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Streptococcus pneumoniae: transmission, colonization and invasion

Abstract

Streptococcus pneumoniae has a complex relationship with its obligate human host. On the one hand, the pneumococci are highly adapted commensals, and their main reservoir on the mucosal surface of the upper airways of carriers enables transmission. On the other hand, they can cause severe disease when bacterial and host factors allow them to invade essentially sterile sites, such as the middle ear spaces, lungs, bloodstream and meninges. Transmission, colonization and invasion depend on the remarkable ability of S. pneumoniae to evade or take advantage of the host inflammatory and immune responses. The different stages of pneumococcal carriage and disease have been investigated in detail in animal models and, more recently, in experimental human infection. Furthermore, widespread vaccination and the resulting immune pressure have shed light on pneumococcal population dynamics and pathogenesis. Here, we review the mechanistic insights provided by these studies on the multiple and varied interactions of the pneumococcus and its host.

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Fig. 1: The life cycle of Streptococcus pneumoniae and the pathogenesis of pneumococcal disease.
Fig. 2: Bacterial and host factors affecting pneumococcal shedding from carriers.
Fig. 3: Molecular mechanisms of pneumococcal colonization of host surfaces.
Fig. 4: Stages in pneumococcal adherence and invasion.

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References

  1. Abdullahi, O. et al. The prevalence and risk factors for pneumococcal colonization of the nasopharynx among children in Kilifi District, Kenya. PLoS ONE 7, e30787 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Yahiaoui, R. Y. et al. Prevalence and antibiotic resistance of commensal Streptococcus pneumoniae in nine European countries. Future Microbiol. 11, 737–744 (2016).

    Article  CAS  PubMed  Google Scholar 

  3. Bogaert, D., De Groot, R. & Hermans, P. W. Streptococcus pneumoniae colonisation: the key to pneumococcal disease. Lancet Infect. Dis. 4, 144–154 (2004).

    Article  CAS  PubMed  Google Scholar 

  4. Whitney, C. G. et al. Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine. N. Engl. J. Med. 348, 1737–1746 (2003).

    Article  PubMed  Google Scholar 

  5. Musher, D. How contagious are common respiratory tract infections? N. Engl. J. Med. 348, 1256–1266 (2003).

    Article  PubMed  Google Scholar 

  6. Numminen, E. et al. Climate induces seasonality in pneumococcal transmission. Sci. Rep. 5, 11344 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Gwaltney, J. J., Sande, M., Austrian, R. & Hendley, J. Spread of Streptococcus pneumoniae in families. II. Relation of transfer of S. pneumoniae to incidence of colds and serum antibody. J. Infect. Dis. 132, 62–68 (1975).

    Article  PubMed  Google Scholar 

  8. McCullers, J. et al. Influenza enhances susceptibility to natural acquisition of and disease due to Streptococcus pneumoniae in ferrets. J. Infect. Dis. 202, 1287–1295 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Diavatopoulos, D. A. et al. Influenza A virus facilitates Streptococcus pneumoniae and disease. FASEB. J. 24, 1789–1798 (2010). This study demonstrates the role of influenza virus in pneumococcal transmission in an infant mouse model.

    Article  CAS  PubMed  Google Scholar 

  10. Barbier, D. et al. Influenza A induces the major secreted airway mucin MUC5AC in a protease-EGFR-extracellular regulated kinase-Sp1-dependent pathway. Am. J. Respir. Cell. Mol. Biol. 47, 149–157 (2012).

    Article  CAS  PubMed  Google Scholar 

  11. Siegel, S., Roche, A. & Weiser, J. Influenza promotes pneumococcal growth during coinfection by providing host sialylated substrates as a nutrient source. Cell Host Microbe 16, 55–67 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Richard, A. L., Siegel, S. J., Erikson, J. & Weiser, J. N. TLR2 signaling decreases transmission of Streptococcus pneumoniae by limiting bacterial shedding in an infant mouse Influenza A co-infection model. PLoS Pathog. 10, e1004339 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Kono, M. et al. Single cell bottlenecks in the pathogenesis of Streptococcus pneumoniae. PLoS Pathog. 12, e1005887 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Zafar, M. A., Kono, M., Wang, Y., Zangari, T. & Weiser, J. N. Infant mouse model for the study of shedding and transmission during Streptococcus pneumoniae monoinfection. Infect. Immun. 84, 2714–2722 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Rodrigues, F. et al. Relationships between rhinitis symptoms, respiratory viral infections and nasopharyngeal colonization with Streptococcus pneumoniae. Haemophilus influenza and Staphylococcus aureus in children attending daycare. Pediatr. Infect. Dis. J. 32, 227–232 (2013).

    Article  PubMed  Google Scholar 

  16. Zafar, M. A., Wang, Y., Hamaguchi, S. & Weiser, J. N. Host-to-host transmission of Streptococcus pneumoniae is driven by its inflammatory toxin, pneumolysin. Cell Host Microbe 21, 73–83 (2017). This study provides evidence that the toxin Ply promotes mucosal inflammation, which facilitates pneumococcal transmission in infant mice.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Matthias, K. A., Roche, A. M., Standish, A. J., Shchepetov, M. & Weiser, J. N. Neutrophil-toxin interactions promote antigen delivery and mucosal clearance of Streptococcus pneumoniae. J. Immunol. 180, 6246–6254 (2008).

    Article  CAS  PubMed  Google Scholar 

  18. Lipsitch, M. & Moxon, E. R. Virulence and transmissibility of pathogens: what is the relationship? Trends Microbiol. 5, 31–37 (1997).

    Article  CAS  PubMed  Google Scholar 

  19. Zafar, M. A., Hamaguchi, S., Zangari, T., Cammer, M. & Weiser, J. N. Capsule type and amount affect shedding and transmission of Streptococcus pneumoniae. mBio 8, e00989–17 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Marks, L. R., Reddinger, R. M. & Hakansson, A. P. Biofilm formation enhances fomite survival of Streptococcus pneumoniae and Streptococcus pyogenes. Infect. Immun. 82, 1141–1146 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Verhagen, L. M. et al. Genome-wide identification of genes essential for the survival of Streptococcus pneumoniae in human saliva. PLoS. ONE. 9, e89541 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Hamaguchi, S., Zafar, M. A., Cammer, M. & Weiser, J. N. Capsule prolongs survival of Streptococcus pneumoniae during starvation. Infect. Immun. https://doi.org/10.1128/IAI.00802-17 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Walsh, R. L. & Camilli, A. Streptococcus pneumoniae is desiccation tolerant and infectious upon rehydration. mBio 2, e00092–11 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Zangari, T., Wang, Y. & Weiser, J. N. Streptococcus pneumoniae transmission is blocked by type-specific immunity in an infant mouse model. mBio 8, e00188–17 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Roche, A. M., Richard, A. L., Rahkola, J. T., Janoff, E. N. & Weiser, J. N. Antibody blocks acquisition of bacterial colonization through agglutination. Mucosal Immunol. 8, 176–185 (2015).

    Article  CAS  PubMed  Google Scholar 

  26. Janoff, E. N. et al. Pneumococcal IgA1 protease subverts specific protection by human IgA1. Mucosal Immunol. 7, 249–256 (2014).

    Article  CAS  PubMed  Google Scholar 

  27. Pennington, S. H. et al. Polysaccharide-specific memory b cells predict protection against experimental human pneumococcal carriage. Am. J. Respir. Crit. Care Med. 194, 1523–1531 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Mitsi, E. et al. Agglutination by anti-capsular polysaccharide antibody is associated with protection against experimental human pneumococcal carriage. Mucosal Immunol. 10, 385–394 (2017). This study shows that the agglutinating activity of anticapsular antibody mediates protection from experimental pneumococcal carriage in humans.

    Article  CAS  PubMed  Google Scholar 

  29. Lemon, J. K. & Weiser, J. N. Degradation products of the extracellular pathogen Streptococcus pneumoniae access the cytosol via its pore-forming toxin. mBio 6, e02110–e02114 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Davis, K., Nakamura, S. & Weiser, J. Nod2 sensing of lysozyme-digested peptidoglycan promotes macrophage recruitment and clearance of S. pneumoniae colonization in mice. J. Clin. Invest. 121, 3666–3676 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Karmakar, M. et al. Neutrophil IL-1beta processing induced by pneumolysin is mediated by the NLRP3/ASC inflammasome and caspase-1 activation and is dependent on K+ efflux. J. Immunol. 194, 1763–1775 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Parker, D. et al. Streptococcus pneumoniae DNA initiates type I interferon signaling in the respiratory tract. mBio 2, e00016–11 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Davis, K., Akinbi, H., Standish, A. & Weiser, J. Resistance to mucosal lysozyme compensates for the fitness deficit of peptidoglycan modifications by Streptococcus pneumoniae. PLoS Pathog. 4, e1000241 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Rose, M. C. & Voynow, J. A. Respiratory tract mucin genes and mucin glycoproteins in health and disease. Physiol. Rev. 86, 245–278 (2006).

    Article  CAS  PubMed  Google Scholar 

  35. Feldman, C. et al. The interaction of Streptococcus pneumoniae with intact human respiratory mucosa in vitro. Eur. Respir. J. 5, 576–583 (1992).

    CAS  PubMed  Google Scholar 

  36. Nelson, A. L. et al. Capsule enhances pneumococcal colonization by limiting mucus-mediated clearance. Infect. Immun. 75, 83–90 (2007).

    Article  CAS  PubMed  Google Scholar 

  37. Holmes, A. R. et al. The pavA gene of Streptococcus pneumoniae encodes a fibronectin-binding protein that is essential for virulence. Mol. Microbiol. 41, 1395–1408 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Bergmann, S., Rohde, M., Chhatwal, G. S. & Hammerschmidt, S. α-Enolase of Streptococcus pneumoniae is a plasmin(ogen)-binding protein displayed on the bacterial cell surface. Mol. Microbiol. 40, 1273–1287 (2001).

    Article  CAS  PubMed  Google Scholar 

  39. Jensch, I. et al. PavB is a surface-exposed adhesin of Streptococcus pneumoniae contributing to nasopharyngeal colonization and airways infections. Mol. Microbiol. 77, 22–43 (2010).

    Article  CAS  PubMed  Google Scholar 

  40. Cundell, D. R., Gerard, N. P., Gerard, C., Idanpaan-Heikkila, I. & Tuomanen, E. I. Streptococcus pneumoniae anchor to activated human cells by the receptor for platelet-activating factor. Nature 377, 435–438 (1995).

    Article  CAS  PubMed  Google Scholar 

  41. Zhang, J. R. et al. The polymeric immunoglobulin receptor translocates pneumococci across human nasopharyngeal epithelial cells. Cell 102, 827–837 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. Hauck, C. R. Cell adhesion receptors - signaling capacity and exploitation by bacterial pathogens. Med. Microbiol. Immunol. 191, 55–62 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Kc, R., Shukla, S. D., Walters, E. H. & O’Toole, R. F. Temporal upregulation of host surface receptors provides a window of opportunity for bacterial adhesion and disease. Microbiology 163, 421–430 (2017).

    Article  CAS  PubMed  Google Scholar 

  44. Cron, L. E. et al. Surface-associated lipoprotein PpmA of Streptococcus pneumoniae is involved in colonization in a strain-specific manner. Microbiology 155, 2401–2410 (2009).

    Article  CAS  PubMed  Google Scholar 

  45. Hermans, P. W. et al. The streptococcal lipoprotein rotamase A (SlrA) is a functional peptidyl-prolyl isomerase involved in pneumococcal colonization. J. Biol. Chem. 281, 968–976 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Gutierrez-Fernandez, J. et al. Modular architecture and unique teichoic acid recognition features of choline-binding protein L (CbpL) contributing to pneumococcal pathogenesis. Sci. Rep. 6, 38094 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. King, S. J. Pneumococcal modification of host sugars: a major contributor to colonization of the human airway? Mol. Oral Microbiol. 25, 15–24 (2010).

    Article  CAS  PubMed  Google Scholar 

  48. Uchiyama, S. et al. The surface-anchored NanA protein promotes pneumococcal brain endothelial cell invasion. J. Exp. Med. 206, 1845–1852 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Limoli, D. H., Sladek, J. A., Fuller, L. A., Singh, A. K. & King, S. J. BgaA acts as an adhesin to mediate attachment of some pneumococcal strains to human epithelial cells. Microbiology 157, 2369–2381 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Andersson, B. et al. Identification of an active dissaccharide unit of a glycoconjugate receptor for pneumococci attaching to human pharyngeal epithelial cells. J. Exp. Med. 158, 559–570 (1983).

    Article  CAS  PubMed  Google Scholar 

  51. Krivan, H. C., Roberts, D. D. & Ginsberg, V. Many pulmonary pathogenic bacteria bind specifically to the carbohydrate sequence GalNAcb1-4 Gal found in some glycolipids. Proc. Natl. Acad. Sci. USA 85, 6157–6161 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Shak, J. R., Vidal, J. E. & Klugman, K. P. Influence of bacterial interactions on pneumococcal colonization of the nasopharynx. Trends. Microbiol. 21, 129–135 (2013).

    Article  CAS  PubMed  Google Scholar 

  53. Lysenko, E. S. et al. Nod1-signaling overcomes resistance of Streptococcus pneumoniae to opsonophagocytic killing. PLoS Pathog. 3, 1073–1081 (2007). This study elucidates how H. influenzae signalling via NOD1 enhances neutrophil killing of S. pneumoniae, leading to bacterial clearance.

  54. Cremers, A. J. et al. The adult nasopharyngeal microbiome as a determinant of pneumococcal acquisition. Microbiome 2, 44 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Biesbroek, G. et al. Early respiratory microbiota composition determines bacterial succession patterns and respiratory health in children. Am. J. Respir. Crit. Care Med. 190, 1283–1292 (2014).

    Article  PubMed  Google Scholar 

  56. Miller, E. L., Abrudan, M. I., Roberts, I. S. & Rozen, D. E. Diverse ecological strategies are encoded by Streptococcus pneumoniae bacteriocin-like peptides. Genome Biol. Evol. 8, 1072–1090 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Dawid, S., Roche, A. & Weiser, J. The blp bacteriocins of Streptococcus pneumoniae mediate intraspecies competition both in vitro and in vivo. Infect. Immun. 75, 443–451 (2007).

    Article  CAS  PubMed  Google Scholar 

  58. Bogaardt, C., van Tonder, A. J. & Brueggemann, A. B. Genomic analyses of pneumococci reveal a wide diversity of bacteriocins — including pneumocyclicin, a novel circular bacteriocin. BMC Genom. 16, 554 (2015).

    Article  CAS  Google Scholar 

  59. Nakamura, S., Davis, K. & Weiser, J. Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice. J. Clin. Invest. 121, 3657–3665 (2011). This study demonstrates a mechanism by which concurrent influenza virus infection leads to increased pneumococcal carriage.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. McCullers, J. A. & Rehg, J. E. Lethal synergism between influenza virus and Streptococcus pneumoniae: characterization of a mouse model and the role of platelet-activating factor receptor. J. Infect. Dis. 186, 341–350 (2002).

    Article  CAS  PubMed  Google Scholar 

  61. Avadhanula, V. et al. Respiratory viruses augment the adhesion of bacterial pathogens to respiratory epithelium in a viral species- and cell type-dependent manner. J. Virol. 80, 1629–1636 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Mina, M. J., McCullers, J. A. & Klugman, K. P. Live attenuated influenza vaccine enhances colonization of Streptococcus pneumoniae and Staphylococcus aureus in mice. mBio 5, e01040–13 (2014).

    PubMed  PubMed Central  Google Scholar 

  63. Mina, M. J. Generalized herd effects and vaccine evaluation: impact of live influenza vaccine on off-target bacterial colonisation. J. Infect. 74, (Suppl. 1), S101–s107 (2017).

    Article  PubMed  Google Scholar 

  64. Thors, V. et al. The effects of live attenuated influenza vaccine on nasopharyngeal bacteria in healthy 2 to 4 year olds. A randomized controlled trial. Am. J. Respir. Crit. Care Med. 193, 1401–1409 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. McCullers, J. The co-pathogenesis of influenza viruses with bacteria in the lung. Nat. Rev. Microbiol. 12, 252–262 (2014). Provides a good overview of how influenza virus co-infection leads to bacterial superinfection in the lungs.

    Article  CAS  PubMed  Google Scholar 

  66. Lees, J. A. et al. Genome-wide identification of lineage and locus specific variation associated with pneumococcal carriage duration. eLife 6, e26255 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Kadioglu, A., Weiser, J., Paton, J. & Andrew, P. The role of Streptococcus pneumoniae virulence factors in host respiratory colonization and disease. Nat. Rev. Microbiol. 6, 288–301 (2008).

    Article  CAS  PubMed  Google Scholar 

  68. Jochems, S. P. et al. Novel analysis of immune cells from nasal microbiopsy demonstrates reliable, reproducible data for immune populations, and superior cytokine detection compared to nasal wash. PLoS ONE 12, e0169805 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Zhang, Z., Clarke, T. & Weiser, J. Cellular effectors mediating Th17-dependent clearance of pneumococcal colonization in mice. J. Clin. Invest. 119, 1899–1909 (2009). This study shows that IL-17A by CD4 + T cells is required for the recruitment of monocytes and macrophages and effective pneumococcal clearance in unimmunized mice.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Siegel, S., Tamashiro & Weiser, J. Clearance of pneumococcal colonization in infants is delayed through altered macrophage trafficking. PLoS Pathog. 11, e1005004 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Puchta, A. et al. TNF drives monocyte dysfunction with age and results in impaired anti-pneumococcal immunity. PLoS. Pathog 12, e1005368 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Malley, R. et al. Antibody-independent, interleukin-17A-mediated, cross-serotype immunity to pneumococci in mice immunized intranasally with the cell wall polysaccharide. Infect. Immun. 74, 2187–2195 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. van Rossum, A., Lysenko, E. & Weiser, J. Host and bacterial factors contributing to the clearance of colonization by Streptococcus pneumoniae in a murine model. Infect. Immun. 73, 7718–7726 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. McCool, T. L., Cate, T. R., Moy, G. & Weiser, J. N. The immune response to pneumococcal proteins during experimental human carriage. J. Exp. Med. 195, 359–365 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Ferreira, D. M. et al. Controlled human infection and rechallenge with Streptococcus pneumoniae reveals the protective efficacy of carriage in healthy adults. Am. J. Respir. Crit. Care. Med. 187, 855–864 (2013). This study uses a human infection model to demonstrate that immunity induced by a previous colonization episode protects against reacquisition.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Holmlund, E. et al. Antibodies to pneumococcal proteins PhtD, CbpA, and LytC in Filipino pregnant women and their infants in relation to pneumococcal carriage. Clin. Vaccine Immunol. 16, 916–923 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Jackson, L. A. et al. Effectiveness of pneumococcal polysaccharide vaccine in older adults. N. Engl. J. Med. 348, 1747–1755 (2003).

    Article  CAS  PubMed  Google Scholar 

  78. Richards, L., Ferreira, D. M., Miyaji, E. N., Andrew, P. W. & Kadioglu, A. The immunising effect of pneumococcal nasopharyngeal colonisation; protection against future colonisation and fatal invasive disease. Immunobiology 215, 251–263 (2010).

    Article  CAS  PubMed  Google Scholar 

  79. Cohen, J. M., Wilson, R., Shah, P., Baxendale, H. E. & Brown, J. S. Lack of cross-protection against invasive pneumonia caused by heterologous strains following murine Streptococcus pneumoniae nasopharyngeal colonisation despite whole cell ELISAs showing significant cross-reactive IgG. Vaccine 31, 2328–2332 (2013).

    Article  CAS  PubMed  Google Scholar 

  80. Wright, A. K. et al. Experimental human pneumococcal carriage augments IL-17A-dependent T-cell defence of the lung. PLoS Pathog. 9, e1003274 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Wright, A. K. et al. Human nasal challenge with Streptococcus pneumoniae is immunising in the absence of carriage. PLoS. Pathog. 8, e1002622 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Malley, R. et al. CD4+ T cells mediate antibody-independent acquired immunity to pneumococcal colonization. Proc. Natl Acad. Sci. USA. 102, 4848–4853 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Trzcinski, K. et al. Protection against nasopharyngeal colonization by Streptococcus pneumoniae is mediated by antigen-specific CD4+ T cells. Infect. Immun. 76, 2678–2684 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Mubarak, A. et al. A dynamic relationship between mucosal T helper type 17 and regulatory T-cell populations in nasopharynx evolves with age and associates with the clearance of pneumococcal carriage in humans. Clin. Microbiol. Infect. 22, 736.e1–736.e7 (2016).

    Article  CAS  Google Scholar 

  85. Polissi, A. et al. Large-scale identification of virulence genes from Streptococcus pneumoniae. Infect. Immun. 66, 5620–5629 (1998).

    CAS  PubMed  Google Scholar 

  86. Lau, G. W. et al. A functional genomic analysis of type 3 Streptococcus pneumoniae virulence. Mol. Microbiol. 40, 555–571 (2001).

    Article  CAS  PubMed  Google Scholar 

  87. Hava, D. L. & Camilli, A. Large-scale identification of serotype 4 Streptococcus pneumoniae virulence factors. Mol. Microbiol. 45, 1389–1406 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Orihuela, C. J. et al. Microarray analysis of pneumococcal gene expression during invasive disease. Infect. Immun. 72, 5582–5596 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Ogunniyi, A. D. et al. Identification of genes that contribute to the pathogenesis of invasive pneumococcal disease by in vitro transcriptomic analysis. Infect. Immun. 80, 3268–3278 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Honsa, E. S., Johnson, M. D. & Rosch, J. W. The roles of transition metals in the physiology and pathogenesis of Streptococcus pneumoniae. Front. Cell. Infect. Microbiol. 3, 92 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Brown, J. S., Gilliland, S. M. & Holden, D. W. A. Streptococcus pneumoniae pathogenicity island encoding an ABC transporter involved in iron uptake and virulence. Mol. Microbiol. 40, 572–585 (2001).

    Article  CAS  PubMed  Google Scholar 

  92. McAllister, L. J. et al. Molecular analysis of the psa permease complex of Streptococcus pneumoniae. Mol. Microbiol. 53, 889–901 (2004).

    Article  CAS  PubMed  Google Scholar 

  93. Plumptre, C. D. et al. AdcA and AdcAII employ distinct zinc acquisition mechanisms and contribute additively to zinc homeostasis in. Streptococcus pneumoniae. Mol. Microbiol. 91, 834–851 (2014).

    Article  CAS  PubMed  Google Scholar 

  94. Bajaj, M. et al. Discovery of novel pneumococcal surface antigen A (PsaA) inhibitors using a fragment-based drug design approach. ACS Chem. Biol. 10, 1511–1520 (2015).

    Article  CAS  PubMed  Google Scholar 

  95. McDevitt, C. A. et al. A molecular mechanism for bacterial susceptibility to zinc. PLoS Pathog. 7, e1002357 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Counago, R. M. et al. Imperfect coordination chemistry facilitates metal ion release in the Psa permease. Nat. Chem. Biol. 10, 35–41 (2014).

    Article  CAS  PubMed  Google Scholar 

  97. Kumar, S., Awasthi, S., Jain, A. & Srivastava, R. C. Blood zinc levels in children hospitalized with severe pneumonia: a case control study. Indian Pediatr. 41, 486–491 (2004).

    PubMed  Google Scholar 

  98. Coles, C. L. et al. Zinc modifies the association between nasopharyngeal Streptococcus pneumoniae carriage and risk of acute lower respiratory infection among young children in rural Nepal. J. Nutr. 138, 2462–2467 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Hakansson, A. et al. Characterization of binding of human lactoferrin to pneumococcal surface protein A. Infect. Immun. 69, 3372–3381 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Mirza, S. et al. The effects of differences in pspA alleles and capsular types on the resistance of Streptococcus pneumoniae to killing by apolactoferrin. Microb. Pathog. 99, 209–219 (2016).

    Article  CAS  PubMed  Google Scholar 

  101. Bidossi, A. et al. A functional genomics approach to establish the complement of carbohydrate transporters in Streptococcus pneumoniae. PLoS ONE 7, e33320 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Buckwalter, C. M. & King, S. J. Pneumococcal carbohydrate transport: food for thought. Trends Microbiol. 20, 517–522 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. King, S. J., Hippe, K. R. & Weiser, J. N. Deglycosylation of human glycoconjugates by the sequential activities of exoglycosidases expressed by Streptococcus pneumoniae. Mol. Microbiol. 59, 961–974 (2006).

    Article  CAS  PubMed  Google Scholar 

  104. Robb, M. et al. Molecular characterization of N-glycan degradation and transport in Streptococcus pneumoniae and its contribution to virulence. PLoS Pathog. 13, e1006090 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Trappetti, C. et al. Autoinducer 2 signaling via the phosphotransferase frua drives galactose utilization by Streptococcus pneumoniae, resulting in hypervirulence. mBio 8, e02269–16 (2017). This study was the first to identify an AI-2 receptor in Gram-positive bacteria and describe a mechanism whereby quorum sensing of AI-2 promotes invasive disease.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Hatcher, B. L., Hale, J. Y. & Briles, D. E. Free sialic acid acts as a signal that promotes Streptococcus pneumoniae invasion of nasal tissue and nonhematogenous invasion of the central nervous system. Infect. Immun. 84, 2607–2615 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Hentrich, K. et al. Streptococcus pneumoniae senses a human-like sialic acid profile via the response regulator ciaR. Cell Host Microbe 20, 307–317 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Gratz, N. et al. Pneumococcal neuraminidase activates TGF-beta signalling. Microbiology 163, 1198–1207 (2017).

    Article  CAS  PubMed Central  Google Scholar 

  109. Hall-Stoodley, L. et al. Direct detection of bacterial biofilms on the middle-ear mucosa of children with chronic otitis media. JAMA 296, 202–211 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Weimer, K. E. et al. Coinfection with Haemophilus influenzae promotes pneumococcal biofilm formation during experimental otitis media and impedes the progression of pneumococcal disease. J. Infect. Dis. 202, 1068–1075 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Trappetti, C., Ogunniyi, A. D., Oggioni, M. R. & Paton, J. C. Extracellular matrix formation enhances the ability of Streptococcus pneumoniae to cause invasive disease. PLoS ONE 6, e19844 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Blanchette, K. A. et al. Neuraminidase A-exposed galactose promotes Streptococcus pneumoniae biofilm formation during colonization. Infect. Immun. 84, 2922–2932 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Sanchez, C. J. et al. The pneumococcal serine-rich repeat protein is an intra-species bacterial adhesin that promotes bacterial aggregation in vivo and in biofilms. PLoS. Pathog 6, e1001044 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Rose, L. et al. Antibodies against PsrP, a novel Streptococcus pneumoniae adhesin, block adhesion and protect mice against pneumococcal challenge. J. Infect. Dis. 198, 375–383 (2008).

    Article  CAS  PubMed  Google Scholar 

  115. Kim, J. O. & Weiser, J. N. Association of intrastrain phase variation in quantity of capsular polysaccharide and teichoic acid with the virulence of Streptococcus pneumoniae. J. Infect. Dis. 177, 368–377 (1998).

    Article  CAS  PubMed  Google Scholar 

  116. Manso, A. S. et al. A random six-phase switch regulates pneumococcal virulence via global epigenetic changes. Nat. Commun. 5, 5055 (2014). This study elucidates the mechanism underlying the phenomenon of colony opacity phase variation in S. pneumoniae.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Trappetti, C., Potter, A. J., Paton, A. W., Oggioni, M. R. & Paton, J. C. LuxS mediates iron-dependent biofilm formation, competence, and fratricide in Streptococcus pneumoniae. Infect. Immun. 79, 4550–4558 (2011).

    Article  CAS  PubMed  Google Scholar 

  118. Orihuela, C. J. et al. Laminin receptor initiates bacterial contact with the blood brain barrier in experimental meningitis models. J. Clin. Invest. 119, 1638–1646 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Brown, A. O. et al. Streptococcus pneumoniae translocates into the myocardium and forms unique microlesions that disrupt cardiac function. PLoS Pathog. 10, e1004383 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Iovino, F. et al. pIgR and PECAM-1 bind to pneumococcal adhesins RrgA and PspC mediating bacterial brain invasion. J. Exp. Med. 214, 1619–1630 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. van Ginkel, F. W. et al. Pneumococcal carriage results in ganglioside-mediated olfactory tissue infection. Proc. Natl. Acad. Sci. USA 100, 14363–14367 (2003).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. Talbot, U. M., Paton, A. W. & Paton, J. C. Uptake of Streptococcus pneumoniae by respiratory epithelial cells. Infect. Immun. 64, 3772–3777 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Hammerschmidt, S. et al. Illustration of pneumococcal polysaccharide capsule during adherence and invasion of epithelial cells. Infect. Immun. 73, 4653–4667 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Kietzman, C. C., Gao, G., Mann, B., Myers, L. & Tuomanen, E. I. Dynamic capsule restructuring by the main pneumococcal autolysin LytA in response to the epithelium. Nat. Commun. 7, 10859 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Mitchell, T. J. & Dalziel, C. E. The biology of pneumolysin. Subcell. Biochem. 80, 145–160 (2014).

    Article  CAS  PubMed  Google Scholar 

  126. Rayner, C. F. et al. Interaction of pneumolysin-sufficient and -deficient isogenic variants of Streptococcus pneumoniae with human respiratory mucosa. Infect. Immun. 63, 442–447 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Mahdi, L. K., Wang, H., Van der Hoek, M. B., Paton, J. C. & Ogunniyi, A. D. Identification of a novel pneumococcal vaccine antigen preferentially expressed during meningitis in mice. J. Clin. Invest. 122, 2208–2220 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Berry, A. M. & Paton, J. C. Additive attenuation of virulence of Streptococcus pneumoniae by mutation of the genes encoding pneumolysin and other putative pneumococcal virulence proteins. Infect. Immun. 68, 133–140 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Chiavolini, D. et al. The three extra-cellular zinc metalloproteinases of Streptococcus pneumoniae have a different impact on virulence in mice. BMC Microbiol. 3, 14 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Attali, C., Durmort, C., Vernet, T. & Di Guilmi, A. M. The interaction of Streptococcus pneumoniae with plasmin mediates transmigration across endothelial and epithelial monolayers by intercellular junction cleavage. Infect. Immun. 76, 5350–5356 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Bergmann, S., Rohde, M., Preissner, K. T. & Hammerschmidt, S. The nine residue plasminogen-binding motif of the pneumococcal enolase is the major cofactor of plasmin-mediated degradation of extracellular matrix, dissolution of fibrin and transmigration. Thromb. Haemostasis 94, 304–311 (2005).

    CAS  Google Scholar 

  132. Standish, A. & Weiser, J. Human neutrophils kill Streptococcus pneumoniae via serine proteases. J. Immunol. 183, 2602–2609 (2009).

    Article  CAS  PubMed  Google Scholar 

  133. Hergott, C. B. et al. Bacterial exploitation of phosphorylcholine mimicry suppresses inflammation to promote airway infection. J. Clin. Invest. 125, 3878–3890 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Andre, G. O. et al. Role of Streptococcus pneumoniae proteins in evasion of complement-mediated immunity. Front. Microbiol. 8, 224 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  135. Hyams, C., Camberlein, E., Cohen, J. M., Bax, K. & Brown, J. S. The Streptococcus pneumoniae capsule inhibits complement activity and neutrophil phagocytosis by multiple mechanisms. Infect. Immun. 78, 704–715 (2010).

    Article  CAS  PubMed  Google Scholar 

  136. Hyams, C. et al. Streptococcus pneumoniae capsular serotype invasiveness correlates with the degree of factor H binding and opsonization with C3b/iC3b. Infect. Immun. 81, 354–363 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Hammerschmidt, S., Talay, S. R., Brandtzaeg, P. & Chhatwal, G. S. SpsA, a novel pneumococcal surface protein with specific binding to secretory immunoglobulin A and secretory component. Mol. Microbiol. 25, 1113–1124 (1997).

    Article  CAS  PubMed  Google Scholar 

  138. Dieudonne-Vatran, A. et al. Clinical isolates of Streptococcus pneumoniae bind the complement inhibitor C4b-binding protein in a PspC allele-dependent fashion. J. Immunol. 182, 7865–7877 (2009).

    Article  CAS  PubMed  Google Scholar 

  139. Kohler, S. et al. Binding of vitronectin and Factor H to Hic contributes to immune evasion of Streptococcus pneumoniae serotype 3. Thromb. Haemostasis 113, 125–142 (2015).

    Article  Google Scholar 

  140. Tu, A. H., Fulgham, R. L., McCrory, M. A., Briles, D. E. & Szalai, A. J. Pneumococcal surface protein A inhibits complement activation by Streptococcus pneumoniae. Infect. Immun. 67, 4720–4724 (1999).

    CAS  PubMed  Google Scholar 

  141. Paton, J. C., Rowan-Kelly, B. & Ferrante, A. Activation of human complement by the pneumococcal toxin pneumolysin. Infect. Immun. 43, 1085–1087 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Yuste, J., Botto, M., Paton, J. C., Holden, D. W. & Brown, J. S. Additive inhibition of complement deposition by pneumolysin and PspA facilitates Streptococcus pneumoniae septicemia. J. Immunol. 175, 1813–1819 (2005).

    Article  CAS  PubMed  Google Scholar 

  143. Dalia, A., Standish, A. & Weiser, J. Three surface exoglycosidases from Streptococcus pneumoniae, NanA, BgaA, and StrH, promote resistance to opsonophagocytic killing by human neutrophils. Infect. Immun. 78, 2108–2116 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Dalia, A. & Weiser, J. Minimization of bacterial size allows for complement evasion and is overcome by the agglutinating effect of antibody. Cell Host Microbe 10, 486–496 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. O’Brien, K. L. et al. Effect of pneumococcal conjugate vaccine on nasopharyngeal colonization among immunized and unimmunized children in a community-randomized trial. J. Infect. Dis. 196, 1211–1220 (2007).

    Article  PubMed  CAS  Google Scholar 

  146. Geno, K. A. et al. Pneumococcal capsules and their types: past, present, and future. Clin. Microbiol. Rev. 28, 871–899 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Klugman, K. The significance of serotype replacement for pneumococcal disease and antibiotic resistance. Adv. Exp. Med. Biol. 634, 121–128 (2009).

    Article  PubMed  Google Scholar 

  148. von Gottberg, A. et al. Effects of vaccination on invasive pneumococcal disease in South Africa. N. Engl. J. Med. 371, 1889–1899 (2014).

    Article  CAS  Google Scholar 

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Acknowledgements

The authors thank J. Pagano for editorial assistance. J.N.W. is funded by grants from the United States Public Health Service (AI038446 and AI105168). Research in J.C.P.’s laboratory is supported by program grant 1071659 from the National Health and Medical Research Council of Australia (NHMRC); J.C.P. is an NHMRC Senior Principal Research Fellow. D.M.F. is supported by the Medical Research Council (grant MR/M011569/1) and the Bill and Melinda Gates Foundation (grant OPP1117728).

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Nature Reviews Microbiology thanks Sven Hammerschmidt and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Glossary

Upper respiratory tract

(URT). Includes the nasal cavity, paranasal sinuses, mouth, pharynx and larynx and forms the major passages above the trachea.

Community-acquired pneumonia

Infection of the lung acquired outside of hospitals or nursing facilities.

Natural competence

The endogenous ability of a bacterium to alter its genes by taking up extracellular DNA from its environment through transformation.

PolyIC

Polyinosinic:polycytidylic acid is an agonist of Toll-like receptor 3 and mimics double-stranded RNA found in some viruses.

Dexamethasone

An anti-inflammatory corticosteroid.

Fc fragment

The tail region of an antibody that interacts with cell surface receptors and some proteins of the complement system.

Agglutinating function

The clumping of antigens through multivalent binding by antibodies.

Mucociliary flow

A non-immunological defence mechanism that involves ciliary action and the flow of mucus; it clears the respiratory tract of pathogens and particles.

Lectin domains

The carbohydrate-binding domains on proteins.

Bacteriocins

The proteinaceous or peptidic toxins produced by bacteria to inhibit the growth of similar or closely related bacteria.

Type 1 interferons

A group of signalling proteins expressed and released by host cells to regulate immune responses to pathogens.

Signature-tagged mutagenesis

A genetic technique using DNA signature tags (molecular barcodes) to identify mutants in mixed populations.

Two-component response regulator

The transcription factor component of a stimulus-response mechanism for bacteria to sense and respond to environmental changes.

Quorum sensing

(QS). A system of stimuli and responses that is correlated to microbial population density.

Restriction-modification system

A bacterial defence system in which restriction endonucleases cleave and inactivate specific target sequences in foreign DNA (for example, from phages); cleavage sites in host DNA are protected by methylation.

Leloir pathway

The predominant route of cellular galactose metabolism.

Opsonophagocytosis

A process by which a microorganism is labelled (opsonized) by host immune factors to facilitate uptake by phagocytic cells.

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Weiser, J.N., Ferreira, D.M. & Paton, J.C. Streptococcus pneumoniae: transmission, colonization and invasion. Nat Rev Microbiol 16, 355–367 (2018). https://doi.org/10.1038/s41579-018-0001-8

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