CAREER: Biophysical investigations of immune-mediated pathogen trapping in mucus

This Career award by the Biomaterials program in the Division of Materials Research to University of North Carolina at Chapel Hill is to investigate the role of mucus, a viscoelastic biopolymer composed of a dense matrix of mucin fibers and secreted by human body, as a barrier against virus. This research project will combine bioengineering, biophysics and computational modeling to investigate the protective role of antibodies in mucus. Most infections are transmitted at mucosal surfaces, and viruses have evolved to readily penetrate mucus. Nevertheless, how antibodies are secreted into mucus protect against infections remain poorly understood. This study is based on the hypothesis that antibodies can immobilize viruses in mucus with permanent avidity via polyvalent and low-affinity crosslinks, thereby blocking viruses from reaching target cells. Most previous studies have failed to detect possible polyvalent-adhesive trapping effects of mucus because these studies attempted to measure only the low-affinity mono-valent interactions between a single antibody and mucus constituents. To overcome these drawbacks of the previous studies, this project will focus on quantifying the potency of anti-biotin immunoglobulin-G mediated trapping by mucus using biotin-coated, mucus-penetrating and mucus-inert polystyrene-based nanoparticles as the model system. Numerical modeling of particle diffusion across mucus, accumulation of antibody on particle surface, and trapping by surface-bound antibody are parts of this research. The proposed studies are expected to develop an overarching set of equations that will attempt to predict the effectiveness of antibody-mediated trapping against a wide range of viral pathogens. In addition, this study could elucidate a largely unrecognized mechanism of immune protection of human body, and could lead to development of new vaccines and passive immunization against viral infections such as Herpes, HIV, etc. Through this multidisciplinary research, graduate and undergraduate students will receive training across nanoscience, biophysics, mathematics and immunology. Additionally, the PI plans to develop a new curriculum, focusing on the role of mucus in health, and will be used by the outreach programs at the Morehead Planetarium and Science Center to reach out to many K-12 students in North Carolina every year.

Most infections take place in organs coated with mucus, such as the airways, gastrointestinal tract, etc. Viruses have evolved to quickly move through mucus to infect; thus, methods that can block viruses from penetrating mucus represents an attractive approach to reinforce our body?s defense against infections. In this project, we will explore how the immune system can be tuned to transform mucus into a sticky mesh against diverse pathogens, effectively trapping them in mucus and reducing infections in the process. Specifically, this project will prepare synthetic nanoparticles that will rigorously quantify the stickiness of mucus as a function of basic parameters such as virus particle size and surface characteristics. In addition it will develop an overarching set of equations to predict how one could protect against a wide range of viral pathogens. A successful outcome of this research could not only explain with which immune system can protect against infections, but also could guide in the development of new generations of vaccines. Due to the multidisciplinary nature of this research, the project will train students across nanoscience, biophysics, mathematics and immunology. The researcher plans to leverage existing outreach programs at the Morehead Planetarium and Science Center, and will develop a new science curriculum focusing on the role of mucus in health that will reach many K-12 students in North Carolina. These efforts are expected to motivate students to pursue higher education in Science, Technology, Engineering, & Mathematics.