Human Biomimetics for Mucosal Infections

OVERALL PROJECT SUMMARY This application request is a renewal of a previous funded NAMSED Cooperative Research Center that encompassed a multidisciplinary team of basic scientists, physician scientists and engineers from institutions in the Texas Medical Center (Baylor College of Medicine, Rice University, and the MD Anderson Cancer Center). The objective of this new Biomimetic Cooperative Research Center (BCRC) is to build upon substantial progress that included 42 publications from the previous funding period to use human intestinal organoids (HIOs) and recent success in making nose and lung organoids (HNOs and HLOs) as biomimetics for the study of mucosal infectious diseases. Enteric and respiratory infections are a leading cause of worldwide morbidity and mortality; our understanding of the molecular and cellular drivers of infection of the key causal agents (studied in this proposal) is hampered due to the lack of sufficient cellular, animal, and human models and substantial host-dependent variation in infection susceptibility. The use of organoids will include next-generation engineering that augments cellular complexity to now include immune and neuronal cell and microbiome co-culture, integration of multiple organ or tissues systems, use of many donor lines to examine host-specific genetics and responses to infection, and higher-order 3D mechano-physiologic processes that may alter infection outcomes. This BCRC application integrates a team with multidisciplinary expertise in basic and translational research and innovation in virology, bacteriology, genomics, developmental biology and physiology, and biomedical engineering and biomaterial development to address important questions in the field. Project 1 will use HIOs to examine how human rotavirus and norovirus infection replication and immune responses are impacted by autologous immune and neuronal cell co-culture, co-infection with other pathogens, and commensal bacteria. Project 2 will examine the immunological response to respiratory syncytial virus and coronavirus infection in nasal and lung organoids and with autologous immune cells to establish preclinical HNO/HLO models that recapitulate human disease. HIOs will also be infected to evaluate mechanistically the lung-gut axis of respiratory virus disease. Project 3 will determine the molecular drivers of susceptibility to infection by enteroaggregative E. coli, including the effect of autologous immune co- culture, mechano-physiologic cues such as flow and stiffness, and a fully integrated intestinal system comprised of all four intestinal segments. All three projects, which have substantial synergy in theme and method, will be supported by three Cores: the Administrative Core (AC - to facilitate governing aspects of the team), Human Biomimetic Scientific Core (HBSC - to provide organoids and establish co-cultures), and the Engineering MicroEnvironment Scientific Core (EMEC - to provide platforms and bioengineering of mechano-physiologic cues into the organoid systems). At the completion of this funded period, our BCRC team will have advanced our understanding of the molecular, cellular and mechano-physiologic drivers of mucosal disease while generating new pre-clinical platforms to evaluate effective and safe therapeutics.