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Principal Investigator: Pedro A Piedra
Organization: BAYLOR COLLEGE OF MEDICINE
Fiscal Year: 2024
Award: $344,608
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><Airway challenge><Airway infections><Alimentary Canal><Alimentary System><Animal Model><Animal Models and Related Studies><Animals><Apical><Automobile Driving><BSL-3 facility><BSL3 facility><Biological Mimetics><Biomimetics><Bronchioalveolar Lavage><Bronchoalveolar Lavage><Bronchopulmonary Lavage><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 vaccine><COVID-19 virus><COVID-19 years><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><Coronaviridae><Coronavirus><Data><Deglutition><Development><Digestive System><Digestive Tract><Disease><Disease Pathway><Disorder><Donor Screening><Donor Selection><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><Licensing><Liquid substance><Lung><Lung Lavage><Lung Respiratory System><Lung symptom><Modeling><Modern Man><Molecular><Mucosa><Mucosal Tissue><Mucous Membrane><Nasal><Nasal Epithelium><Nasal Lavage Fluid><Nasal Passages Nose><Nasal Washing><Nasal Washings><Nose><Organoids><Pathogenesis><Pathway interactions><Position><Positioning Attribute><Pre-Clinical Model><Preclinical Models><Progenitor Cells><Proteoheparan Sulfate><Proxy><RSV infection><Receptor Protein><Research><Respiratory Disease><Respiratory Epithelium><Respiratory Infections><Respiratory Syncytial Virus Infections><Respiratory System Disease><Respiratory System Disorder><Respiratory System, Nose, Nasal Passages><Respiratory Tract Infections><Respiratory syncytial virus><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-CoV-2 vaccine><SARS-CoV2><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 Coronavirus 2><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 coronavirus 2><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome coronavirus 2 vaccine><Severe acute respiratory syndrome related corona virus 2><Site><Structure of respiratory epithelium><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><biosafety level 3 facility><bowel><bronchopulmonary lavage therapy><corona virus><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 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease 2019 vaccine><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus disease-19 vaccine><coronavirus disease-19 virus><cost><cytokine release syndrome><cytokine storm><developmental><digestive canal><driving><evaluate vaccines><experience><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><injured airway><kids><liquid><male><model of animal><nCoV vaccine><nCoV-19 vaccine><nCoV19 vaccine><nCoV2><neutralizing antibody><non-human primate><nonhuman primate><novel><pathogen><pathway><pediatric><pulmonary><pulmonary symptom><receptor><respiratory><respiratory challenge><respiratory infection virus><respiratory injury><respiratory pathogen><respiratory tract epithelium><respiratory tract injury><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 COVID-19><vaccine against SARS-CoV-2><vaccine against SARS-coronavirus-2><vaccine against Severe Acute Respiratory Syndrome CoV 2><vaccine against Severe acute respiratory syndrome coronavirus 2><vaccine candidate><vaccine candidates against SARS-CoV-2><vaccine evaluation><vaccine for novel coronavirus><vaccine screening><vaccine testing><vaccines preventing COVID><vaccines to prevent COVID><viral infection><viral multiplication><viral replication><virus infection><virus multiplication><virus pathogenesis><virus-induced disease><youngster>