title: S1P-Dependent trafficking of intracellular yersinia pestis through lymph nodes establishes Buboes and systemic infection.
abstract: Pathologically swollen lymph nodes (LNs), or buboes, characterize Yersinia pestis infection, yet how they form and function is unknown. We report that colonization of the draining LN (dLN) occurred due to trafficking of infected dendritic cells and monocytes in temporally distinct waves in response to redundant chemotactic signals, including through CCR7, CCR2, and sphingosine-1-phospate (S1P) receptors. Retention of multiple subsets of phagocytes within peripheral LNs using the S1P receptor agonist FTY720 or S1P1-specific agonist SEW2871 increased survival, reduced colonization of downstream LNs, and limited progression to transmission-associated septicemic or pneumonic disease states. Conditional deletion of S1P1 in mononuclear phagocytes abolished node-to-node trafficking of infected cells. Thus, Y. pestis-orchestrated LN remodeling promoted its dissemination via host cells through the lymphatic system but can be blocked by prevention of leukocyte egress from DLNs. These findings define a novel trafficking route of mononuclear phagocytes and identify S1P as a therapeutic target during infection.
authors.affiliation: Program in Emerging Infectious Diseases, Duke-National University of Singapore, Singapore 169857, Singapore; Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: ashley.st.john@duke-nus.edu.sg.
authors.forename: Ashley L
authors.initials: AL
authors.lastname: St John
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: W X Gladys
authors.initials: WXG
authors.lastname: Ang
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Min-Nung
authors.initials: MN
authors.lastname: Huang
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Kunder
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Elizabeth W
authors.initials: EW
authors.lastname: Chan
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA; Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Gunn
authors.affiliation: Program in Emerging Infectious Diseases, Duke-National University of Singapore, Singapore 169857, Singapore; Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA; Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA; Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Soman N
authors.initials: SN
authors.lastname: Abraham
mesh_terms: D000818:Animals; D018845:CD11 Antigens / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D002465:Cell Movement; D054421:Chemokine CCL21 / Q000235:genetics; D003713:Dendritic Cells / Q000382:microbiology; D005260:Female; D000068876:Fingolimod Hydrochloride; D039001:Integrin alpha Chains / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology / Q000382:microbiology / Q000473:pathology*; D008246:Lysophospholipids / Q000819:agonists / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000382:microbiology; D010069:Oxadiazoles / Q000494:pharmacology; D010586:Phagocytes / Q000276:immunology; D010930:Plague / Q000276:immunology / Q000473:pathology*; D011409:Propylene Glycols / Q000494:pharmacology; D054390:Receptors, CCR2 / Q000276:immunology; D054400:Receptors, CCR7 / Q000235:genetics / Q000276:immunology; D049349:Receptors, Lysosphingolipid / Q000819:agonists / Q000276:immunology*; D013110:Sphingosine / Q000819:agonists / Q000031:analogs & derivatives* / Q000235:genetics / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D015010:Yersinia pestis / Q000276:immunology / Q000472:pathogenicity*
chemical_list: D018845:CD11 Antigens; D039481:CD11b Antigen; C515335:Ccr2 protein, mouse; C515371:Ccr7 protein, mouse; D054421:Chemokine CCL21; D039001:Integrin alpha Chains; D008246:Lysophospholipids; D010069:Oxadiazoles; D011409:Propylene Glycols; D054390:Receptors, CCR2; D054400:Receptors, CCR7; D049349:Receptors, Lysosphingolipid; C503964:SEW2871; D013876:Thiophenes; C527123:integrin alphaD, mouse; C060506:sphingosine 1-phosphate; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine