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Retargeting pre-existing human antibodies to a bacterial pathogen with an alpha-Gal conjugated aptamer.

ABSTRACT: The ever-increasing threat of multi-drug resistant bacterial infections has spurred renewed interest in alternative approaches to classical antibiotic therapy. In contrast to other mammals, humans do not express the galactose-?-1,3-galactosyl-?-1,4-N-acetyl-glucosamine (?-Gal) epitope. As a result of exposure of humans to ?-Gal in the environment, a large proportion of circulating antibodies are specific for the trisaccharide. In this study, we examine whether these anti-Gal antibodies can be recruited and redirected to exert anti-bacterial activity. We show that a specific DNA aptamer conjugated to an ?-Gal epitope at its 5' end, herein termed an alphamer, can bind to group A Streptococcus (GAS) bacteria by recognition of a conserved region of the surface-anchored M protein. The anti-GAS alphamer was shown to recruit anti-Gal antibodies to the streptococcal surface in an ?-Gal-specific manner, elicit uptake and killing of the bacteria by human phagocytes, and slow growth of invasive GAS in human whole blood. These studies provide a first in vitro proof of concept that alphamers have the potential to redirect pre-existing antibodies to bacteria in a specific manner and trigger an immediate antibacterial immune response. Further validation of this novel therapeutic approach of applying ?-Gal technology in in vivo models of bacterial infection is warranted.. ?-Gal-tagged aptamers lead to GAS opsonization with anti-Gal antibodies. . ?-Gal-tagged aptamers confer phagocytosis and killing of GAS cells by human phagocytes. . ?-Gal-tagged aptamers reduces replication of GAS in human blood. . ?-Gal-tagged aptamers may have the potential to be used as novel passive immunization drugs.

SUBMITTER: Kristian SA

PROVIDER: S-EPMC4469262 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Retargeting pre-existing human antibodies to a bacterial pathogen with an alpha-Gal conjugated aptamer.

Kristian Sascha A SA Hwang John H JH Hall Bradley B Leire Emma E Iacomini John J Old Robert R Galili Uri U Roberts Charles C Mullis Kary B KB Westby Mike M Nizet Victor V

Journal of molecular medicine (Berlin, Germany) 20150505 6

<h4>Unlabelled</h4>The ever-increasing threat of multi-drug resistant bacterial infections has spurred renewed interest in alternative approaches to classical antibiotic therapy. In contrast to other mammals, humans do not express the galactose-α-1,3-galactosyl-β-1,4-N-acetyl-glucosamine (α-Gal) epitope. As a result of exposure of humans to α-Gal in the environment, a large proportion of circulating antibodies are specific for the trisaccharide. In this study, we examine whether these anti-Gal a ...[more]

PMID: 25940316

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Project description:IntroductionAlpha-gal syndrome (AGS) is characterized by delayed hypersensitivity to non-primate mammalian meat in people having specific immunoglobulin E (sIgE) to the oligosaccharide galactose-alpha-1,3-galactose. AGS has been linked to tick bites from Amblyomma americanum (Aa) in the U.S. A small animal model of meat allergy is needed to study the mechanism of alpha-gal sensitization, the effector phase leading to delayed allergic responses and potential therapeutics to treat AGS.MethodsEight- to ten-weeks old mice with a targeted inactivation of alpha-1,3-galactosyltransferase (AGKO) were injected intradermally with 50 μg of Aa tick salivary gland extract (TSGE) on days 0, 7, 21, 28, 42, and 49. Total IgE and alpha-gal sIgE were quantitated on Day 56 by enzyme-linked immunosorbent assay. Mice were challenged orally with 400 mg of cooked pork kidney homogenate or pork fat. Reaction severity was assessed by measuring a drop in core body temperature and scoring allergic signs.ResultsCompared to control animals, mice treated with TSGE had 190-fold higher total IgE on Day 56 (0.60 ± 0.12 ng/ml vs. 113.2 ± 24.77 ng/ml; p < 0.001). Alpha-gal sIgE was also produced in AGKO mice following TSGE sensitization (undetected vs. 158.4 ± 72.43 pg/ml). Further, sensitized mice displayed moderate clinical allergic signs along with a drop in core body temperature of ≥2°C as an objective measure of a systemic allergic reaction. Interestingly, female mice had higher total IgE responses to TSGE treatment but male mice had larger declines in mean body temperature.ConclusionTSGE-sensitized AGKO mice generate sIgE to alpha-gal and demonstrate characteristic allergic responses to pork fat and pork kidney. In keeping with the AGS responses documented in humans, mice reacted more rapidly to organ meat than to high fat pork challenge. This mouse model establishes the central role of tick bites in the development of AGS and provides a small animal model to mechanistically study mammalian meat allergy.

Dataset Information

Retargeting pre-existing human antibodies to a bacterial pathogen with an alpha-Gal conjugated aptamer.

Publications

Retargeting pre-existing human antibodies to a bacterial pathogen with an alpha-Gal conjugated aptamer.

Similar Datasets

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