Intracellular Sequestration of the NKG2D Ligand MIC B by Species F Adenovirus

Abstract

The enteric human adenoviruses of species F (HAdVs-F), which comprise HAdV-F40 and HAdV-F41, are significant pathogens that cause acute gastroenteritis in children worldwide. The early transcription unit 3 (E3) of HAdVs-F is markedly different from that of all other HAdV species. To date, the E3 proteins unique to HAdVs-F have not been characterized and the mechanism by which HAdVs-F evade immune defenses in the gastrointestinal (GI) tract is poorly understood. Here, we show that HAdV-F41 infection of human intestinal HCT116 cells upregulated the expression of MHC class I-related chain A (MIC A) and MIC B relative to uninfected cells. Our results also showed that, for MIC B, this response did not however result in a significant increase of MIC B on the cell surface. Instead, MIC B was largely sequestered intracellularly. Thus, although HAdV-F41 infection of HCT116 cells upregulated MIC B expression, the ligand remained inside infected cells. A similar observation could not be made for MIC A in these cells. Our preliminary findings represent a novel function of HAdVs-F that may enable these viruses to evade immune surveillance by natural killer (NK) cells in the infected gut, thereby paving the way for the future investigation of their unique E3 proteins.

Multiplex MinION sequencing suggests enteric adenovirus F41 genetic diversity comparable to pre-COVID-19 era

“…Enzymes intended for blood direct PCR may be beneficial as they are more tolerant of inhibition. Lack of amplification from blood samples may also be due to increased fragmentation of DNA extracted from blood, previously shown to be a factor for adenovirus [56,57] and other DNA viruses such as human cytomegalovirus [58] in cell-free DNA from human plasma.…”

“…Adenovirus species A and F do not produce the E3-19K protein found in other HAdVs [ 56 ], but make other unique E3 products (19.4K and 31.6K) with immune modulatory functions. The species F E3 region appears to have a role in preventing infected cells from signalling to natural killer (NK) cells via intracellular sequestration of MICB [ 57 ]. Lineage 3b viruses show evidence of decreased genome similarity to other F41 lineages in this region.…”

Pediatric adenovirus pneumonia: clinical practice and current treatment

“…When interacting with E4ORF3 expressed by the E4, E1B-55 K can inactivate the MRN complex, which binds to the adenovirus genome and boost viral genome duplication ( 60 ). Meanwhile, the E3 interferes with the expression of MHC class I and the NK cell activation receptor NKG2D, weakening the effect of antigen presentation by adenovirus-infected cells and alleviating immune attack mediated by CD8+ T cells ( 61 , 62 ). Other E3 genes-14.7 K, 10.4 K, 14.5 K, 6.7 K-work jointly to block tumor necrosis factor (TNF)-induced apoptosis and encode R1D1α that inhibits NF-κB activating cytokines and chemokines, downstream of EGFR signaling pathway ( 63 , 64 ).…”