Identification of CD46 Binding Sites within the Adenovirus Serotype 35 Fiber Knob

Wang, Hongjie; Liaw, Yen-Chywan; Stone, Daniel; Kalyuzhniy, Oleksandr; Amiraslanov, I. R.; Tuve, Sebastian; Verlinde, Christophe L. M. J.; Shayakhmetov, Dmitry M.; Stehle, Thilo; Roffler, Steve R.; Lieber, André

doi:10.1128/jvi.01732-07

Cited by 73 publications

(92 citation statements)

References 31 publications

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“…Fiber trimerization is crucial for binding of Ad35 fiber proteins to human CD46. 31,40 As shown in the upper panel of Figure 2, we detected a band of 110 kDa corresponding to the trimerized fibers in all the lanes for the AdF35 vectors, including the fiber-modified AdF35 vectors. In addition, the mutant Ad35 fibers containing the foreign peptides were detected at a higher position, compared with the wild-type Ad35 fibers, under a denaturing condition (Figure 2, lower panel) due to the incorporation of 13 (RGD peptide) and 16 amino acids (FLAG peptide) into the fiber knob.…”

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confidence: 68%

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confidence: 99%

“…Recent studies have revealed the structure of species B Ad fiber knobs, the mode of interaction with CD46 and several amino acids crucial for CD46 binding in the fiber knob, [28][29][30][31] and that the FG, HI and IJ loops are involved in the association with CD46. [31][32][33] In particular, Phe242 in the FG loop, Arg279 and Ser282 in the HI loop, and Glu302 in the IJ loop are crucial for attachment to CD46 (note that the numbers of amino-acid residues are those of the Ad35 fiber knob). 31 A unique XbaI restriction site was introduced into the proximity of regions encoding these amino-acid residues, between Gln243 and Thr244 in the FG loop, Met280 and Ile281 in the HI loop, or Glu302 and Ser303 in the IJ loop, in the vector plasmid for AdF35 vectors to allow easy insertion of the oligonucleotides corresponding to foreign peptides by means of in vitro ligation.…”

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confidence: 99%

“…[31][32][33] In particular, Phe242 in the FG loop, Arg279 and Ser282 in the HI loop, and Glu302 in the IJ loop are crucial for attachment to CD46 (note that the numbers of amino-acid residues are those of the Ad35 fiber knob). 31 A unique XbaI restriction site was introduced into the proximity of regions encoding these amino-acid residues, between Gln243 and Thr244 in the FG loop, Met280 and Ile281 in the HI loop, or Glu302 and Ser303 in the IJ loop, in the vector plasmid for AdF35 vectors to allow easy insertion of the oligonucleotides corresponding to foreign peptides by means of in vitro ligation. 26,34,35 The vector plasmids pAdHM75-XbaI(FG), -XbaI(HI) and -XbaI(IJ) were constructed as described below.…”

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confidence: 99%

“…An increase in the luciferase production was not observed for the AdF35 vectors with foreign peptides inserted in the IJ loop. The IJ loop of the Ad35 fiber knob is far from the short consensus repeat (SCR)2 in human CD46, compared with Ad serotypes 7 and 11 (Ad11), 28,[30][31][32] suggesting that an RGD peptide inserted into the IJ loop might not be able to make contact with CD46. Unexpectedly, AdF35-FLAG(HI)-L2 also showed increased transduction efficiencies in both cell types.…”

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confidence: 99%

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Development of fiber-substituted adenovirus vectors containing foreign peptides in the adenovirus serotype 35 fiber knob

et al. 2009

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Fiber-substituted adenovirus (Ad) vectors containing fibers of Ad serotype 35 (AdF35) efficiently transduce a variety of human cells because their receptor, human CD46, is ubiquitously expressed on almost all nucleated cells. However, the ubiquitous expression of CD46 might lead to unexpected transduction in untargeted organs. In this study, we developed fiber-modified AdF35 vectors with an integrinbinding Arg-Gly-Asn (RGD) peptide incorporated into the FG, HI or IJ loop, which have been identified as important regions for binding to CD46. Incorporation of foreign peptides into these loops does not inhibit trimerization of the fibers. In CD46-negative cells, fiber-mutant AdF35 vectors containing an RGD peptide in the FG or HI loop showed 6-to 30-fold higher transduction efficiencies in an RGD-peptide-dependent manner than the unmodified AdF35 vectors. In contrast, in CD46-positive cells, insertion of foreign peptides markedly reduced the transduction efficiencies of the AdF35 vectors, indicating that insertion of foreign peptides significantly inhibits binding to CD46. In particular, CD46-mediated transduction was completely diminished by insertion of foreign peptides into the HI loop. Our findings indicate that HI loop is the most suitable domain to mediate a foreign peptide-dependent and CD46-independent transduction by incorporation of foreign peptides into the Ad35 fiber knob.

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confidence: 68%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Development of fiber-substituted adenovirus vectors containing foreign peptides in the adenovirus serotype 35 fiber knob

et al. 2009

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Retargeting adenoviruses for therapeutic applications and vaccines

Barry

Rubin

2020

FEBS Letters

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Adenoviruses (Ads) are robust vectors for therapeutic applications and vaccines, but their use can be limited by differences in their in vitro and in vivo pharmacologies. This review emphasizes that there is not just one Ad, but a whole virome of diverse viruses that can be used as therapeutics. It discusses that true vector targeting involves not only retargeting viruses, but importantly also detargeting the viruses from off-target cells.

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CD46 accelerates macrophage‐mediated host susceptibility to meningococcal sepsis in a murine model

et al. 2016

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Eur. J. Immunol. 2017. 47: 119-130 Macrophages play an essential role in controlling bacterial infection, as they efficiently eliminate pathogens, provide a significant source of cytokines, and represent and link between innate and adaptive immunity [6]. Both the environmental milieu and cellular mitochondrial metabolism [7] can alter the functional polarization of macrophages, which can be broadly classified as classically activated (M1) and alternatively activated (M2) [8]. M1 macrophages triggered by IFN-γ alone or in combination with bacterial LPS are characterized by the production of type 1 inflammatory cytokines and bactericidal mediators such as nitric oxide and reactive oxygen intermediates. Thus, M1 macrophages play a dominant role in controlling acute infections, but also have the potential to induce a cytokine storm that is associated with tissue injury. In contrast, M2 macrophages triggered by IL-4/IL-13, glucocorticoids, IL-10, or immune complexes produce elevated amounts of anti-inflammatory cytokines and Th2-recruiting chemokines. M2 macrophages exhibit efficient phagocytic activity as well as increased expression of arginase 1, and therefore contribute to tissue healing and resolution of harmful inflammation. However, prolonged M2 polarization can generate a survival niche that leads to chronic microbial infection [9]. Initial overwhelming inflammatory responses, followed by macrophage dysfunction during the later stages of infection, have been widely observed in patients with severe sepsis. This probably occurs due to a switch in the macrophage phenotype from M1 to M2, implying a close association between macrophage phenotype and the progression of sepsis [10].The transmembrane protein CD46 was initially identified as a co-factor for complement factor I, which is involved in protecting host cells from autologous complement-mediated attack [11]. CD46 also serves as a receptor for several pathogens including measles virus [12] (Fig. 1A). Systemic meningococcal dissemination was well controlled in the WT mice, but not in the CD46 +/+ mice (Fig. 1B).To investigate whether this phenomenon was a general response to gram-negative bacterial infection, we repeated the experiments, challenging the mice with E. coli LPS. A non-lethal dose (20 mg/kg) for WT mice led to 67% mortality in CD46 +/+ mice within 4 days (Fig. 1C). A reduction in body weight, a common indicator of the severity of sepsis, was observed in the CD46 +/+ mice. Body weight was maintained in WT mice even though an initial decline was observed (Fig. 1D). The levels of circulatory cytokines IL-10, IL-6, and TNF, which are closely associated with sepsis severity and a fatal outcome [27], were significantly higher in the CD46 +/+ mice than in the WT mice upon meningococcal infection (Fig. 1E). Stronger cytokine responses were also observed in CD46 +/+ mice, compared to that in WT mice, following LPS challenge even though the effect was transient and lost after 24 h for IL-10 and TNF ( hand, LPS degradation in vivo might also contribute t...

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Identification of CD46 Binding Sites within the Adenovirus Serotype 35 Fiber Knob

Cited by 73 publications

References 31 publications

Development of fiber-substituted adenovirus vectors containing foreign peptides in the adenovirus serotype 35 fiber knob

Development of fiber-substituted adenovirus vectors containing foreign peptides in the adenovirus serotype 35 fiber knob

Retargeting adenoviruses for therapeutic applications and vaccines

CD46 accelerates macrophage‐mediated host susceptibility to meningococcal sepsis in a murine model

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