Chemokine-Releasing Microparticles Improve Bacterial Clearance and Survival of Anthrax Spore-Challenged Mice

Taissia G Popova,Lance A Liotta,Allison Teunis,Virginia Espina,Serguei G Popov,Nupur Gangopadhyay

doi:10.1371/journal.pone.0163163

Taissia G Popova, Lance A Liotta + Show 4 more

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https://doi.org/10.1371/journal.pone.0163163

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Journal: PloS one	Publication Date: Sep 15, 2016
Citations: 5	License type: CC BY 4.0

Affiliation: George Mason University

Abstract

In this study the hydrogel microparticles (MPs) were used to enhance migration of neutrophils in order to improve outcome of anthrax infection in a mouse model. Two MP formulations were tested. In the first one the polyacrylamide gel MPs were chemically coupled with Cibacron Blue (CB) affinity bait. In the second one the bait molecules within the MPs were additionally loaded with neutrophil-attracting chemokines (CKs), human CXCL8 and mouse CCL3. A non-covalent interaction of the bait with the CKs provided their gradual release after administration of the MPs to the host. Mice were challenged into footpads with Bacillus anthracis Sterne spores and given a dose of MPs a few hours before and/or after the spores. Pre-treatment with a single dose of CK-releasing MPs without any additional intervention was able to induce influx of neutrophils to the site of spore inoculation and regional lymph nodes correlating with reduced bacterial burden and decreased inflammatory response in footpads. On average, in two independent experiments, up to 53% of mice survived over 13 days. All control spore-challenged but MP-untreated mice died. The CB-coupled particles were also found to improve survival likely due to the capacity to stimulate release of endogenous CKs, but were less potent at decreasing the inflammatory host response than the CK-releasing MPs. The CK post-treatment did not improve survival compared to the untreated mice which died within 4 to 6 days with a strong inflammation of footpads, indicating quick dissemination of spores though the lymphatics after challenge. This is the first report on the enhanced innate host resistance to anthrax in response to CKs delivered and/or endogenously induced by the MPs.

Highlights

Spatial and temporal concentration gradients of chemoattractants direct many biological processes involving leukocyte migration during development, regulation of homeostasis and ongoing immune responses within lymphoid organs and peripheral tissues
MPs were co-incubated with CKs at 4°C overnight and the loaded MPs pelleted for analysis by centrifugation to separate them from the supernatants
CCL3 incubated without MPs in the conditions of CK loading lost a substantial part of its activity, likely due to its aggregation in a diluted solution [14]

Summary

Introduction

Spatial and temporal concentration gradients of chemoattractants direct many biological processes involving leukocyte migration during development, regulation of homeostasis and ongoing immune responses within lymphoid organs and peripheral tissues. There are reports that non-functionalized nanoparticles and microparticles (MPs) of several kinds are themselves capable of eliciting the immune responses such as production of cytokines and activation of neutrophils raising questions of their potential utility for a stimulation of host defenses as well as their safety upon a prolonged contact with normal tissues [6]. It was recently proposed using a new class of CK-releasing MPs consisting of a nontoxic polyacrylamide hydrogel covalently coupled with a variety of affinity baits such as dyes of different chemical nature [7]. The hydrogel structure protects the loaded cargo to assure preservation of its function from degradation in the complex biological environment

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