Neutrophils play an ongoing role in preventing bacterial pneumonia by blocking the dissemination of Staphylococcus aureus from the upper to the lower airways
Chenghao Ge
Department of Microbiology and Immunology, The University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, 3000 Australia
School of Medicine, Tsinghua University, Beijing, China
Equal contributors.Search for more papers by this authorIan R Monk
Department of Microbiology and Immunology, The University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, 3000 Australia
Equal contributors.Search for more papers by this authorSarah C Monard
Department of Microbiology and Immunology, The University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, 3000 Australia
Search for more papers by this authorJames G Bedford
Department of Microbiology and Immunology, The University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, 3000 Australia
Search for more papers by this authorJessica Braverman
Department of Microbiology and Immunology, The University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, 3000 Australia
Search for more papers by this authorTimothy P Stinear
Department of Microbiology and Immunology, The University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, 3000 Australia
Search for more papers by this authorCorresponding Author
Linda M Wakim
Department of Microbiology and Immunology, The University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, 3000 Australia
Correspondence
Linda M Wakim, Department of Microbiology and Immunology, University of Melbourne, The Doherty Institute for Infection & Immunity, Level 8, 792 Elizabeth Street, Melbourne, VIC 3000, Australia.
E-mail: [email protected]
Search for more papers by this authorChenghao Ge
Department of Microbiology and Immunology, The University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, 3000 Australia
School of Medicine, Tsinghua University, Beijing, China
Equal contributors.Search for more papers by this authorIan R Monk
Department of Microbiology and Immunology, The University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, 3000 Australia
Equal contributors.Search for more papers by this authorSarah C Monard
Department of Microbiology and Immunology, The University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, 3000 Australia
Search for more papers by this authorJames G Bedford
Department of Microbiology and Immunology, The University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, 3000 Australia
Search for more papers by this authorJessica Braverman
Department of Microbiology and Immunology, The University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, 3000 Australia
Search for more papers by this authorTimothy P Stinear
Department of Microbiology and Immunology, The University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, 3000 Australia
Search for more papers by this authorCorresponding Author
Linda M Wakim
Department of Microbiology and Immunology, The University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, 3000 Australia
Correspondence
Linda M Wakim, Department of Microbiology and Immunology, University of Melbourne, The Doherty Institute for Infection & Immunity, Level 8, 792 Elizabeth Street, Melbourne, VIC 3000, Australia.
E-mail: [email protected]
Search for more papers by this authorAbstract
Staphylococcus aureus is found in the nasal cavity of up to 30% of the human population. Persistent nasal carriage of S. aureus is a risk factor for influenza virus-induced secondary bacterial pneumonia. There is limited understanding of the factors that cause S. aureus to shift from the upper to the lower respiratory tract and convert from a commensal organism to an invasive pathogen. Here we show that neutrophils actively prevent S. aureus dissemination. Establishment of a mouse model of localized S. aureus nasal carriage revealed variations in the longevity of persistence of S. aureus isolates. Improved persistence within this site was associated with reduced nasal inflammation, less neutrophil egress into the airways and reduced neutrophil–bacteria association. Neutrophil depletion of mice with localized S. aureus nasal carriage triggered the development of an invasive S. aureus infection. Moreover, utilizing a model of influenza-induced staphylococcal pneumonia we showed that treatment with granulocyte–colony-stimulating factor, a potent enhancer of neutrophil number and function, significantly reduced bacterial loads in the lung and improved disease outcomes. These data reveal that neutrophils play an important and active role in confining S. aureus to the upper respiratory tract and highlight the use of approaches that improve neutrophil function as effective strategies to attenuate morbidity associated with staphylococcal pneumonia.
Conflict of Interest
The authors declare that they have no competing interests.
Supporting Information
| Filename | Description |
|---|---|
| imcb12343-sup-0001-Supinfo.docxWord document, 1.7 MB | Supplementary Material |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1Sakr A, Bregeon F, Mege JL, Rolain JM, Blin O. Staphylococcus aureus nasal colonization: an update on mechanisms, epidemiology, risk factors, and subsequent infections. Front Microbiol 2018; 9: 2419.
- 2Breuer K, HAussler S, Kapp A, Werfel T. Staphylococcus aureus: colonizing features and influence of an antibacterial treatment in adults with atopic dermatitis. Br J Dermatol 2002; 147: 55–61.
- 3Kluytmans J, van Belkum A, Verbrugh H. Nasal carriage of Staphylococcus aureus: epidemiology, underlying mechanisms, and associated risks. Clin Microbiol Rev 1997; 10: 505–520.
- 4Boucher HW, Corey GR. Epidemiology of methicillin-resistant Staphylococcus aureus. Clin Infect Dis 2008; 46(Suppl 5): S344–S349.
- 5 System N. National Nosocomial Infections Surveillance (NNIS) system report, data summary from January 1990-May 1999, issued June 1999. A report from the NNIS system. Am J Infect Control 1999; 27: 520–532.
- 6Wertheim HF, Vos MC, Ott A, et al. Risk and outcome of nosocomial Staphylococcus aureus bacteraemia in nasal carriers versus non-carriers. Lancet 2004; 364: 703–705.
- 7Klevens RM, Morrison MA, Nadle J, et al. Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA 2007; 298: 1763–1771.
- 8von Eiff C, Becker K, Machka K, Stammer H, Peters G. Nasal carriage as a source of Staphylococcus aureus bacteremia. Study Group. N Engl J Med 2001; 344: 11–16.
- 9Rubinstein E, Kollef MH, Nathwani D. Pneumonia caused by methicillin-resistant Staphylococcus aureus. Clin Infect Dis 2008; 46(Suppl 5): S378–S385.
- 10Jacobs DM, Shaver A. Prevalence of and outcomes from Staphylococcus aureus pneumonia among hospitalized patients in the United States, 2009–2012. Am J Infect Control 2017; 45: 404–409.
- 11Vardakas KZ, Matthaiou DK, Falagas ME. Incidence, characteristics and outcomes of patients with severe community acquired-MRSA pneumonia. Eur Respir J 2009; 34: 1148–1158.
- 12Vardakas KZ, Matthaiou DK, Falagas ME. Comparison of community-acquired pneumonia due to methicillin-resistant and methicillin-susceptible Staphylococcus aureus producing the Panton-Valentine leukocidin. Int J Tuberc Lung Dis 2009; 13: 1476–1485.
- 13Williams DJ, Hall M, Brogan TV, et al. Influenza coinfection and outcomes in children with complicated pneumonia. Arch Pediatr Adolesc Med 2011; 165: 506–512.
- 14Craig A, Mai J, Cai S, Jeyaseelan S. Neutrophil recruitment to the lungs during bacterial pneumonia. Infect Immun 2009; 77: 568–575.
- 15Rigby KM, DeLeo FR. Neutrophils in innate host defense against Staphylococcus aureus infections. Semin Immunopathol 2012; 34: 237–259.
- 16Robertson CM, Perrone EE, McConnell KW, et al. Neutrophil depletion causes a fatal defect in murine pulmonary Staphylococcus aureus clearance. J Surg Res 2008; 150: 278–285.
- 17van Belkum A, Melles DC. Not all Staphylococcus aureus strains are equally pathogenic. Discov Med 2005; 5: 148–152.
- 18Chua KY, Seemann T, Harrison PF, et al. The dominant Australian community-acquired methicillin-resistant Staphylococcus aureus clone ST93-IV [2B] is highly virulent and genetically distinct. PLoS One 2011; 6: e25887.
- 19Gonzalez-Zorn B, Senna JP, Fiette L, et al. Bacterial and host factors implicated in nasal carriage of methicillin-resistant Staphylococcus aureus in mice. Infect Immun 2005; 73: 1847–1851.
- 20Cowan ST, Shaw C, Williams RE. Type strain for Staphylococcus aureus Rosenbach. J Gen Microbiol 1954; 10: 174–176.
- 21Sahibzada S, Abraham S, Coombs GW, et al. Transmission of highly virulent community-associated MRSA ST93 and livestock-associated MRSA ST398 between humans and pigs in Australia. Sci Rep 2017; 7: 5273.
- 22Kuroda M, Ohta T, Uchiyama I, et al. Whole genome sequencing of meticillin-resistant Staphylococcus aureus. Lancet 2001; 357: 1225–1240.
- 23Planet PJ, Parker D, Cohen TS, et al. Lambda interferon restructures the nasal microbiome and increases susceptibility to Staphylococcus aureus superinfection. mBio 2016; 7: e01939–e01915.
- 24Desbois AP, Sattar A, Graham S, Warn PA, Coote PJ. MRSA decolonization of cotton rat nares by a combination treatment comprising lysostaphin and the antimicrobial peptide ranalexin. J Antimicrob Chemother 2013; 68: 2569–2575.
- 25Mulcahy ME, Geoghegan JA, Monk IR, et al. Nasal colonisation by Staphylococcus aureus depends upon clumping factor B binding to the squamous epithelial cell envelope protein loricrin. PLoS Pathog 2012; 8: e1003092.
- 26Kiser KB, Cantey-Kiser JM, Lee JC. Development and characterization of a Staphylococcus aureus nasal colonization model in mice. Infect Immun 1999; 67: 5001–5006.
- 27Chua K, Seemann T, Harrison PF, et al. Complete genome sequence of Staphylococcus aureus strain JKD6159, a unique Australian clone of ST93-IV community methicillin-resistant Staphylococcus aureus. J Bacteriol 2010; 192: 5556–5557.
- 28Balamayooran G, Batra S, Fessler MB, Happel KI, Jeyaseelan S. Mechanisms of neutrophil accumulation in the lungs against bacteria. Am J Respir Cell Mol Biol 2010; 43: 5–16.
- 29Miller LS, O'Connell RM, Gutierrez MA, et al. MyD88 mediates neutrophil recruitment initiated by IL-1R but not TLR2 activation in immunity against Staphylococcus aureus. Immunity 2006; 24: 79–91.
- 30Moore DC. Drug-induced neutropenia: a focus on rituximab-induced late-onset neutropenia. Pharm Ther 2016; 41: 765–768.
- 31Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 Update by the Infectious Diseases Society of America. Clin Infect Dis 2011; 52: 427–431.
- 32McNamee LA, Harmsen AG. Both influenza-induced neutrophil dysfunction and neutrophil-independent mechanisms contribute to increased susceptibility to a secondary Streptococcus pneumoniae infection. Infect Immun 2006; 74: 6707–6721.
- 33Reddinger RM, Luke-Marshall NR, Hakansson AP, Campagnari AA. Host physiologic changes induced by influenza a virus lead to Staphylococcus aureus biofilm dispersion and transition from asymptomatic colonization to invasive disease. mBio 2016; 7: e01235-16.
- 34Gorwitz RJ, Kruszon-Moran D, McAllister SK, et al. Changes in the prevalence of nasal colonization with Staphylococcus aureus in the United States, 2001–2004. J Infect Dis 2008; 197: 1226–1234.
- 35Lekstrom-Himes JA, Gallin JI. Immunodeficiency diseases caused by defects in phagocytes. N Engl J Med 2000; 343: 1703–1714.
- 36Leibovici L, Paul M, Cullen M, et al. Antibiotic prophylaxis in neutropenic patients: new evidence, practical decisions. Cancer 2006; 107: 1743–1751.
- 37Archer NK, Harro JM, Shirtliff ME. Clearance of Staphylococcus aureus nasal carriage is T cell dependent and mediated through interleukin-17A expression and neutrophil influx. Infect Immun 2013; 81: 2070–2075.
- 38Schulz A, Jiang L, de Vor L, et al. Neutrophil recruitment to noninvasive MRSA at the stratum corneum of human skin mediates transient colonization. Cell Rep 2019; 29: 1074–1081.e5.
- 39Tseng CW, Biancotti JC, Berg BL, et al. Increased susceptibility of humanized NSG mice to panton-valentine leukocidin and Staphylococcus aureus skin infection. PLoS Pathog 2015; 11: e1005292.
- 40Reizner W, Hunter JG, O'Malley NT, Southgate RD, Schwarz EM, Kates SL. A systematic review of animal models for Staphylococcus aureus osteomyelitis. Eur Cell Mater 2014; 27: 196–212.
- 41Kim HK, Missiakas D, Schneewind O. Mouse models for infectious diseases caused by Staphylococcus aureus. J Immunol Methods 2014; 410: 88–99.
- 42Buer J, Balling R. Mice, microbes and models of infection. Nat Rev Genet 2003; 4: 195–205.
- 43Loffler B, Hussain M, Grundmeier M, et al. Staphylococcus aureus panton-valentine leukocidin is a very potent cytotoxic factor for human neutrophils. PLoS Pathog 2010; 6: e1000715.
- 44de Haas CJ, Veldkamp KE, Peschel A, et al. Chemotaxis inhibitory protein of Staphylococcus aureus, a bacterial antiinflammatory agent. J Exp Med 2004; 199: 687–695.
- 45Otto M. Basis of virulence in community-associated methicillin-resistant Staphylococcus aureus. Annu Rev Microbiol 2010; 64: 143–162.
- 46Foster TJ. Immune evasion by staphylococci. Nat Rev Microbiol 2005; 3: 948–958.
- 47Postma B, Poppelier MJ, van Galen JC, et al. Chemotaxis inhibitory protein of Staphylococcus aureus binds specifically to the C5a and formylated peptide receptor. J Immunol 2004; 172: 6994–7001.
- 48Goldmann O, Medina E. Staphylococcus aureus strategies to evade the host acquired immune response. Int J Med Microbiol 2018; 308: 625–630.
- 49Yang D, Ho YX, Cowell LM, Jilani I, Foster SJ, Prince LR. A genome-wide screen identifies factors involved in S. aureus-induced human neutrophil cell death and pathogenesis. Front Immunol 2019; 10: 45.
- 50Gresham HD, Lowrance JH, Caver TE, Wilson BS, Cheung AL, Lindberg FP. Survival of Staphylococcus aureus inside neutrophils contributes to infection. J Immunol 2000; 164: 3713–3722.
- 51Thwaites GE, Gant V. Are bloodstream leukocytes Trojan Horses for the metastasis of Staphylococcus aureus? Nat Rev Microbiol 2011; 9: 215–222.
- 52Karzai W, von Specht BU, Parent C, et al. G-CSF during Escherichia coli versus Staphylococcus aureus pneumonia in rats has fundamentally different and opposite effects. Am J Respir Crit Care Med 1999; 159: 1377–1382.
- 53Sevransky JE, Parent C, Cui X, et al. Granulocyte colony-stimulating factor has differing effects comparing intravascular versus extravascular models of sepsis. J Trauma 2004; 57: 618–625.
- 54Alp E, Gozukucuk S, Canoz O, Kirmaci B, Doganay M. Effect of granulocyte colony-stimulating factor in experimental methicillin resistant Staphylococcus aureus sepsis. BMC Infect Dis 2004; 4: 43.
- 55Nelson S, Belknap SM, Carlson RW, et al. A randomized controlled trial of filgrastim as an adjunct to antibiotics for treatment of hospitalized patients with community-acquired pneumonia. CAP Study Group. J Infect Dis 1998; 178: 1075–1080.
- 56Dale DC, Liles WC, Summer WR, Nelson S. Review: granulocyte colony-stimulating factor–role and relationships in infectious diseases. J Infect Dis 1995; 172: 1061–1075.
- 57Bosmann M, Grailer JJ, Ruemmler R, et al. Extracellular histones are essential effectors of C5aR- and C5L2-mediated tissue damage and inflammation in acute lung injury. FASEB J 2013; 27: 5010–5021.
- 58Xu J, Zhang X, Pelayo R, et al. Extracellular histones are major mediators of death in sepsis. Nat Med 2009; 15: 1318–1321.
- 59Saffarzadeh M, Juenemann C, Queisser MA, et al. Neutrophil extracellular traps directly induce epithelial and endothelial cell death: a predominant role of histones. PLoS One 2012; 7: e32366.
- 60Takeuchi O, Hoshino K, Akira S. Cutting edge: TLR2-deficient and MyD88-deficient mice are highly susceptible to Staphylococcus aureus infection. J Immunol 2000; 165: 5392–5396.
- 61Skerrett SJ, Liggitt HD, Hajjar AM, Wilson CB. Cutting edge: myeloid differentiation factor 88 is essential for pulmonary host defense against Pseudomonas aeruginosa but not Staphylococcus aureus. J Immunol 2004; 172: 3377–3381.
- 62Naiki Y, Michelsen KS, Schroder NW, et al. MyD88 is pivotal for the early inflammatory response and subsequent bacterial clearance and survival in a mouse model of Chlamydia pneumoniae pneumonia. J Biol Chem 2005; 280: 29242–29249.
- 63Mulcahy ME, McLoughlin RM. Host-bacterial crosstalk determines Staphylococcus aureus nasal colonization. Trends Microbiol 2016; 24: 872–886.
- 64Stinear TP, Holt KE, Chua K, et al. Adaptive change inferred from genomic population analysis of the ST93 epidemic clone of community-associated methicillin-resistant Staphylococcus aureus. Genome Biol Evol 2014; 6: 366–378.
- 65van Hal SJ, Steinig EJ, Andersson P, et al. Global scale dissemination of ST93: a divergent Staphylococcus aureus epidemic lineage that has recently emerged from remote Northern Australia. Front Microbiol 2018; 9: 1453.
- 66Chua KY, Monk IR, Lin YH, et al. Hyperexpression of α-hemolysin explains enhanced virulence of sequence type 93 community-associated methicillin-resistant Staphylococcus aureus. BMC Microbiol 2014; 14: 31.
- 67Tojo S, Tanaka Y, Ochi K. Activation of antibiotic production in bacillus spp. by cumulative drug resistance mutations. Antimicrob Agents Chemother 2015; 59: 7799–7804.
- 68Yepes A, Koch G, Waldvogel A, Garcia-Betancur JC, Lopez D. Reconstruction of mreB expression in Staphylococcus aureus via a collection of new integrative plasmids. Appl Environ Microbiol 2014; 80: 3868–3878.
- 69Kofoed EM, Yan D, Katakam AK, et al. De novo guanine biosynthesis but not the Riboswitch-regulated purine salvage pathway is required for Staphylococcus aureus infection in vivo. J Bacteriol 2016; 198: 2001–2015.
- 70Monk IR, Tree JJ, Howden BP, Stinear TP, Foster TJ. Complete bypass of restriction systems for major Staphylococcus aureus lineages. mBio 2015; 6: e00308–e00315.
- 71Monk IR, Shaikh N, Begg SL, et al. Zinc-binding to the cytoplasmic PAS domain regulates the essential WalK histidine kinase of Staphylococcus aureus. Nat Commun 2019; 10: 3067.
- 72Monk IR, Gahan CG, Hill C. Tools for functional postgenomic analysis of listeria monocytogenes. Appl Environ Microbiol 2008; 74: 3921–3934.
- 73Foster TJ. 7.9 Molecular genetic analysis of staphylococcal virulence. Method Microbiol 1998; 27: 433.
Citing Literature
Journal of the Australian and New Zealand Society for Immunology
