ADIN process requiring TRIM21 is a cellular self‐protection mechanism, which is very well characterised for nonenveloped viruses (Mallery et al ., ; McEwan et al ., , ; Vaysburd et al ., ; Watkinson et al ., ). Here, we present that TRIM21‐dependent ADIN is also able to restrict intracellular Salmonella enterica .…”

Intrinsic Cellular Defenses (TRIMS) in Modulating Viral Infection and Immunity

“…However, more recently TRIM21 also emerged as a widely expressed cytosolic antibody receptor, which interacts with the antibody Fc region via its C-terminal PRY-SPRY domain (Keeble et al, 2008). Thanks to the high-affinity interaction with the antibody Fc region, TRIM21 was shown to directly neutralize infection by targeting antibody-opsonized viruses and bacteria for proteasomal degradation (Mallery et al, 2010;McEwan et al, 2013;Vaysburd et al, 2013;Watkinson et al, 2013).…”

Intracellular immunity: finding the enemy within—how cells recognize and respond to intracellular pathogens

“…Notably, most of the methods that act to remove the pathogen directly also lead to some level of signaling. For example, TRIM5α [154] and TRIM21 [88, 90] signal via the production of lysine-63-linked ubiquitin chains, APOBECs and RNase L can lead to sensing of viral nucleic acids from their edited products [37, 121, 129], and tetherin leads to transcription factor activation [151]. …”