Document text
Principal Investigator: Kristina M. Adams Waldorf
Organization: UNIVERSITY OF WASHINGTON
Fiscal Year: 2024
Award: $843,733
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
Pregnant women are highly vulnerable to influenza A virus (IAV) and are at increased risk for maternal death,
preterm birth and stillbirth. Universal influenza vaccines (UFV) are thought to be possible if conserved regions of
influenza virus are targeted and appropriate immune responses generated. However, relevant animal models are
lacking in which to test such a vaccine, particularly for pregnant women. This proposal is focused on investigating
maternal and placental immune responses to IAV in a pregnant nonhuman primate (NHP) model to understand the
viral-host factors driving enhanced maternal disease. Our central hypothesis is that an aberrant Th17 response
during an acute IAV infection leads to a broadly dysfunctional innate and adaptive immune response that
prevents viral clearance and enhances risk for maternal death and stillbirth. Th17 cells produce high levels of
the inflammatory cytokines IL-17 and IL-2218,19 with early Th17 polarization considered to be critical for IAV
resolution; aberrant and/or late activation of the Th17 pathway by IL-23 in murine models is thought to impair viral
clearance and promote lung injury.20,21 Our preliminary data in a pregnant NHP model of an acute IAV H1N1 infection
demonstrates pneumonia in all animals by Day 5 post-IAV inoculation. In pregnant NHP, influenza disease scores
were higher than non-pregnant animals with notable extra-pulmonary organ injury (myocarditis, white matter injury).
Pregnant NHP demonstrated a nearly absent early Th17 CD4+ T cell response in whole blood and PBMC coupled
with a marked increase in Th17 cells in the lung at peak immunopathology compared to non-pregnant animals.
Inflammatory cytokines and chemokines in the lungs and bronchoalveolar lavage fluid (BAL) were also greater in
pregnant versus non-pregnant animals. In Aim 1, non-pregnant and pregnant pigtail macaques will be challenged
with either IAV H1N1 A/CA/04/09 or H3N2 A/Texas/71/2017 (N=8, each group) and undergo blood and BAL
sampling until necropsy at Day 5 (peak immunopathology). In Aims 1A and 1B, we will determine pregnancy-
specific immune correlates of IAV disease by evaluating the frequency of Th17 CD4+ T cells and a broad spectrum
of innate/adaptive immune responses (i.e. immune cell subsets, cytokines/chemokines, Type I/III interferons) in the
blood, BAL and lung. In Aim 1C, we will evaluate antiviral responses in the placenta linked to adverse pregnancy
outcomes (e.g. cytokines/chemokines, NLRP3 inflammasome activation, CD8+ T cells). In Aim 2, we will use bulk
and single cell RNA-sequencing to define changes in the transcriptome within PBMC, BAL, lung and placenta with
a focus on Th17 transcriptional networks and antiviral innate immune pathways. In summary, the preliminary data
indicates an aberrant Th17 response in pregnant animals, which is critical to promoting viral clearance and
preventing lung injury. These studies will be the first to comprehensively analyze innate/adaptive immune responses
during an acute IAV infection to elucidate the pathogenesis of severe lung disease in pregnant women. Results from
these studies are critical for IAV pandemic preparedness to enable testing of efficacy and safety of new UFV.
Terms: <Acute><Alveolar Lavage Fluids><Animal Model><Animal Models and Related Studies><Animals><Anti-viral Response><Automobile Driving><Autopsy><Basal Transcription Factor><Basal transcription factor genes><Blood><Blood Reticuloendothelial System><Body Tissues><Bronchial Lavage Fluid><Bronchioalveolar Lavage><Bronchoalveolar Lavage><Bronchoalveolar Lavage Fluid><Bronchopulmonary Lavage><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CTLA-8><CTLA-8 Gene><CTLA8><CTLA8 Gene><Cell Body><Cells><Cells Placenta-Tissue><Cessation of life><Chemotactic Cytokines><Chronologic Fetal Maturity><Clinical><Coupled><Cytotoxic T-Lymphocyte-Associated Antigen 8><Cytotoxic T-Lymphocyte-Associated Antigen 8 Gene><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8 Gene><DNA><Data><Death><Deoxyribonucleic Acid><Development><Diathesis><Disease><Disease susceptibility><Disorder><Fetal Age><Fetus><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Frequencies><Future><Gene Expression><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic Transcription><Gestation><Gestational Age><Grippe><H1N1><H1N1 Virus><H3N2><H3N2 Virus><Heart><Histopathology><Homologous Chemotactic Cytokines><Host Defense><Host Factor><Host Factor Protein><Human><IFN><IL-17><IL-17 Gene><IL-17A><IL-17A Gene><IL-23><IL17><IL17 Protein><IL17 gene><IL17A><IL17A Gene><Immune><Immune Cell Activation><Immune response><Immunes><Immunological response><Impairment><Infection><Inflammasome><Inflammatory><Influenza><Influenza A><Influenza A Virus, H1N1 Subtype><Influenza A Virus, H3N2 Subtype><Influenza A virus><Influenza Virus><Influenza Viruses Type A><Influenzavirus A><Injury><Innate Immune Response><Integration Host Factors><Intercrines><Interferons><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8)><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8) Gene><Interleukin 17 Precursor><Interleukin 17 Precursor Gene><Interleukin-17><Link><Lung><Lung Diseases><Lung Lavage><Lung Lavage Fluid><Lung Parenchyma><Lung Respiratory System><Lung Tissue><Lung damage><M nemestrina><M. nemestrina><Macaca nemestrina><Maps><Maternal Mortality><Messenger RNA><Modeling><Modern Man><Morbidity><Morbidity - disease rate><Myocarditis><NIAID><National Institute of Allergy and Infectious Disease><Normal Placentoma><Orthomyxovirus Type A><PBMC><Pathogenesis><Pathogenicity><Pathway interactions><Patients><Peripheral Blood Mononuclear Cell><Phenotype><Pigtail Macaque><Pigtail Monkey><Placenta><Placenta Embryonic Tissue><Placentome><Pneumonia><Pregnancy><Pregnant Women><Premature Birth><Prematurely delivering><Preterm Birth><Pulmonary Diseases><Pulmonary Disorder><Quantitative RTPCR><Quantitative Reverse Transcriptase PCR><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Resolution><Risk><SIS cytokines><Safety><Sampling><Site><Staining method><Stains><Strategic Planning><Structure of parenchyma of lung><T cell response><T4 Cells><T4 Lymphocytes><T8 Cells><T8 Lymphocytes><Testing><Texas><Time><Tissues><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Type A Influenza><Vaccination><Vaccines><Villous><Viral><Viral Burden><Viral Diseases><Viral Load><Viral Load result><Virus Diseases><Vulnerable Populations><Whole Blood><adaptive immune response><adverse pregnancy outcome><bronchopulmonary lavage therapy><cardiac inflammation><chemoattractant cytokine><chemokine><cytokine><developmental><disease of the lung><disorder of the lung><driving><economic cost><efficacy testing><expectant mother><expecting mother><fetal><flow cytophotometry><gene network><global gene expression><global transcription profile><host response><immune activation><immune system response><immunopathology><immunoresponse><influenzavirus><injuries><injury to organs><innate immune pathways><interleukin-23><liability to disease><lung disorder><lung injury><mRNA><maternal death><maternal risk><model of animal><mouse model><murine model><necropsy><non-human primate><nonhuman primate><organ injury><pan influenza vaccine><pan influenza viral vaccine><pan influenza virus vaccine><pandemic disease preparedness><pandemic planning><pandemic preparedness><pandemic readiness><pandemic virus><pathogen><pathway><phenotypic data><pig-tailed macaque><postmortem><pregnant><pregnant mothers><premature childbirth><premature delivery><preterm delivery><prevent><preventing><pulmonary><pulmonary damage><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><qRTPCR><resolutions><response><safety testing><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><stillbirth><stillborn><transcription factor><transcriptome><transcriptome sequencing><transcriptomic sequencing><universal flu vaccine><universal influenza vaccine><universal influenza virus vaccine><universal vaccine against flu><universal vaccine against influenza><vaccine platform><viral infection><virus infection><virus-induced disease><vulnerable group><vulnerable individual><vulnerable people><white matter injury>