Downregulation of human CD46 by adenovirus serotype 35 vectors

Sakurai, Fuminori; Akitomo, Kimiyo; Kono, Kenji; Hayakawa, Tetsuo; Mizuguchi, Hiroyuki

doi:10.1038/sj.gt.3302946

Cited by 27 publications

(21 citation statements)

References 46 publications

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“…Disappearance of CD46 from the cell surface through internalization is MOI dependent and reached a peak at about 8 h postinfection. Our observation is in agreement with a study by Sakurai et al, who reported downregulation of CD46 after Ad35 infection (21). Furthermore, we found that, in MO7e cells, Ad5/35 particles with higher affinity to CD46 remain longer in endosomes (Fig.…”

Section: Discussionsupporting

confidence: 83%

In Vitro and In Vivo Properties of Adenovirus Vectors with Increased Affinity to CD46

Wang

Liu

et al. 2008

J Virol

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Human adenoviruses (Ads) have been classified into six species (A to F) containing 51 defined serotypes. Most Ad serotypes utilize the coxsackievirus Ad receptor (CAR) as a primary attachment receptor. Recently, we suggested a new grouping of species B Ads based on their receptor usage (32). Group 1 (Ad serotype 16 [Ad16], Ad21, Ad35, and Ad50) nearly exclusively utilize CD46 as a cellular receptor; group 2 (Ad3, Ad7, and Ad14) share the same nonidentified receptor, which we refer to as receptor X; group 3 (Ad11p) preferentially interacts with CD46 but also utilizes receptor X if CD46 is blocked (32).Recent studies performed in U.S. military training facilities indicate an emergence of diverse species B serotypes at the majority of sites. This included the group 1 serotype 21 and the group 2 serotypes 3, 7, and 14 (17, 39). Species B-derived, replication-deficient vectors have recently shown promise as vehicles for gene transfer into multiple human cell types including cancer cells and tissue stem cells (30,35).Because of the importance of species B Ads as pathogens and application of species B-derived vectors for gene transfer, we studied the interaction between group 2 Ad35 and CD46 in more detail. Ad35 engages CD46 via residues in the C-terminal trimeric fiber knob domain (7). Within CD46 the Ad35-interacting areas are located in the two distal extracellular domains of the receptor (6,8). More recently, we used an expression library of the Ad35 fiber knob with random mutations to identify the amino acid residues within the Ad35 knob that mediate binding to CD46. We identified four critical residues (Phe242, Arg279, Ser282, and Glu302) which, when mutated, ablated Ad35 knob binding to CD46 without affecting knob trimerization (36).In the present study we used the same Ad35 expression library to screen for Ad35 knob mutants with increased binding to CD46 compared to the wild-type Ad35 knob. Our goal was to construct Ad vectors with substantially increased affinity for CD46. The rationale for such vectors comes from studies with phage antibody expression libraries (33) and more recently from studies with aptamers, protein-binding oligonucleotides (23). The goal of phage and aptamer library screening is to identify variants with the highest affinity, because in in vitro and in vivo studies with single-chain variable fragment fragments and aptamers, higher affinity usually directly translates into more-efficient binding to receptor-positive cells. Along this line, attempts were undertaken to incorporate high-affinity ligands into measles virus (9) and Ad vectors (2,3,40) in order to increase efficacy and specificity of target cell infection in vivo or to establish new receptor-ligand systems for the propagation of vectors.

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Section: Discussionsupporting

confidence: 83%

In Vitro and In Vivo Properties of Adenovirus Vectors with Increased Affinity to CD46

Wang

Liu

et al. 2008

J Virol

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“…CD46 serves as a receptor for several pathogens including strains of measles virus (10), human herpesvirus type 6 (42), group A streptococci (38), adenovirus (13,45), and Neisseria (24). Among these pathogens, infection by certain strains of measles virus (33,43), human herpesvirus type 6 (42), serogroup B adenovirus (41), and Neisseria gonorrhoeae (15) has been shown to cause CD46 downregulation from the cell surface. The detailed mechanisms of surface CD46 downregulation upon infection by these pathogens remain to be elucidated; however, the decrease in the surface density of CD46 renders the cells more susceptible to lysis by complement, as demonstrated in vitro (44), and may contribute to the attenuation of these pathogens by the rapid clearing of infected cells.…”

Section: Resultsmentioning

confidence: 99%

CD46 Contributes to the Severity of Group A Streptococcal Infection

et al. 2008

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Streptococcus pyogenes (group A Streptococcus) is a human pathogen that causes a wide variety of diseases ranging from uncomplicated superficial infections to severe infections such as streptococcal toxic shock syndrome and necrotizing fasciitis. These bacteria interact with several host cell receptors, one of which is the cell surface complement regulator CD46. In this study, we demonstrate that infection of epithelial cells with S. pyogenes leads to the shedding of CD46 at the same time as the bacteria induce apoptosis and cell death. Soluble CD46 attached to the streptococcal surface, suggesting that bacteria might bind available extracellular CD46 as a strategy to survive and avoid host defenses. The protective role of human CD46 was demonstrated in ex vivo whole-blood assays showing that the growth of S. pyogenes was enhanced in blood from mice expressing human CD46. Finally, in vivo experimental infection showed that bacteremia levels, arthritis frequency, and mortality were higher in CD46 transgenic mice than in nontransgenic mice. Taken together, these results argue that bacterial exploitation of human CD46 enhances bacterial survival and represents a novel pathogenic mechanism that contributes to the severity of group A streptococcal disease.

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“…The cells were incubated with UV-inactivated ML from MV Edmonston strain-infected rhesus monkey kidney (RMK) cells (4 ϫ 10 5 PFU/ml, kindly provided by Steven Wesselingh, Macfarlane Burnet Institute for Medical Research, Melbourne, Australia [12]) or control RMK cell lysate alone, for 24 h as previously described (25), or with PHA (1 g/ml; Murex Biotech, Kent, United Kingdom) for 48 h. The data were acquired using a FACSCalibur flow cytometer and analyzed by using CellQuest (BD Biosciences) and FlowJo software (Tree Star, Ashland, OR). The percent CD46 downregulation after ML or PHA stimulation was calculated using the method of Sakurai et al (26).…”

Section: Methodsmentioning

confidence: 99%

CD46Measles Virus Receptor Polymorphisms Influence Receptor Protein Expression and Primary Measles Vaccine Responses in Naive Australian Children

Clifford¹,

Hayden²,

Khoo³

et al. 2012

Clin. Vaccine Immunol.

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ABSTRACTDespite the availability of measles vaccines, infants continue to die from measles. Measles vaccine responses vary between individuals, and poor immunogenicity is likely to preclude protection against measles. CD46 is a ubiquitously expressed specific receptor for vaccine strains of measles virus.CD46polymorphisms have not been functionally investigated but may affect CD46 protein expression, which in turn may mediate primary measles antibody responses in infants. In a cohort of children aged 12 to 14 months from Perth, Australia (n= 137), after their first dose of measles-mumps-rubella (MMR) vaccine,CD46polymorphisms were genotyped, and postvaccination measles IgG and CD46 protein expression before and after measles lysate stimulation of cells were measured. ThreeCD46variants (rs7144, rs11118580, and rs2724384) were significantly associated with measles virus-specific IgG levels (P= 0.008,P= 0.026, andP= 0.018, respectively). There were significant differences betweenCD46rs7144 genotypes and CD46 protein expression on T cells, as well as the downregulation of CD46 and T-cell frequency after measles lysate stimulation. We show thatCD46polymorphisms were associated with primary measles antibody responses in naive infants. We also report the first association of a measles virus receptor polymorphism with functional effects on the receptor, suggesting a possible mechanism through which antibody responses are altered. Elucidating all of the interconnecting genetic factors that alter primary measles vaccine responses may be important for identifying children at risk of poor immunogenicity or vaccine failure and for the future design of vaccine strategies to help these children.

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Downregulation of human CD46 by adenovirus serotype 35 vectors

Cited by 27 publications

References 46 publications

In Vitro and In Vivo Properties of Adenovirus Vectors with Increased Affinity to CD46

In Vitro and In Vivo Properties of Adenovirus Vectors with Increased Affinity to CD46

CD46 Contributes to the Severity of Group A Streptococcal Infection

CD46Measles Virus Receptor Polymorphisms Influence Receptor Protein Expression and Primary Measles Vaccine Responses in Naive Australian Children

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