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PEGylation of bacteriophages increases blood circulation time and reduces T-helper type 1 immune response.

ABSTRACT: The increasing occurrence of antibiotic-resistant pathogens is of growing concern, and must be counteracted by alternative antimicrobial treatments. Bacteriophages represent the natural enemies of bacteria. However, the strong immune response following application of phages and rapid clearance from the blood stream are hurdles which need to be overcome. Towards our goal to render phages less immunogenic and prolong blood circulation time, we have chemically modified intact bacteriophages by conjugation of the non-immunogenic polymer monomethoxy-polyethylene glycol (mPEG) to virus proteins. As a proof of concept, we have used two different polyvalent and strictly virulent phages of the Myoviridae, representing typical candidates for therapeutical approaches: Felix-O1 (infects Salmonella) and A511 (infects Listeria). Loss of phage infectivity after PEGylation was found to be proportional to the degree of modification, and could be conveniently controlled by adjusting the PEG concentration. When injected into naïve mice, PEGylated phages showed a strong increase in circulation half-life, whereas challenge of immunized mice did not reveal a significant difference. Our results suggest that the prolonged half-life is due to decreased susceptibility to innate immunity as well as avoidance of cellular defence mechanisms. PEGylated viruses elicited significantly reduced levels of T-helper type 1-associated cytokine release (IFN-? and IL-6), in both naïve and immunized mice. This is the first study demonstrating that PEGylation can increases survival of infective phage by delaying immune responses, and indicates that this approach can increase efficacy of bacteriophage therapy.

SUBMITTER: Kim KP

PROVIDER: S-EPMC3815886 | biostudies-literature | 2008 May

REPOSITORIES: biostudies-literature

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PEGylation of bacteriophages increases blood circulation time and reduces T-helper type 1 immune response.

Kim Kwang-Pyo KP Cha Jeong-Dan JD Jang Eun-Hye EH Klumpp Jochen J Hagens Steven S Hardt Wolf-Dietrich WD Lee Kyung-Yeol KY Loessner Martin J MJ

Microbial biotechnology 20080501 3

The increasing occurrence of antibiotic-resistant pathogens is of growing concern, and must be counteracted by alternative antimicrobial treatments. Bacteriophages represent the natural enemies of bacteria. However, the strong immune response following application of phages and rapid clearance from the blood stream are hurdles which need to be overcome. Towards our goal to render phages less immunogenic and prolong blood circulation time, we have chemically modified intact bacteriophages by conj ...[more]

PMID: 21261844

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Project description:BACKGROUND:The systemic low-frequency oscillation (sLFO) functional (f)MRI signals extracted from the internal carotid artery (ICA) and the superior sagittal sinus (SSS) are found to have valuable physiological information. PURPOSE:1) To further develop and validate a method utilizing these signals to measure the delay times from the ICAs and the SSS. 2) To establish the delay time as an effective perfusion biomarker that associates with cerebral circulation time (CCT). 3) To explore within subject variations, and the effects of gender and age on the delay times. STUDY TYPE:Prospective. SUBJECTS:In all, 100 healthy adults (Human Connectome Project [HCP], age range 22-36 years, 54 females and 46 males), 56 healthy children (Adolescent Brain Cognitive Development project) were included. FIELD STRENGTH/SEQUENCE:Echo planar imaging (EPI) sequence at 3T. ASSESSMENT:The sLFO fMRI signals from the ICAs and the SSSs were extracted from the resting state fMRI data. The maximum cross-correlation coefficients and their corresponding delay times were calculated. The gender and age differences of delay times were assessed statistically. STATISTICAL TESTS:T-tests were conducted to measure the gender differences. The Kruskal-Wallis test was used to detect age differences. RESULTS:Consistent and robust results were found from 80% of the 400 HCP scans included. Negative correlations (-0.67) between the ICA and the SSS signals were found with the ICA signal leading the SSS signal by ?5 sec. Within subject variation was 2.23 sec at the 5% significance level. The delay times were not significantly different between genders (P = 0.9846, P = 0.2288 for the left and right ICA, respectively). Significantly shorter delay times (4.3 sec) were found in the children than in the adults (P < 0.01). DATA CONCLUSION:We have shown that meaningful perfusion information (ie, CCT) can be derived from the sLFO fMRI signals of the large blood vessels. LEVEL OF EVIDENCE:1 Technical Efficacy Stage: 1 J. Magn. Reson. Imaging 2019;50:1504-1513.

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PEGylation of bacteriophages increases blood circulation time and reduces T-helper type 1 immune response.

Publications

PEGylation of bacteriophages increases blood circulation time and reduces T-helper type 1 immune response.

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