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Principal Investigator: Pedro A Piedra
Organization: BAYLOR COLLEGE OF MEDICINE
Fiscal Year: 2021
Award: $352,938
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY – Project 2
Respiratory syncytial virus (RSV) is a major global respiratory pathogen. The Severe Acute Respiratory
Syndrome Coronavirus 2 (SARS-CoV-2) pandemic has resulted in an unprecedented crisis. Respiratory virus
infections are often accompanied by gastrointestinal (GI) symptoms, but how respiratory pathogens cause GI
disease is not understood. Moreover, a number of vaccines and therapeutics are being developed against these
important pathogens, however, the existing models do not recapitulate the human experience. Small animal and
non-human primate models fall short of mimicking human disease, and the human RSV challenge model is
expensive and raises safety concerns. The requirement for BSL-3 facilities to study SARS-CoV-2 hampers data
generation and increases cost. The human endemic CoV-NL63 can serve as a proxy for SARS-CoV-2 because
it uses the same host receptor, angiotensin-converting enzyme 2. This project will develop an ex-vivo Human
Challenge Airway Model by advancing our current 3-dimensional (3D) nose/lung model for studies on
RSV and CoV-NL63 (proxy for SARS-CoV-2) to address the urgent need for a preclinical model that
recapitulates the human disease. In collaboration with the Human Biomimetic Scientific Core, we have
developed the expertise for isolating stems cells and generating 3D nose and lung organoid lines from nasal
wash and bronchoalveolar fluids, respectively. Our internationally recognized expertise in RSV and other
respiratory viruses uniquely positions us to develop advanced 3D nose/lung models for dissecting the
pathogenesis of RSV (Aim 1), and develop airway and GI platforms with the Engineering Micro-Environment
Core (EMEC) to evaluate molecular mechanisms driving the lung-gut axis of respiratory virus disease (Aim 2).
We will select donors based on sex and age so that we can comprehensively study the complex interactions of
host (age, sex, distinct airway sites, and immune cells) and virus, and the contribution of humoral and cellular
immune responses in an HLA-restricted system. We will also evaluate the lung-gut axis by studying the
downstream effects of RSV and CoV-NL63 airway infection on the GI tract by either direct (infection) or indirect
(inflammation) pathways using lung-gut flow systems. This project is responsive to the RFA by the development
of an advanced nose/lung model with increased complexity that includes humoral and cellular immunity, as well
as defining novel mechanistic pathways in the lung-gut axis of respiratory virus disease. The global scientific
community will benefit immensely from a 3-D nose/lung airway-virus model that recapitulates human virus
infection and serves as a platform to evaluate therapeutics and vaccines.
Terms: <0-11 years old><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV vaccine><21+ years old><3-D><3-Dimensional><3D><ACE2><Address><Adult><Adult Human><Advanced Development><Age><Ailmentary System><Air><Alimentary Canal><Alimentary System><Animal Model><Animal Models and Related Studies><Animals><Apical><Automobile Driving><BSL-3 facility><BSL3 facility><Biological Mimetics><Biomimetics><Blood Circulation><Bloodstream><Bronchioalveolar Lavage><Bronchoalveolar Lavage><Bronchopulmonary Lavage><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 infection><COVID-19 pandemic><COVID-19 public health crisis><COVID-19 vaccine><COVID-19 virus><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 infection><COVID19 pandemic><COVID19 public health crisis><COVID19 vaccine><COVID19 virus><Cell Body><Cell Mediated Immunology><Cell-Mediated Immunity><Cells><Cellular Immunity><Child><Child Youth><Childhood><Children (0-21)><Circulation><Clinical Trials><Co-culture><CoV-2><CoV2><Cocultivation><Coculture><Coculture Techniques><Collaborations><Communities><Complex><Data><Deglutition><Development><Digestive System><Digestive Tract><Disease><Disease Pathway><Disorder><Engineering><Female><GI Tract><Gastrointestinal Body System><Gastrointestinal Diseases><Gastrointestinal Organ System><Gastrointestinal Tract><Gastrointestinal tract structure><Generations><HSPG><Heparan Sulfate Proteoglycan><Human><Humoral Immunities><Immune><Immune response><Immunes><Immunity><Immunological response><Infection><Inflammation><Innate Immune Response><International><Intestinal><Intestines><Kinetics><Liquid substance><Lung><Lung Lavage><Lung Respiratory System><Lung diseases><Modeling><Modern Man><Molecular><Mucosa><Mucosal Tissue><Mucous Membrane><Nasal><Nasal Epithelium><Nasal Passages Nose><Nose><Organoids><Pathogenesis><Pathway interactions><Position><Positioning Attribute><Pre-Clinical Model><Preclinical Models><Progenitor Cells><Proteoheparan Sulfate><Proxy><Pulmonary Diseases><Pulmonary Disorder><RSV infection><Receptor Protein><Research><Respiratory Disease><Respiratory Syncytial Virus Infections><Respiratory System Disease><Respiratory System Disorder><Respiratory System, Nose, Nasal Passages><Respiratory syncytial virus><Role><SARS corona virus 2><SARS-CoV-2><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 infection><SARS-CoV-2 pandemic><SARS-CoV-2 vaccine><SARS-CoV2><SARS-CoV2 epidemic><SARS-CoV2 infection><SARS-CoV2 pandemic><SARS-CoV2 vaccine><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-coronavirus-2 vaccine><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Safety><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome CoV 2 vaccine><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome coronavirus 2 vaccine><Severe acute respiratory syndrome related corona virus 2><Site><Study models><Swallowing><System><Therapeutic><Time><Tropism><Vaccines><Viral><Viral Diseases><Viral Pathogenesis><Virus><Virus Diseases><Virus Replication><Wuhan coronavirus><adaptive immune response><adulthood><ages><airway epithelium><airway injury><alimentary tract><angiotensin converting enzyme 2><angiotensin converting enzyme II><antibody-based immunity><base><biosafety level 3 facility><bowel><bronchopulmonary lavage therapy><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><corona virus disease 2019 vaccine><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 infection><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease 2019 vaccine><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><cost><cytokine release syndrome><cytokine storm><developmental><digestive canal><disease of the lung><disorder of the lung><driving><evaluate vaccines><experience><falls><fluid><gastrointestinal><gastrointestinal disorder><gastrointestinal symptom><gastrointestinal system><gut lung communication><gut-lung axis><hCoV19><host response><human disease><immune system response><immunoprophylaxis><immunoresponse><impaired airway><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><injured airway><liquid><lung disorder><lung pathogen><male><model of animal><model organism><nCoV2><neutralizing antibody><non-human primate><nonhuman primate><novel><pathogen><pathway><pediatric><pulmonary><pulmonary pathogen><receptor><respiratory><respiratory infection virus><respiratory pathogen><respiratory virus><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><sex><social role><stem cells><three dimensional><vaccine against 2019-nCov><vaccine against SARS-CoV-2><vaccine against SARS-CoV2><vaccine against SARS-coronavirus-2><vaccine against Severe Acute Respiratory Syndrome CoV 2><vaccine against Severe acute respiratory syndrome coronavirus 2><vaccine candidate><vaccine evaluation><vaccine for novel coronavirus><vaccine screening><vaccine testing><viral infection><viral multiplication><viral replication><virus infection><virus multiplication><virus pathogenesis><virus-induced disease><youngster>