Document text
Principal Investigator: John F Alcorn
Organization: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Fiscal Year: 2024
Award: $518,055
Funding agency: National Heart Lung and Blood Institute
SUMMARY
Despite intense research focus, Staphylococcus aureus has remained an important cause of both community
acquired pneumonia and viral-related super-infections. The field has recently determined host mediated
mechanisms induced by S. aureus that drive lung infection and injury. In the context of preceding influenza
infection, our group and many others have delineated aberrant immune pathway regulation as key drivers of S.
aureus susceptibility and pathogenesis. In addition to host mediated interactions, S. aureus expresses a number
of secreted and cell wall virulence factors that have not been fully characterized in pulmonary infection. We
performed a transposon mutant screen of S. aureus cell wall anchored proteins in pulmonary infection and super-
infection in mice. This screen revealed a novel S. aureus virulence factor, SasD, which is required for lung
inflammation, injury, and mortality. SasD was also required for lung epithelial cell attachment and inflammatory
cytokine induction by macrophages. In this application, we hypothesize that S. aureus SasD is a critical virulence
factor in pulmonary infection, which mediates bacterial adherence to the lung stroma and interactions with
primary lung phagocytes. We will test this hypothesis with two independent, but related Aims; 1) investigate the
role of SasD in bacterial adhesion to lung epithelial cells and in vivo growth in the lung, 2) examine the role of
SasD in mediating S. aureus interaction with pulmonary phagocytes and the impact on lung inflammation. We
will determine the context dependent roles of S. aureus SasD in single and influenza super-infection. Further,
we will utilize cutting edge tools to determine these interactions in human and mouse systems. Data generated
in this project will inform upon focusing on S. aureus SasD at a potential therapeutic or vaccine target in
pulmonary infections.
Terms: <Address><Adherence><Adhesions><Alveolar Macrophages><Animal Model><Animal Models and Related Studies><Antibiotic Agents><Antibiotic Drugs><Antibiotic Therapy><Antibiotic Treatment><Antibiotics><Antigen Presentation><Attenuated><Bacteria><Bacteria resistance><Bacteria resistant><Bacterial Adhesion><Bacterial Attachment Site><Bacterial resistant><Beta Proprotein Interleukin 1><Binding><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 years><Cell Attachment><Cell Body><Cell Communication and Signaling><Cell Culture Techniques><Cell Death><Cell Signaling><Cell Wall><Cell-Matrix Adhesions><Cell-Matrix Junction><Cells><Clinical><Clinical Treatment Moab><Data><Enzyme Gene><Enzymes><Epithelial Attachment><Epithelial Cells><Epithelium><Extracellular Matrix Proteins><Future><Generalized Growth><Genetic Alteration><Genetic Change><Genetic defect><Genome><Grippe><Growth><Human><IL-1 beta><IL-1 β><IL-1-b><IL-1β><IL1-Beta><IL1-β><IL1B Protein><IL1F2><IL1β><Imaging Procedures><Imaging Technics><Imaging Techniques><Immune><Immune system><Immunes><Immunity><Immunomodulation><In Vitro><Individual><Infection><Inflammasome><Inflammation><Inflammatory><Influenza><Influenza Virus><Injury><Interleukin 1beta><Interleukin-1 beta><Interleukin-1β><Intracellular Communication and Signaling><Junctional Epithelium><Laboratories><Lung><Lung Inflammation><Lung Respiratory System><Lung damage><Lung infections><MRSA><Macrophage><Mediating><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Methicillin Resistant S. Aureus><Mice><Mice Mammals><Microbial Superinvasion><Miscellaneous Antibiotic><Modern Man><Molecular Interaction><Monoclonal Antibodies><Murine><Mus><Mutation><Mφ><Organoids><Pathogenesis><Pathogenicity Factors><Pathway interactions><Phagocytes><Phagocytic Cell><Phagolysosome><Pneumonia><Pneumonitis><Predisposition><Preinterleukin 1 Beta><Prevention><Production><Protein Family><Proteins><Publishing><Pulmonary Inflammation><Pulmonary Macrophages><Regulation><Research><Role><S aureus><S. aureus><S. aureus infection><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Signal Transduction><Signal Transduction Systems><Signaling><Staining method><Stains><Staph aureus><Staph aureus infection><Staphylococcus aureus><Staphylococcus aureus infection><Surface Proteins><Susceptibility><System><T-Cells><T-Lymphocyte><Testing><Therapeutic><Tissue Growth><Vaccine Design><Vaccines><Viral><Viral Diseases><Virulence><Virulence Factors><Virus Diseases><Work><amebocyte><attenuate><attenuates><attenuation><bacterial attachment><bacterial disease treatment><bacterial infectious disease treatment><bacterial resistance><biological signal transduction><cell culture><cell cultures><community acquired pneumonia><community associated pneumonia><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 crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><cytokine><experiment><experimental research><experimental study><experiments><flu infection><flu virus infection><genome mutation><human model><humanized mice><humanized mouse><immune modulation><immune regulation><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><in vitro Assay><in vivo><infected with S. aureus><infected with Staph aureus><infected with Staphylococcus aureus><infected with flu><infected with flu virus><infected with influenza><infected with influenza virus><influenza infection><influenza virus infection><influenzavirus><injuries><intervention design><lung injury><mAbs><member><methicillin resistance Staphylococcus aureus><methicillin resistant Staphylococcus aureus><methicillin resistant strains of Staphylococcus aureus><model of animal><model of human><monoclonal Abs><mortality><mutant><necrocytosis><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><ontogeny><pathway><pre-clinical><preclinical><protein expression><pulmonary><pulmonary damage><pulmonary infections><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><recruit><resistance to Bacteria><resistance to Bacterial><resistant to Bacteria><resistant to Bacterial><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><social role><sortase><srtA gene product><super infection><superinfection><therapeutic evaluation><therapeutic target><therapeutic testing><therapy design><thymus derived lymphocyte><tool><treatment design><uptake><viral infection><virus infection><virus-induced disease>