Adenoviruses (Ads) are important human pathogens and valuable gene delivery vehicles. We report here the crystal structure of the species B Ad11 knob complexed with the Ad11-binding region of its receptor CD46. The conformation of bound CD46 differs profoundly from its unbound state, with the bent surface structure straightened into an elongated rod. This mechanism of interaction is likely to be conserved among many pathogens that target CD46 or related molecules.

Severe acute respiratory syndrome coronavirus 2 (SARS–CoV–2) has led to the coronavirus disease 2019 (COVID–19) pandemic, severely affecting public health and the global economy. Adaptive immunity plays a crucial role in fighting against SARS–CoV–2 infection and directly influences the clinical outcomes of patients. Clinical studies have indicated that patients with severe COVID–19 exhibit delayed and weak adaptive immune responses; however, the mechanism by which SARS–CoV–2 impedes adaptive immunity remains unclear. Here, by using an in vitro cell line, we report that the SARS–CoV–2 spike protein significantly inhibits DNA damage repair, which is required for effective V(D)J recombination in adaptive immunity. Mechanistically, we found that the spike protein localizes in the nucleus and inhibits DNA damage repair by impeding key DNA repair protein BRCA1 and 53BP1 recruitment to the damage site. Our findings reveal a potential molecular mechanism by which the spike protein might impede adaptive immunity and underscore the potential side effects of full-length spike-based vaccines.

No abstract

Comparative analysis of the genome organization of human adenovirus 11, a member of the human adenovirus species B, and the commonly used human adenovirus 5 vector, a member of species C Adenovirus type 11 (Ad11), a member of the human adenovirus species B (HAdV-B), has a tropism for the urinary tract. The genome of Ad11 was found to comprise 34 794 bp and is 1141 bp shorter than the Ad5 genome of species HAdV-C. The G+C content of the Ad11 genome is 48?9 %, whereas that of Ad5 is 55?2 %. Ad11 and Ad5 share 57 % nucleotide identity and possess the same four early regions, but the E3 region of Ad11 could not be divided into E3A and E3B. The late genes of Ad11 and Ad5 are organized into six and five regions, respectively. Thirty-eight putative ORFs were identified in the Ad11 genome. The ORFs in the late regions, the E2B region and IVa2 show high amino acid identity between Ad11 and Ad5, whereas the ORFs in E1, E2A, E3 and E4, protein IX and the fibre protein show low amino acid identity. The highest and lowest identities were noted in the pre-terminal protein and fibre proteins: 85 % and 24?6 %, respectively. The E3 20?3K and 20?6K ORFs and the L6 agnoprotein were present in the Ad11 genome only, whereas the E3 11?6K cell death protein was identified only in Ad5. All ORFs but the E3 10?3K and L4 pVIII protein vary not only in composition but also in size. Ad11 may have a higher vector capacity than Ad5, since it has a shorter genome and a shorter fibre. Furthermore, in the E3 region, two additional ORFs can be deleted to give extra capacity for foreign DNA. INTRODUCTIONHuman adenoviruses constitute a large group within the family Adenoviridae, with 51 serotypes identified so far. These serotypes are divided into six species, designated A-F, based on DNA homology (Green et al., 1979; Wadell et al., 1980;Wadell, 1984). The nine human adenovirus members of species B have been classified further into two subspecies, B:1 and B:2. Adenovirus 3 (Ad3), Ad7, Ad16, Ad21 and Ad50 belong to subspecies B:1 and cause respiratory infection, whereas Ad11, Ad34 and Ad35 of subspecies B:2 are associated with persistent infections of the urinary tract and kidney. Ad11 was first isolated from a stool sample of a patient with poliomyelitis and has subsequently been isolated from the urine of patients with haemorrhagic cystitis, as well as from pregnant women. Ad11 can also be found in healthy children and adults. Ad11, Ad34 and Ad35 are strongly over-represented among isolates from immunosuppressed patients and bone marrow transplant recipients.Ad11 targets an unknown cellular receptor, which is more widely distributed than the usual coxsackie-adenovirus receptor (CAR) and is highly expressed on the surface of cells from various organs. Furthermore, relatively few persons have been exposed to Ad11 and, consequently, seroprevalence is low (D'Ambrosio et al., 1982). Previously, we demonstrated that Ad11 binds strongly to and replicates in kidney cells (HEK 293 cells), an endothelial cell line, and committed haematopoietic cell lines. ...

Adenovirus infections are widespread in society and are occasionally associated with severe, but rarely with life-threatening, disease in otherwise healthy individuals. In contrast, adenovirus infections present a real threat to immunocompromised individuals and can result in disseminated and fatal disease. The number of patients undergoing immunosuppressive therapy for solid organ or hematopoietic stem cell transplantation is steadily increasing, as is the number of AIDS patients, and this makes the problem of adenovirus infections even more urgent to solve. There is no formally approved treatment of adenovirus infections today, and existing antiviral agents evaluated for their antiadenoviral effect give inconsistent results. We have developed a whole cell-based assay for high-throughput screening of potential antiadenoviral compounds. The assay is unique in that it is based on a replication-competent adenovirus type 11p green fluorescent protein (GFP)-expressing vector (RCAd11pGFP). This allows measurement of fluorescence changes as a direct result of RCAd11pGFP genome expression. Using this assay, we have screened 9,800 commercially available small organic compounds. Initially, we observed approximately 400 compounds that inhibited adenovirus expression in vitro by >80%, but only 24 were later confirmed as dose-dependent inhibitors of adenovirus. One compound in particular, 2-{[2-(benzoylamino)benzoyl]amino}-benzoic acid, turned out to be a potent inhibitor of adenovirus replication.