Many pathogens evolved sophisticated means to influence the chemotactic behavior of immune cells for colonization of the host. Development of technology to restore and predictably manipulate the chemotaxis of immune cells can lead to biomedical breakthroughs for infectious disease treatment. A promising approach is to locally engineer chemokine (CK) gradients with the goal of promoting the accumulation of key immune players or eliciting cascades of immune responses to eliminate pathogens or tumors. For this purpose we propose using a new multifunctional micro- and nanoparticle (NP) platform technology recently invented by us. The NPs consist of a hydrogel scaffold chemically coupled with a variety of inner baits capable of capturing and protecting from degradation a wide range of molecules from their environment in one step. In addition, the NPs can be loaded with pharmacoactive substances that can be reversibly released from the baits with a controlled rate. Based on this platform we propose a simple and versatile approach for creating CK-loaded NPs which could serve both as a research tool and a prototype of future immunotherapies for manipulating leukocyte trafficking. The main goal of this project is to demonstrate feasibility of the CK gradient remodeling approach using our NP technology. As the first step we will model the nanoparticles' in an in vivo environment to study the pharmacodynamics of sustained release of four CK-loaded NPs chosen to target neutrophils participating in the immune response infections. Next, we will demonstrate the capacity of CK-loaded NPs to increase leukocyte recruitment to draining lymph nodes after subcutaneous administration of B. anthracis spores to mice as a model of an infectious disease with well-known abnormalities in the recruitment of immune cells. To gain new insights into host responses to infection within lymph nodes and their modulation by administered CKs we will carry out global proteomic analysis of lymph from the infected LNs. Our chemokine-loaded nanoparticles for in vivo delivery, coupled with global elucidation of the lymph proteome during infection will vastly increase our understanding bacterial pathogenesis and host cellular immune response to infecting pathogens.

Public Health Relevance

We will develop a new micro-and nanoparticle technology based on a hydrogel incorporating affinity baits capable of controlled binding and release of chemokines, providing a predictable manipulation of the immune cell chemotaxis. The biological activity of the different chemokine-loaded particles will be investigated in a mouse model challenged with B. anthracis spores by assessing increased trafficking of neutrophils to lymph nodes. A global proteomic analysis of lymph from the infected lymph nodes will be conducted to gain new insights into host responses to infection and their modulation by administered chemokines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI117425-02
Application #
9089857
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Mukhopadhyay, Suman
Project Start
2015-06-15
Project End
2017-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
George Mason University
Department
Public Health & Prev Medicine
Type
Schools of Arts and Sciences
DUNS #
077817450
City
Fairfax
State
VA
Country
United States
Zip Code
22030
Steinberg, Hannah E; Russo, Paul; Angulo, Noelia et al. (2018) Toward detection of toxoplasmosis from urine in mice using hydro-gel nanoparticles concentration and parallel reaction monitoring mass spectrometry. Nanomedicine 14:461-469
Teunis, Allison L; Popova, Taissia G; Espina, Virginia et al. (2017) Immune-modulating Activity of Hydrogel Microparticles Contributes to the Host Defense in a Murine Model of Cutaneous Anthrax. Front Mol Biosci 4:62
Paris, Luisa; Magni, Ruben; Zaidi, Fatima et al. (2017) Urine lipoarabinomannan glycan in HIV-negative patients with pulmonary tuberculosis correlates with disease severity. Sci Transl Med 9:
Zhou, Weidong; Liotta, Lance A; Petricoin, Emanuel F (2017) The Warburg Effect and Mass Spectrometry-based Proteomic Analysis. Cancer Genomics Proteomics 14:211-218
Pin, Elisa; Stratton, Steven; Belluco, Claudio et al. (2016) A pilot study exploring the molecular architecture of the tumor microenvironment in human prostate cancer using laser capture microdissection and reverse phase protein microarray. Mol Oncol 10:1585-1594
Liotta, Lance A (2016) Adhere, Degrade, and Move: The Three-Step Model of Invasion. Cancer Res 76:3115-7
Popova, Taissia G; Teunis, Allison; Magni, Ruben et al. (2015) Chemokine-Releasing Nanoparticles for Manipulation of the Lymph Node Microenvironment. Nanomaterials (Basel) 5:298-320
Silvestri, Alessandra; Calvert, Valerie; Belluco, Claudio et al. (2013) Protein pathway activation mapping of colorectal metastatic progression reveals metastasis-specific network alterations. Clin Exp Metastasis 30:309-16
Bosch, Jaume; Luchini, Alessandra; Pichini, Simona et al. (2013) Analysis of urinary human growth hormone (hGH) using hydrogel nanoparticles and isoform differential immunoassays after short recombinant hGH treatment: preliminary results. J Pharm Biomed Anal 85:194-7
Zhou, Weidong; Capello, Michela; Fredolini, Claudia et al. (2013) Mass spectrometric analysis reveals O-methylation of pyruvate kinase from pancreatic cancer cells. Anal Bioanal Chem 405:4937-43

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