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.
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.
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