葡萄球菌腸毒素 B 誘導的急性呼吸窘迫綜合征中巨噬細胞的異質性.pdf

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1、Heterogeneity of macrophages in Staphylococcal Enterotoxin B induced Acute Respiratory Distress SyndromeKiesha Wilson,PhDAssistant ProfessorDepartment of Pathology,Microbiology,&ImmunologyAcute Respiratory Distress Syndrome(ARDS)Acute Respiratory Distress Syndrome(ARDS)Cytokine storm Fluid build Epi

2、demiology 30-40%mortality based on severity of disease.No Cure Treatment includes:Ventilation,Oxygen Support,and Fluid Management.Matthay et al(2019)Staphylococcus Enterotoxin B(SEB)Staphylococcal Enterotoxin B(SEB)Superantigenic region of SEB similar to SARS-CoV-2 spike protein motif(Function Diffe

3、rs)Superantigen sAG binds to MHC and activates T-cells Toxic Shock Syndrome,Food Poisoning,ARDS,Sepsis BiowarfareCheng et al(2021)SuperantigenConventionalAntigenAntigen Binding CleftPROJECT OVERVIEWSEB-induced ARDS is fatal in C3H/HeJmice when given as a dual dose within 7 days Tissues collected 72

4、hours post-toxin introduction Single Cell RNA-seq and Single Cell ATAC-seq performed on whole lung single cell suspension5g Intranasal2g Intraperitoneal2 Hours5-7 DaysMacrophage Differentiation Monocyte/Macrophage Differentiation Bone Marrow Derived CD14+,CD14+/CD16+,CD16+APC Alveolar and Interstiti

5、al Macrophages SiglecF+,CD11c+,CD11b-Cx3cr1+,CD11b+,CD64 Martinez et.Al(2020)Single Cell RNA Seq SEB causes Increased chromatin accessibility of IFSG in myeloid cells MacrophagesIncreased chromatin accessibility Stat1 and Irf9 critical regulators of severe COVID-19 associated ARDSIrf9Stat1scRNA-seq

6、shows SEB increases myeloid cellsscRNA-seqshows SEB increases myeloid cellsSEB+VEHNaive+VEHCell Distribution%NaveSEBMafb Mac2.1724.02Memory B22.384.61Memory T11.3112.14Neutrophils1.6314.53Alveolar Macrophage15.364.17Activated T12.123.78Ifitm6 Mac1.2210.68PM7.911.96CD8 Proliferating T0.898.94NK6.062.

7、05Ace Mac4.571.97App Mac1.642.52Activated B4.211.32cDC0.951.94Alveolar Epithelial3.741.47Endothelial2.151.29pDC0.431.36Pulmonary Alveolar1.261.2524.02%2.17%4.61%22.38%1.63%14.53%15.36%4.17%12.12%3.78%scRNA-seq shows SEB increases Ccr2 positive myeloid cellsSEB induces diverse macrophage populations

8、associated with M1 and M2 phenotypeM1M2Group SpecificSEB induces diverse macrophage populations that express factors associated with Interferon and JAK/STAT signalingJak/StatISGActivation/ChemotaxisCell Trajectory of MacrophagesAlveolar MacAce MacMafb MacIfitm6 MacApp MacPseudotime analysis is used

9、to order individual cells along a continuous trajectory representing a biological process.This ordering is inferred based on similarities in gene expression profilesConclusions Infiltrating macrophages were the most abundant cell type post-SEB treatment.Increased chromatin accessibility was observed

10、 for interferon and STAT genes found in the macrophage.Interferon-regulated macrophage activation may play a significant role in ARDS progression.Resident macrophage may be polarizing to a more M1 phenotype as well as a M2 phenotype.Future DirectionsARDSMacrophage FunctionalDetermine fate of residen

11、t and recruited MacrophageEvaluate effect of microbiome dysregulationInvestigate the role of Neutrophil-Macrophage FunctioningDeletions effects of target genesEvaluate the effects of dysregulation of miRNAIMPLICATIONS FOR PUBLIC HEALTH?Precision Medicine Disease Understanding and Diagnosis Infectiou

12、s Disease Management Public Health Surveillance Therapeutic Monitoring and Prognosis Health Disparities and EquityAcknowledgmentsGraduate StudentsJordan WilliamsShanieka StaleyAlexandra Jean-LouisMauya ZannatulLab TechnicianTeavian HarvinPMI StaffElizabeth CaulderNicki HoltMargaret WhisenantFacultyM

13、itzi Nagarkatti,Ph.D.Prakash Nagarkatti,Ph.D.K99/R00 Award Committee MembersAngela Murphy,Ph.D.Jiajia Zhang,Ph.D.CAM/COBRE External Advisory CommitteeNagarkatti Lab MembersMOSAIC MentorsSuzanne Barbour,Ph.D.Ruma Banerjee,Ph.D.Kenneth Gibbs,Ph.D.IRF ARFPMINIH FundingK99GM147910R00GM147910THANKS!QUESTIONS?Name:Kiesha Wilson,PhDTitle:Assistant ProfessorEmail:Kiesha.Wilsonuscmed.sc.eduSocial:https:/