Stanford/UNC Biomimetic U19 Research Center

Stanford/UNC Biomimetic U19 Research Center
PROJECT SUMMARY/ABSTRACT – CENTER OVERVIEW
Infectious diseases continue to pervasively afflict global health and socioeconomic stability despite substantial
prevention and treatment initiatives. Respiratory and gastrointestinal pathogens rank amongst the most
intractable infectious diseases, particularly notable for recurrent waves of zoonotic coronaviruses and the recent
COVID-19 pandemic, engendered by SARS-CoV-2. Overall, an urgent need exists for improved in vitro
experimental models of human disease to study pathogenesis and to validate therapeutics. The central mission
of the Stanford/UNC Biomimetic U19 Research Center is thus to deploy novel 3-dimensional organoid culture
models to elucidate the biology and therapy of respiratory and gastrointestinal infectious pathogens.
Our application is a renewal of our prior Stanford NAMSED U19 Research Center and is comprised of
two Cores and three research Projects, leveraging complementary and synergistic expertise of our investigators
at Stanford University and the University of North Carolina. The Center continues to be led by the Multi-PIs,
Calvin Kuo and Manuel Amieva, who also co-lead Core A (Administrative Core). Core B (Organoid Core) is led
by Calvin Kuo and provides novel capabilities for lung and GI organoid culture, gene editing and multiplexed
screening. The three Projects extensively utilize organoid biomimetics for exploration of GI and respiratory
pathogens. Project 1, (PI, Manuel Amieva) investigates H. pylori and Salmonella colonization, competition and
invasion in the GI tract, while Project 2 (PI, Harry Greenberg) investigates rotavirus host range, neutralization,
and M cell interactions in enteric biomimetics. Project 3 (PI, Ralph Baric) is a new addition and extensively uses
organoids to model SARS-CoV-2, other closely related epidemic and pre-epidemic emerging coronaviruses and
1918 H1N1 influenza to reveal common and unique host networks associated with severe pulmonary outcomes.
The activities of the Stanford/UNC Biomimetic U19 Research Center reside within three overarching
Aims. In Aim 1, our Center performs organoid modeling of the epithelium-pathogen interface to investigate
pathogenesis, susceptibility and host range restriction. This employs robust reverse genetics and CRISPR
screens to systematically manipulate host versus viral/bacterial compartments, within novel apical-basal polarity
modulated distal lung/alveolar, nasal sinus, stomach and intestinal organoid systems. Aim 2 defines how SARS-
CoV-2, pre-epidemic coronaviruses, rotavirus and Salmonella can perturb reciprocal cross-talk between tissue
epithelium and resident immune cells. This exploits a unique 3D air-liquid interface organoid method preserving
GI and lung epithelium en bloc with diverse endogenous infiltrating immune cell types without artificial
reconstitution. Lastly, Aim 3 performs organoid-based evaluation of therapeutic candidates against SARS-CoV-
2, pre-epidemic coronaviruses and rotavirus in medium- to high-throughput formats including epithelium and/or
immune cells. Overall, the explorations of the Stanford/UNC Biomimetic U19 Research Center directly apply
advanced organoid systems to the investigation and therapy of recalcitrant infectious pathogens.