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Principal Investigator: Emmie De Wit
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2024
Award: $2,081,320
Funding agency: National Institute of Allergy and Infectious Diseases
In any given year, lower respiratory tract infections are the leading cause of infectious disease deaths worldwide, and the fifth most important cause of death overall. The emergence of SARS-CoV-2 and the resulting COVID-19 pandemic highlighted how devastating the effect of emerging respiratory viruses on global public health and economies can be. The COVID-19 pandemic also showed the difficulty of effectively treating severe viral lower respiratory tract infections, once again highlighting that our current understanding of the pathogenesis of viral lower respiratory tract infections is insufficient to drive the development of effective treatments. Many emerging respiratory viruses cause neurological besides disease. The main goal of the Molecular Pathogenesis Section is to contribute to our understanding of the pathogenesis of emerging viruses that cause severe lower respiratory tract disease such as Nipah virus, influenza A virus and coronaviruses on the level of the host and individual cell. We are investigating the pathogenesis of these viruses in the respiratory tract and the brain. Ultimately, our goal is to identify common pathways involved in lower respiratory tract and neurological disease progression and druggable targets within those pathways.
Model systems
We continued the development of model systems to study pathogenesis of emerging respiratory viruses in the respiratory tract and the central nervous system (CNS). We further optimized the procedures to establish and maintain human lung organoids (hLO) derived from adult stem cells. We found that these stem cells, although type 2 pneumocyte-like initially, tend to differentiate over time into a more basal cell-like phenotype based on several markers of cell identity. We worked to optimize culture methods to ensure they maintain their alveolar phenotype. We additional established induced pluripotent stem cell (iPSC)-derived human lung organoids in our lab as an additional tool. We developed a new protocol to differentiate our type 2 pneumocyte organoid cultures into type I pneumocytes in air-liquid interface cultures. This is a major step forward since type I pneumocytes are the cells responsible for gas exchange in the lungs.
We continued the development of a new Syrian hamster model of neurological disease using a combination of Nipah virus inoculation and suboptimal remdesivir treatment to skew the disease in these animals to neurological signs rather than respiratory disease. We have also initiated the development of in vitro models using differentiated neuronal cultures and human cerebral organoids. We have shown that these culture systems are susceptible to infection with Nipah virus and that the response to Nipah virus changes with the age of the organoid.
Pathogenesis
We continued our work to assess the pathogenicity of SARS-CoV-2 variants of concern (VOC), focusing on contemporary Omicron variants XBB.1.5, XBB.1.16, EG.5.1, and JN.1. We evaluated the fitness and pathogenesis of contemporary Omicron variants in the upper (URT) and lower respiratory tract (LRT). Using primary human nasal and lung epithelium cells, we assessed differences in replication kinetics, induction of cell death, and innate immune activation. Contemporary Omicrons exhibited substantially increased fitness in human nasal epithelium compared to both Delta and Omicron lineage founder BA.1, indicating ongoing adaptation within the Omicron lineage towards fitness in the upper respiratory tract. Additionally, Omicron lineage variants induced substantially stronger interferon responses compared to the Delta VOC, indicating a loss of innate immune evasion proficiency in this lineage. Together, our data demonstrate that Omicron lineage evolution has favored increased fitness in the URT in the absence of lower respiratory tract pathogenesis, which is likely advantageous for transmission in the non-naive human population.
Using histologic characterization of African green monkeys infected with Nipah virus, we have shown which cell types are infected, which cell types mount an inflammatory response to infection, and which cells are extravasating into the CNS during infection.
We contributed to several clinical studies on SARS-CoV-2, including the first description of replication-competent SARS-CoV-2 in the blood of a COVID-19 patient.
Emergence of HPAI H5N1 virus in dairy cows
Since the emergence of HPAI H5N1 virus in dairy cows in the US in March 2024, we have initiated pathogenesis studies on this virus. We have isolated HPAI H5N1 viruses from tissues collected from dead mountain lions in Montana and used these, together with the viruses isolated from cattle and humans to investigate the pathogenicity in the upper and lower human respiratory tract and in the CNS.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV variant><2019-nCoV variant forms><2019-nCoV variant strains><African Green Monkey><Air><Alveolar><Alveolar Cell Type I><Animal Model><Animal Models and Related Studies><Animals><Area><B.1.1.529><B.1.617.2><Basal Cell><Biologic Models><Biological Models><Blood><Blood Reticuloendothelial System><Body Tissues><Bovine Species><Brain><Brain Nervous System><CNS Nervous System><COVID crisis><COVID epidemic><COVID infected patient><COVID pandemic><COVID patient><COVID positive patient><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 infected patient><COVID-19 pandemic><COVID-19 patient><COVID-19 period><COVID-19 positive patient><COVID-19 public health crisis><COVID-19 variant><COVID-19 variant forms><COVID-19 variant strains><COVID-19 virus><COVID-19 years><COVID19 patient><COVID19 positive patient><COVID19 virus><Cattle><Cause of Death><Cell Body><Cell Death Induction><Cells><Central Nervous System><Cerebrum><Cessation of life><Chlorocebus aethiops><Chlorocebus sabaeus><Clinical Research><Clinical Study><CoV-2><CoV2><Communicable Diseases><Coronaviridae><Coronavirus><Cougars><Dairying><Data><Death><Delta variant><Development><Disease><Disease Progression><Disorder><Encephalon><Ensure><Epithelial Cells><Evolution><Exhibits><Extravasation><Felis concolor><GS-5734><Gases><Goals><Golden Hamsters><Golden Syrian Hamsters><Green Monkey><H5N1><H5N1 virus><Histologic><Histologically><Human><IFN><Immune Cell Activation><Immune Evasion><Individual><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammatory Response><Influenza A><Influenza A H5N1><Influenza A Virus, H5N1 Subtype><Influenza A virus><Influenza Viruses Type A><Influenzavirus A><Interferons><Kinetics><Leakage><Liquid substance><Lower Respiratory Tract Infection><Lower respiratory infection><Lower respiratory tract structure><Lung><Lung Respiratory System><Mesocricetus auratus><Methods><Model System><Modern Man><Molecular><Montana><Mountain Lion><Nasal><Nasal Epithelium><Nasal Passages Nose><Nervous System Diseases><Nervous System Disorder><Neuraxis><Neurologic><Neurologic Disorders><Neurologic Models><Neurologic Signs><Neurological><Neurological Disorders><Neurological Models><Neuronal Differentiation><Neuropathogenesis><Nipah Virus><Nipah henipavirus><Nose><Omicron variant><Organ><Organoids><Orthomyxovirus Type A><Pathogenesis><Pathogenicity><Pathway interactions><Phenotype><Population><Predisposition><Procedures><Progenitor Cells><Protocol><Protocols documentation><Public Health><Pulmonary Body System><Pulmonary Organ System><Puma concolor><Respiratory Disease><Respiratory System><Respiratory System Disease><Respiratory System Disorder><Respiratory System, Nose, Nasal Passages><Respiratory Tract Diseases><Respiratory Tracts><Respiratory tract structure><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 B.1.1.529><SARS-CoV-2 B.1.617.2><SARS-CoV-2 delta><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 infected patient><SARS-CoV-2 omicron><SARS-CoV-2 omicron variant><SARS-CoV-2 pandemic><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 variant><SARS-CoV-2 variant forms><SARS-CoV-2 variant strains><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><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-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 related corona virus 2><Spillage><Susceptibility><Syndrome><Syrian Hamsters><System><Therapeutic><Time><Tissues><Transmission><Type A Influenza><Type I Pneumocyte><Upper respiratory tract><Variant><Variation><Veklury><Viral><Viral Pathogenesis><Virus><Work><Wuhan coronavirus><adult progenitor><adult stem cell><age associated alterations><age associated changes><age correlated alterations><age correlated changes><age dependent alterations><age dependent changes><age related alterations><age related changes><age specific alterations><age specific changes><alterations with age><animal data><avian influenza H5N1><avian influenza H5N1 virus><bovid><bovine><cell type><cerebral><changes with age><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 infected patient><coronavirus disease 2019 pandemic><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 public health crisis><coronavirus disease 2019 variant><coronavirus disease 2019 variant forms><coronavirus disease 2019 variant strains><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease infected patient><coronavirus disease pandemic><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus disease-19 patient><coronavirus disease-19 virus><coronavirus patient><cow><developmental><druggable target><effective therapy><effective treatment><emergent virus><emerging virus><fitness><fluid><hCoV19><iPS><iPSC><iPSCs><immune activation><immune evasive><in vitro Model><induced pluripotent cell><induced pluripotent stem cell><inducible pluripotent stem cell><insight><interest><liquid><lower respiratory tract><model development><model developments><model of animal><nCoV2><neurological disease><omicron variant of COVID-19><omicron variant of SARS-CoV-2><pathway><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><pneumocyte><pulmonary><remdesivir><respiratory virus><response><severe acute respiratory syndrome coronavirus 2 B.1.1.529><severe acute respiratory syndrome coronavirus 2 B.1.617.2><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe acute respiratory syndrome coronavirus 2 variant><severe acute respiratory syndrome coronavirus 2 variant forms><severe acute respiratory syndrome coronavirus 2 variant strains><somatic progenitor><somatic stem cell><stem cells><tool><transmission process><upper airway tract><variants of concern><viral emergence><virus pathogenesis>