Platelets are critical for survival and tissue integrity during murine pulmonary Aspergillus fumigatus infection

Autoři: Benjamin Y. Tischler aff001;  Nicholas L. Tosini aff002;  Robert A. Cramer aff003;  Tobias M. Hohl aff001
Působiště autorů: Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America aff001;  Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America aff002;  Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America aff003;  Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America aff004
Vyšlo v časopise: Platelets are critical for survival and tissue integrity during murine pulmonary Aspergillus fumigatus infection. PLoS Pathog 16(5): e1008544. doi:10.1371/journal.ppat.1008544
Kategorie: Research Article
doi: 10.1371/journal.ppat.1008544


Beyond their canonical roles in hemostasis and thrombosis, platelets function in the innate immune response by interacting directly with pathogens and by regulating the recruitment and activation of immune effector cells. Thrombocytopenia often coincides with neutropenia in patients with hematologic malignancies and in allogeneic hematopoietic cell transplant recipients, patient groups at high risk for invasive fungal infections. While neutropenia is well established as a major clinical risk factor for invasive fungal infections, the role of platelets in host defense against human fungal pathogens remains understudied. Here, we examined the role of platelets in murine Aspergillus fumigatus infection using two complementary approaches to induce thrombocytopenia without concurrent neutropenia. Thrombocytopenic mice were highly susceptible to A. fumigatus challenge and rapidly succumbed to infection. Although platelets regulated early conidial phagocytosis by neutrophils in a spleen tyrosine kinase (Syk)-dependent manner, platelet-regulated conidial phagocytosis was dispensable for host survival. Instead, our data indicated that platelets primarily function to maintain hemostasis and lung integrity in response to exposed fungal antigens, since thrombocytopenic mice exhibited severe hemorrhage into the airways in response to fungal challenge in the absence of overt angioinvasion. Challenge with swollen, heat-killed, conidia was lethal in thrombocytopenic hosts and could be reversed by platelet transfusion, consistent with the model that fungus-induced inflammation in platelet-depleted mice was sufficient to induce lethal hemorrhage. These data provide new insights into the role of platelets in the anti-Aspergillus host response and expand their role to host defense against filamentous molds.

Klíčová slova:

Aspergillus fumigatus – Hemorrhage – Inflammation – Neutrophils – Phagocytosis – Platelets – Respiratory infections – Thrombocytopenia


1. Latgé J-P, Chamilos G. Aspergillus fumigatus and Aspergillosis in 2019. Clin Microbiol Rev. American Society for Microbiology Journals; 2019;33: 310. doi: 10.1128/CMR.00140-18 31722890

2. Bongomin F, Gago S, Oladele RO, Denning DW. Global and Multi-National Prevalence of Fungal Diseases-Estimate Precision. J Fungi (Basel). Multidisciplinary Digital Publishing Institute; 2017;3: 57. doi: 10.3390/jof3040057 29371573

3. Garcia-Vidal C, Peghin M, Cervera C, Gudiol C, Ruiz-Camps I, Moreno A, et al. Causes of death in a contemporary cohort of patients with invasive aspergillosis. Fredricks DN, editor. PLoS ONE. Public Library of Science; 2015;10: e0120370. doi: 10.1371/journal.pone.0120370 25803853

4. Nouér SA, Nucci M, Kumar NS, Grazziutti M, Restrepo A, Anaissie E. Baseline platelet count and creatinine clearance rate predict the outcome of neutropenia-related invasive aspergillosis. Clin Infect Dis. 2012;54: e173–83. doi: 10.1093/cid/cis298 22423136

5. Rosenhagen M, Feldhues R, Schmidt J, Hoppe-Tichy T, Geiss HK. A risk profile for invasive aspergillosis in liver transplant recipients. Infection. Urban and Vogel; 2009;37: 313–319. doi: 10.1007/s15010-008-8124-x 19629387

6. Lien M-Y, Chou C-H, Lin C-C, Bai L-Y, Chiu C-F, Yeh S-P, et al. Epidemiology and risk factors for invasive fungal infections during induction chemotherapy for newly diagnosed acute myeloid leukemia: A retrospective cohort study. Hills RK, editor. PLoS ONE. Public Library of Science; 2018;13: e0197851. doi: 10.1371/journal.pone.0197851 29883443

7. Yeaman MR. Platelets: at the nexus of antimicrobial defence. Nat Rev Microbiol. 2014;12: 426–437. doi: 10.1038/nrmicro3269 24830471

8. Cognasse F, Hamzeh H, Chavarin P, Acquart S, Genin C, Garraud O. Evidence of Toll-like receptor molecules on human platelets. Immunol Cell Biol. John Wiley & Sons, Ltd; 2005;83: 196–198. doi: 10.1111/j.1440-1711.2005.01314.x 15748217

9. Ichinohe T, Takayama H, Ezumi Y, Arai M, Yamamoto N, Takahashi H, et al. Collagen-stimulated activation of Syk but not c-Src is severely compromised in human platelets lacking membrane glycoprotein VI. J Biol Chem. American Society for Biochemistry and Molecular Biology; 1997;272: 63–68. doi: 10.1074/jbc.272.1.63 8995228

10. Suzuki-Inoue K, Fuller GLJ, García A, Eble JA, Pöhlmann S, Inoue O, et al. A novel Syk-dependent mechanism of platelet activation by the C-type lectin receptor CLEC-2. Blood. American Society of Hematology; 2006;107: 542–549. doi: 10.1182/blood-2005-05-1994 16174766

11. Begonja AJ, Gambaryan S, Geiger J, Aktas B, Pozgajova M, Nieswandt B, et al. Platelet NAD(P)H-oxidase-generated ROS production regulates alphaIIbbeta3-integrin activation independent of the NO/cGMP pathway. Blood. 2005;106: 2757–2760. doi: 10.1182/blood-2005-03-1047 15976180

12. de Stoppelaar SF, van 't Veer C, Claushuis TAM, Albersen BJA, Roelofs JJTH, van der Poll T. Thrombocytopenia impairs host defense in gram-negative pneumonia-derived sepsis in mice. Blood. American Society of Hematology; 2014;124: 3781–3790. doi: 10.1182/blood-2014-05-573915 25301709

13. Speth C, Rambach G, Lass-Flörl C. Platelet immunology in fungal infections. Thromb Haemost. Schattauer GmbH; 2014;112: 632–639. doi: 10.1160/TH14-01-0074 24990293

14. Christin L, Wysong DR, Meshulam T, Hastey R, Simons ER, Diamond RD. Human platelets damage Aspergillus fumigatus hyphae and may supplement killing by neutrophils. Infect Immun. American Society for Microbiology (ASM); 1998;66: 1181–1189.

15. Perkhofer S, Kehrel BE, Dierich MP, Donnelly JP, Nussbaumer W, Hofmann J, et al. Human platelets attenuate Aspergillus species via granule-dependent mechanisms. J Infect Dis. 2008;198: 1243–1246. doi: 10.1086/591458 18752432

16. Perkhofer S, Trappl K, Nussbaumer W, Dierich MP, Lass-Flörl C. Potential synergistic activity of antimycotic substances in combination with human platelets against Aspergillus fumigatus. J Antimicrob Chemother. 2010;65: 1309–1311. doi: 10.1093/jac/dkq111 20378674

17. Perkhofer S, Trappl K, Striessnig B, Nussbaumer W, Lass-Flörl C. Platelets enhance activity of antimycotic substances against non-Aspergillus fumigatus Aspergillus species in vitro. Med Mycol. 2011;49: 157–166. doi: 10.3109/13693786.2010.510150 20795763

18. Perkhofer S, Striessnig B, Sartori B, Hausott B, Ott HW, Lass-Flörl C. Interaction of platelets and anidulafungin against Aspergillus fumigatus. Antimicrob Agents Chemother. American Society for Microbiology; 2013;57: 626–628. doi: 10.1128/AAC.01534-12 23114752

19. Perkhofer S, Zenzmaier C, Frealle E, Blatzer M, Hackl H, Sartori B, et al. Differential gene expression in Aspergillus fumigatus induced by human platelets in vitro. Int J Med Microbiol. 2015;305: 327–338. doi: 10.1016/j.ijmm.2015.01.002 25661519

20. Rødland EK, Ueland T, Pedersen TM, Halvorsen B, Muller F, Aukrust P, et al. Activation of platelets by Aspergillus fumigatus and potential role of platelets in the immunopathogenesis of Aspergillosis. Infect Immun. 2010;78: 1269–1275. doi: 10.1128/IAI.01091-09 20008537

21. Czakai K, Dittrich M, Kaltdorf M, Müller T, Krappmann S, Schedler A, et al. Influence of Platelet-rich Plasma on the immune response of human monocyte-derived dendritic cells and macrophages stimulated with Aspergillus fumigatus. Int J Med Microbiol. 2017;307: 95–107. doi: 10.1016/j.ijmm.2016.11.010 27965080

22. Frealle E, Gosset P, Leroy S, Delattre C, Wacrenier A, Zenzmaier C, et al. In vitro coagulation triggers anti-Aspergillus fumigatus neutrophil response. Future Microbiol. 2018;13: 659–669. doi: 10.2217/fmb-2017-0190 29790796

23. Jhingran A, Mar KB, Kumasaka DK, Knoblaugh SE, Ngo LY, Segal BH, et al. Tracing conidial fate and measuring host cell antifungal activity using a reporter of microbial viability in the lung. Cell Rep. 2012;2: 1762–1773. doi: 10.1016/j.celrep.2012.10.026 23200858

24. Chen H, Wu S, Lu R, Zhang Y-G, Zheng Y, Sun J. Pulmonary permeability assessed by fluorescent-labeled dextran instilled intranasally into mice with LPS-induced acute lung injury. Zhao Y-Y, editor. PLoS ONE. Public Library of Science; 2014;9: e101925. doi: 10.1371/journal.pone.0101925 25007191

25. Pitchford S, Pan D, Welch HCE. Platelets in neutrophil recruitment to sites of inflammation. Curr Opin Hematol. 2017;24: 23–31. doi: 10.1097/MOH.0000000000000297 27820736

26. Espinosa V, Jhingran A, Dutta O, Kasahara S, Donnelly R, Du P, et al. Inflammatory monocytes orchestrate innate antifungal immunity in the lung. Sheppard DC, editor. PLoS Pathog. Public Library of Science; 2014;10: e1003940. doi: 10.1371/journal.ppat.1003940 24586155

27. Drummond RA, Brown GD. The role of Dectin-1 in the host defence against fungal infections. Curr Opin Microbiol. 2011;14: 392–399. doi: 10.1016/j.mib.2011.07.001 21803640

28. Jhingran A, Kasahara S, Shepardson KM, Junecko BAF, Heung LJ, Kumasaka DK, et al. Compartment-specific and sequential role of MyD88 and CARD9 in chemokine induction and innate defense during respiratory fungal infection. Klein BS, editor. PLoS Pathog. Public Library of Science; 2015;11: e1004589. doi: 10.1371/journal.ppat.1004589 25621893

29. Spalton JC, Mori J, Pollitt AY, Hughes CE, Eble JA, Watson SP. The novel Syk inhibitor R406 reveals mechanistic differences in the initiation of GPVI and CLEC-2 signaling in platelets. J Thromb Haemost. John Wiley & Sons, Ltd (10.1111); 2009;7: 1192–1199. doi: 10.1111/j.1538-7836.2009.03451.x 19422460

30. Goerge T, Ho-Tin-Noé B, Carbo C, Benarafa C, Remold-O'Donnell E, Zhao B-Q, et al. Inflammation induces hemorrhage in thrombocytopenia. Blood. American Society of Hematology; 2008;111: 4958–4964. doi: 10.1182/blood-2007-11-123620 18256319

31. Aimanianda V, Bayry J, Bozza S, Kniemeyer O, Perruccio K, Elluru SR, et al. Surface hydrophobin prevents immune recognition of airborne fungal spores. Nature. Nature Publishing Group; 2009;460: 1117–1121. doi: 10.1038/nature08264 19713928

32. Bayry J, Beaussart A, Dufrêne YF, Sharma M, Bansal K, Kniemeyer O, et al. Surface structure characterization of Aspergillus fumigatus conidia mutated in the melanin synthesis pathway and their human cellular immune response. Deepe GS Jr., editor. Infect Immun. American Society for Microbiology Journals; 2014;82: 3141–3153. doi: 10.1128/IAI.01726-14 24818666

33. Langfelder K, Jahn B, Gehringer H, Schmidt A, Wanner G, Brakhage AA. Identification of a polyketide synthase gene (pksP) of Aspergillus fumigatus involved in conidial pigment biosynthesis and virulence. Med Microbiol Immunol. Springer-Verlag; 1998;187: 79–89. doi: 10.1007/s004300050077 9832321

34. Hohl TM, Van Epps HL, Rivera A, Morgan LA, Chen PL, Feldmesser M, et al. Aspergillus fumigatus triggers inflammatory responses by stage-specific beta-glucan display. PLoS Pathog. Public Library of Science; 2005;1: e30. doi: 10.1371/journal.ppat.0010030 16304610

35. Wuescher LM, Takashima A, Worth RG. A novel conditional platelet depletion mouse model reveals the importance of platelets in protection against Staphylococcus aureus bacteremia. J Thromb Haemost. Wiley/Blackwell (10.1111); 2015;13: 303–313. doi: 10.1111/jth.12795 25418277

36. Amison RT, O'Shaughnessy BG, Arnold S, Cleary SJ, Nandi M, Pitchford SC, et al. Platelet Depletion Impairs Host Defense to Pulmonary Infection with Pseudomonas aeruginosa in Mice. Am J Respir Cell Mol Biol. American Thoracic Society; 2018;58: 331–340. doi: 10.1165/rcmb.2017-0083OC 28957635

37. Rossaint J, Margraf A, Zarbock A. Role of Platelets in Leukocyte Recruitment and Resolution of Inflammation. Front Immunol. 2018;9: 2712. doi: 10.3389/fimmu.2018.02712 30515177

38. Caffrey AK, Lehmann MM, Zickovich JM, Espinosa V, Shepardson KM, Watschke CP, et al. IL-1α signaling is critical for leukocyte recruitment after pulmonary Aspergillus fumigatus challenge. Klein BS, editor. PLoS Pathog. Public Library of Science; 2015;11: e1004625. doi: 10.1371/journal.ppat.1004625 25629406

39. Caffrey-Carr AK, Hilmer KM, Kowalski CH, Shepardson KM, Temple RM, Cramer RA, et al. Host-Derived Leukotriene B4 Is Critical for Resistance against Invasive Pulmonary Aspergillosis. Front Immunol. Frontiers; 2017;8: 1984. doi: 10.3389/fimmu.2017.01984 29375586

40. Kornerup KN, Salmon GP, Pitchford SC, Liu WL, Page CP. Circulating platelet-neutrophil complexes are important for subsequent neutrophil activation and migration. J Appl Physiol. American Physiological Society Bethesda, MD; 2010;109: 758–767. doi: 10.1152/japplphysiol.01086.2009 20558756

41. Asaduzzaman M, Lavasani S, Rahman M, Zhang S, Braun OO, Jeppsson B, et al. Platelets support pulmonary recruitment of neutrophils in abdominal sepsis. Crit Care Med. 2009;37: 1389–1396. doi: 10.1097/CCM.0b013e31819ceb71 19242347

42. Zarbock A, Singbartl K, Ley K. Complete reversal of acid-induced acute lung injury by blocking of platelet-neutrophil aggregation. J Clin Invest. American Society for Clinical Investigation; 2006;116: 3211–3219. doi: 10.1172/JCI29499 17143330

43. Hillgruber C, Pöppelmann B, Weishaupt C, Steingräber AK, Wessel F, Berdel WE, et al. Blocking neutrophil diapedesis prevents hemorrhage during thrombocytopenia. J Exp Med. Rockefeller University Press; 2015;212: 1255–1266. doi: 10.1084/jem.20142076 26169941

44. Lopes-Bezerra LM, Filler SG. Interactions of Aspergillus fumigatus with endothelial cells: internalization, injury, and stimulation of tissue factor activity. Blood. 2004;103: 2143–2149. doi: 10.1182/blood-2003-06-2186 14630829

45. Boulaftali Y, Hess PR, Getz TM, Cholka A, Stolla M, Mackman N, et al. Platelet ITAM signaling is critical for vascular integrity in inflammation. J Clin Invest. American Society for Clinical Investigation; 2013;123: 908–916. doi: 10.1172/JCI65154 23348738

46. Gros A, Syvannarath V, Lamrani L, Ollivier V, Loyau S, Goerge T, et al. Single platelets seal neutrophil-induced vascular breaches via GPVI during immune-complex-mediated inflammation in mice. Blood. American Society of Hematology; 2015;126: 1017–1026. doi: 10.1182/blood-2014-12-617159 26036804

47. Claushuis TAM, de Vos AF, Nieswandt B, Boon L, Roelofs JJTH, de Boer OJ, et al. Platelet glycoprotein VI aids in local immunity during pneumonia-derived sepsis caused by gram-negative bacteria. Blood. American Society of Hematology; 2018;131: 864–876. doi: 10.1182/blood-2017-06-788067 29187378

48. Kousha M, Tadi R, Soubani AO. Pulmonary aspergillosis: a clinical review. Eur Respir Rev. European Respiratory Society; 2011;20: 156–174. doi: 10.1183/09059180.00001011 21881144

49. Albelda SM, Talbot GH, Gerson SL, Miller WT, Cassileth PA. Pulmonary cavitation and massive hemoptysis in invasive pulmonary aspergillosis. Influence of bone marrow recovery in patients with acute leukemia. Am Rev Respir Dis. 1985;131: 115–120. 3966697

50. Reutershan J, Morris MA, Burcin TL, Smith DF, Chang D, Saprito MS, et al. Critical role of endothelial CXCR2 in LPS-induced neutrophil migration into the lung. J Clin Invest. American Society for Clinical Investigation; 2006;116: 695–702. doi: 10.1172/JCI27009 16485040

51. Martin S, Maruta K, Burkart V, Gillis S, Kolb H. IL-1 and IFN-gamma increase vascular permeability. Immunology. Wiley-Blackwell; 1988;64: 301–305.

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