Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Streptococcus pneumoniae epidemiology, pathogenesis and control

Abstract

Infections caused by Streptococcus pneumoniae (also known as pneumococci) pose a threat to human health. Pneumococcal infections are the most common cause of milder respiratory tract infections, such as otitis and sinusitis, and of more severe diseases, including pneumonia (with or without septicaemia) and meningitis. The introduction of pneumococcal conjugate vaccines in the childhood vaccination programme in many countries has led to a notable decrease of severe invasive pneumococcal disease in vaccinated children. However, infections caused by non-vaccine types have concurrently increased, causing invasive pneumococcal disease in unvaccinated populations (such as older adults), which has hampered the effect of these vaccines. Moreover, emerging antibiotic resistance is threatening effective therapy. Thus, new approaches are needed for the treatment and prevention of pneumococcal infections, and recent advances in the field may pave the way for new strategies. Recently, several important findings have been gained regarding pneumococcal epidemiology, genomics and the effect of the introduction of pneumococcal conjugate vaccines and of the COVID-19 pandemic. Moreover, elucidative pathogenesis studies have shown that the interactions between pneumococcal virulence factors and host receptors may be exploited for new therapies, and new vaccine candidates have been suggested. In this Review, we summarize some recent findings from clinical disease to basic pathogenesis studies that may be of importance for future control strategies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Disease course of pneumococcal infections.
Fig. 2: Pneumococcal virulence factors and their distribution on the bacterial surface.
Fig. 3: Respiratory immune responses to S. pneumoniae.
Fig. 4: Prevalence of serotypes in pneumococcal carriage in children in different regions.
Fig. 5: Potential new strategies against pneumococcal colonization and infection.

Similar content being viewed by others

References

  1. Kuta, K. S. et al. Global mortality associated with 33 bacterial pathogens in 2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet 400, 2221–2248 (2022).

    Google Scholar 

  2. Troeger, C. et al. Estimates of the global, regional, and national morbidity, mortality, and aetiologies of lower respiratory infections in 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Infect. Dis. 18, 1191–1210 (2018).

    Google Scholar 

  3. Ginders, M. et al. Characterization of Streptococcus pneumoniae isolates from Austrian companion animals and horses. Acta Vet. Scand. 59, 79 (2017).

    PubMed  PubMed Central  Google Scholar 

  4. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Lu, L. et al. Species-specific interaction of Streptococcus pneumoniae with human complement factor H. J. Immunol. 181, 7138–7146 (2008).

    CAS  PubMed  Google Scholar 

  6. Donati, C. et al. Structure and dynamics of the pan-genome of Streptococcus pneumoniae and closely related species. Genome Biol. 11, R107 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Ganaie, F. et al. A new pneumococcal capsule type, 10D, is the 100th serotype and has a large cps fragment from an oral streptococcus. mBio 11, e00937-20 (2020).

    PubMed  PubMed Central  Google Scholar 

  8. Pimenta, F. et al. New pneumococcal serotype 15D. J. Clin. Microbiol. 59, e00329–e00421 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Sandgren, A. et al. Virulence in mice of pneumococcal clonal types with known invasive disease potential in humans. J. Infect. Dis. 192, 791–800 (2005).

    PubMed  Google Scholar 

  10. Sjostrom, K. et al. Clonal and capsular types decide whether pneumococci will act as a primary or opportunistic pathogen. Clin. Infect. Dis. 42, 451–459 (2006).

    CAS  PubMed  Google Scholar 

  11. Brueggemann, A. B. et al. Temporal and geographic stability of the serogroup-specific invasive disease potential of Streptococcus pneumoniae in children. J. Infect. Dis. 190, 1203–1211 (2004).

    PubMed  Google Scholar 

  12. Sandgren, A. et al. Effect of clonal and serotype-specific properties on the invasive capacity of Streptococcus pneumoniae. J. Infect. Dis. 189, 785–796 (2004).

    CAS  PubMed  Google Scholar 

  13. Manenzhe, R. I. et al. Characterization of pneumococcal colonization dynamics and antimicrobial resistance using shotgun metagenomic sequencing in intensively sampled South African infants. Front. Public Health 8, 543898 (2020).

    PubMed  PubMed Central  Google Scholar 

  14. Tonkin-Hill, G. et al. Pneumococcal within-host diversity during colonization, transmission and treatment. Nat. Microbiol. 7, 1791–1804 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Abruzzo, A. R., Aggarwal, S. D., Sharp, M. E., Bee, G. C. W. & Weiser, J. N. Serotype-dependent effects on the dynamics of pneumococcal colonization and implications for transmission. mBio 13, e0015822 (2022).

    PubMed  Google Scholar 

  16. 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).

    PubMed  PubMed Central  Google Scholar 

  17. Usuf, E. et al. Persistent and emerging pneumococcal carriage serotypes in a rural gambian community after 10 years of pneumococcal conjugate vaccine pressure. Clin. Infect. Dis. 73, e3825–e3835 (2021).

    CAS  PubMed  Google Scholar 

  18. Harboe, Z. B. et al. Pneumococcal serotypes and mortality following invasive pneumococcal disease: a population-based cohort study. PLoS Med. 6, e1000081 (2009).

    PubMed  PubMed Central  Google Scholar 

  19. De Miguel, S. et al. Age-dependent serotype-associated case-fatality rate in invasive pneumococcal disease in the autonomous community of Madrid between 2007 and 2020. Microorganisms 9, 2286 (2021).

    PubMed  PubMed Central  Google Scholar 

  20. Benadji, A. et al. Relationship between serotypes, disease characteristics and 30-day mortality in adults with invasive pneumococcal disease. Infection 50, 223–233 (2022).

    PubMed  Google Scholar 

  21. Sjostrom, K. et al. Clonal success of piliated penicillin nonsusceptible pneumococci. Proc. Natl Acad. Sci. USA 104, 12907–12912 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Henriques-Normark, B., Blomberg, C., Dagerhamn, J., Battig, P. & Normark, S. The rise and fall of bacterial clones: Streptococcus pneumoniae. Nat. Rev. Microbiol. 6, 827–837 (2008).

    CAS  PubMed  Google Scholar 

  23. Barocchi, M. A. et al. A pneumococcal pilus influences virulence and host inflammatory responses. Proc. Natl Acad. Sci. USA 103, 2857–2862 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Orrskog, S. et al. Pilus adhesin RrgA interacts with complement receptor 3, thereby affecting macrophage function and systemic pneumococcal disease. mBio 4, e00535-12 (2012).

    PubMed  PubMed Central  Google Scholar 

  25. Croucher, N. J. et al. Dominant role of nucleotide substitution in the diversification of serotype 3 pneumococci over decades and during a single infection. PLoS Genet. 9, e1003868 (2013).

    PubMed  PubMed Central  Google Scholar 

  26. Kwun, M. J. et al. Post-vaccine epidemiology of serotype 3 pneumococci identifies transformation inhibition through prophage-driven alteration of a non-coding RNA. Genome Med. 14, 144 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Dagerhamn, J. et al. Determination of accessory gene patterns predicts the same relatedness among strains of Streptococcus pneumoniae as sequencing of housekeeping genes does and represents a novel approach in molecular epidemiology. J. Clin. Microbiol. 46, 863–868 (2008).

    CAS  PubMed  Google Scholar 

  28. Blomberg, C. et al. Pattern of accessory regions and invasive disease potential in Streptococcus pneumoniae. J. Infect. Dis. 199, 1032–1042 (2009).

    CAS  PubMed  Google Scholar 

  29. Azarian, T. et al. Global emergence and population dynamics of divergent serotype 3 CC180 pneumococci. PLoS Pathog. 14, e1007438 (2018).

    PubMed  PubMed Central  Google Scholar 

  30. Hollingshead, S. K., Becker, R. & Briles, D. E. Diversity of PspA: mosaic genes and evidence for past recombination in Streptococcus pneumoniae. Infect. Immun. 68, 5889–5900 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Duke, J. A. & Avci, F. Y. Emerging vaccine strategies against the incessant pneumococcal disease. NPJ Vaccines 8, 122 (2023).

    PubMed  PubMed Central  Google Scholar 

  32. Henriques-Normark, B. & Tuomanen, E. I. The pneumococcus: epidemiology, microbiology, and pathogenesis. Cold Spring Harb. Perspect. Med. 3, a010215 (2013).

    PubMed  PubMed Central  Google Scholar 

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

    PubMed  Google Scholar 

  34. Tvedskov, E. S. F., Hovmand, N., Benfield, T. & Tinggaard, M. Pneumococcal carriage among children in low and lower-middle-income countries: a systematic review. Int. J. Infect. Dis. 115, 1–7 (2022).

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  36. Chaguza, C. et al. Carriage dynamics of pneumococcal serotypes in naturally colonized infants in a rural african setting during the first year of life. Front. Pediatr. 8, 587730 (2020).

    PubMed  Google Scholar 

  37. Goldblatt, D. et al. Antibody responses to nasopharyngeal carriage of Streptococcus pneumoniae in adults: a longitudinal household study. J. Infect. Dis. 192, 387–393 (2005).

    CAS  PubMed  Google Scholar 

  38. Nannapaneni, P. et al. Metatranscriptomics of nasopharyngeal microbiota and host distinguish between pneumonia and health. Am. J. Respir. Crit. Care Med. 206, 1564–1567 (2022).

    PubMed  PubMed Central  Google Scholar 

  39. Chien, Y. W. et al. Density interactions among Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus in the nasopharynx of young Peruvian children. Pediatr. Infect. Dis. J. 32, 72–77 (2013).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  41. Claverys, J. P. & Havarstein, L. S. Cannibalism and fratricide: mechanisms and raisons d’etre. Nat. Rev. Microbiol. 5, 219–229 (2007).

    CAS  PubMed  Google Scholar 

  42. Aggarwal, S. D. et al. BlpC-mediated selfish program leads to rapid loss of Streptococcus pneumoniae clonal diversity during infection. Cell Host Microbe 31, 124–134.e5 (2023).

    CAS  PubMed  Google Scholar 

  43. Adler, H. et al. Experimental human pneumococcal colonisation in older adults is feasible and safe, not immunogenic. Am. J. Respir. Crit. Care Med. 203, 604–613 (2020).

    Google Scholar 

  44. Hill, H. et al. A randomised controlled trial of nasal immunisation with live virulence attenuated Streptococcus pneumoniae strains using human infection challenge. Am. J. Respir. Crit. Care Med. 208, 868–878 (2023).

    CAS  PubMed  Google Scholar 

  45. Naucler, P. et al. Chronic disease and immunosuppression increase the risk for nonvaccine serotype pneumococcal disease: a nationwide population-based study. Clin. Infect. Dis. 74, 1338–1349 (2022).

    CAS  PubMed  Google Scholar 

  46. Carter, R. et al. Genomic analyses of pneumococci from children with sickle cell disease expose host-specific bacterial adaptations and deficits in current interventions. Cell Host Microbe 15, 587–599 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Mina, M. J. & Klugman, K. P. The role of influenza in the severity and transmission of respiratory bacterial disease. Lancet Respir. Med. 2, 750–763 (2014).

    PubMed  PubMed Central  Google Scholar 

  48. Chien, Y. W., Klugman, K. P. & Morens, D. M. Bacterial pathogens and death during the 1918 influenza pandemic. N. Engl. J. Med. 361, 2582–2583 (2009).

    PubMed  Google Scholar 

  49. Morris, D. E., Cleary, D. W. & Clarke, S. C. Secondary bacterial infections associated with influenza pandemics. Front. Microbiol. 8, 1041 (2017).

    PubMed  PubMed Central  Google Scholar 

  50. Rowe, H. M. et al. Respiratory bacteria stabilize and promote airborne transmission of influenza a virus. mSystems 5, e00762-20 (2020).

    PubMed  PubMed Central  Google Scholar 

  51. Nakamura, S., Davis, K. M. & Weiser, J. N. Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice. J. Clin. Invest. 121, 3657–3665 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Sun, K. & Metzger, D. W. Inhibition of pulmonary antibacterial defense by interferon-γ during recovery from influenza infection. Nat. Med. 14, 558–564 (2008).

    CAS  PubMed  Google Scholar 

  53. McCullers, J. A. & Bartmess, K. C. Role of neuraminidase in lethal synergism between influenza virus and Streptococcus pneumoniae. J. Infect. Dis. 187, 1000–1009 (2003).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Kash, J. C. et al. Treatment with the reactive oxygen species scavenger EUK-207 reduces lung damage and increases survival during 1918 influenza virus infection in mice. Free Radic. Biol. Med. 67, 235–247 (2014).

    CAS  PubMed  Google Scholar 

  56. Sender, V., Hentrich, K. & Henriques-Normark, B. Virus-induced changes of the respiratory tract environment promote secondary infections with Streptococcus pneumoniae. Front. Cell Infect. Microbiol. 11, 643326 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Sender, V. et al. Capillary leakage provides nutrients and antioxidants for rapid pneumococcal proliferation in influenza-infected lower airways. Proc. Natl Acad. Sci. USA 117, 31386–31397 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Torres, A., Peetermans, W. E., Viegi, G. & Blasi, F. Risk factors for community-acquired pneumonia in adults in Europe: a literature review. Thorax 68, 1057–1065 (2013).

    PubMed  Google Scholar 

  59. Yother, J. Capsules of Streptococcus pneumoniae and other bacteria: paradigms for polysaccharide biosynthesis and regulation. Annu. Rev. Microbiol. 65, 563–581 (2011).

    CAS  PubMed  Google Scholar 

  60. Nakamoto, R. et al. The divisome but not the elongasome organizes capsule synthesis in Streptococcus pneumoniae. Nat. Commun. 14, 3170 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Pathak, A. et al. Factor H binding proteins protect division septa on encapsulated Streptococcus pneumoniae against complement C3b deposition and amplification. Nat. Commun. 9, 3398 (2018).

    PubMed  PubMed Central  Google Scholar 

  62. Cartee, R. T., Forsee, W. T. & Yother, J. Initiation and synthesis of the Streptococcus pneumoniae type 3 capsule on a phosphatidylglycerol membrane anchor. J. Bacteriol. 187, 4470–4479 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Luck, J. N., Tettelin, H. & Orihuela, C. J. Sugar-coated killer: serotype 3 pneumococcal disease. Front. Cell Infect. Microbiol. 10, 613287 (2020).

    PubMed  PubMed Central  Google Scholar 

  64. Weiser, J. N. & Kapoor, M. Effect of intrastrain variation in the amount of capsular polysaccharide on genetic transformation of Streptococcus pneumoniae: implications for virulence studies of encapsulated strains. Infect. Immun. 67, 3690–3692 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Weiser, J. N., Austrian, R., Sreenivasan, P. K. & Masure, H. R. Phase variation in pneumococcal opacity: relationship between colonial morphology and nasopharyngeal colonization. Infect. Immun. 62, 2582–2589 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Kwun, M. J., Ion, A. V., Oggioni, M. R., Bentley, S. D. & Croucher, N. J. Diverse regulatory pathways modulate bet hedging of competence induction in epigenetically-differentiated phase variants of Streptococcus pneumoniae. Nucleic Acids Res. 51, 10375–10394 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Manso, A. S. et al. A random six-phase switch regulates pneumococcal virulence via global epigenetic changes. Nat. Commun. 5, 5055 (2014).

    CAS  PubMed  Google Scholar 

  68. 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).

    CAS  PubMed  Google Scholar 

  69. Iuchi, H., Ohori, J., Kyutoku, T., Ito, K. & Kurono, Y. Role of phosphorylcholine in Streptococcus pneumoniae and nontypeable Haemophilus influenzae adherence to epithelial cells. Auris Nasus Larynx 46, 513–519 (2019).

    PubMed  Google Scholar 

  70. Lane, J. R., Tata, M., Briles, D. E. & Orihuela, C. J. A jack of all trades: the role of pneumococcal surface protein a in the pathogenesis of Streptococcus pneumoniae. Front. Cell Infect. Microbiol. 12, 826264 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Park, S. S. et al. Streptococcus pneumoniae binds to host lactate dehydrogenase via PspA and PspC to enhance virulence. mBio 12, e00673-21 (2021).

    PubMed  PubMed Central  Google Scholar 

  72. Eldholm, V., Johnsborg, O., Haugen, K., Ohnstad, H. S. & Havarstein, L. S. Fratricide in Streptococcus pneumoniae: contributions and role of the cell wall hydrolases CbpD, LytA and LytC. Microbiology 155, 2223–2234 (2009).

    CAS  PubMed  Google Scholar 

  73. Wei, H. & Havarstein, L. S. Fratricide is essential for efficient gene transfer between pneumococci in biofilms. Appl. Env. Microbiol. 78, 5897–5905 (2012).

    CAS  Google Scholar 

  74. Minhas, V. et al. Competence remodels the pneumococcal cell wall exposing key surface virulence factors that mediate increased host adherence. PLoS Biol. 21, e3001990 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Peterson, S. N. et al. Identification of competence pheromone responsive genes in Streptococcus pneumoniae by use of DNA microarrays. Mol. Microbiol. 51, 1051–1070 (2004).

    CAS  PubMed  Google Scholar 

  76. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Vilhena, C. et al. The choline-binding proteins PspA, PspC, and LytA of Streptococcus pneumoniae and their interaction with human endothelial and red blood cells. Infect. Immun. 91, e0015423 (2023).

    PubMed  Google Scholar 

  78. Kharat, A. S. & Tomasz, A. Inactivation of the srtA gene affects localization of surface proteins and decreases adhesion of Streptococcus pneumoniae to human pharyngeal cells in vitro. Infect. Immun. 71, 2758–2765 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Syed, S. et al. Role of pneumococcal NanA neuraminidase activity in peripheral blood. Front. Cell Infect. Microbiol. 9, 218 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Falker, S. et al. Sortase-mediated assembly and surface topology of adhesive pneumococcal pili. Mol. Microbiol. 70, 595–607 (2008).

    PubMed  PubMed Central  Google Scholar 

  81. Nelson, A. L. et al. RrgA is a pilus-associated adhesin in Streptococcus pneumoniae. Mol. Microbiol. 66, 329–340 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Kohler, S., Voss, F., Gomez Mejia, A., Brown, J. S. & Hammerschmidt, S. Pneumococcal lipoproteins involved in bacterial fitness, virulence, and immune evasion. FEBS Lett. 590, 3820–3839 (2016).

    CAS  PubMed  Google Scholar 

  83. Narciso, A. R. et al. Membrane particles evoke a serotype-independent cross-protection against pneumococcal infection that is dependent on the conserved lipoproteins MalX and PrsA. Proc. Natl Acad. Sci. USA 119, e2122386119 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Shak, J. R. et al. Novel role for the Streptococcus pneumoniae toxin pneumolysin in the assembly of biofilms. mBio 4, e00655-13 (2013).

    PubMed  PubMed Central  Google Scholar 

  85. Codemo, M. et al. Immunomodulatory effects of pneumococcal extracellular vesicles on cellular and humoral host defenses. mBio 9, e00559-18 (2018).

    PubMed  PubMed Central  Google Scholar 

  86. Subramanian, K. et al. Pneumolysin binds to the mannose receptor C type 1 (MRC-1) leading to anti-inflammatory responses and enhanced pneumococcal survival. Nat. Microbiol. 4, 62–70 (2019).

    CAS  PubMed  Google Scholar 

  87. Pinho-Ribeiro, F. A. et al. Bacteria hijack a meningeal neuroimmune axis to facilitate brain invasion. Nature 615, 472–481 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Subramanian, K. et al. Mannose receptor-derived peptides neutralize pore-forming toxins and reduce inflammation and development of pneumococcal disease. EMBO Mol. Med. 12, e12695 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Badgujar, D. C. et al. Structural insights into loss of function of a pore forming toxin and its role in pneumococcal adaptation to an intracellular lifestyle. PLoS Pathog. 16, e1009016 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Henriques Normark, B. et al. Dynamics of penicillin-susceptible clones in invasive pneumococcal disease. J. Infect. Dis. 184, 861–869 (2001).

    CAS  PubMed  Google Scholar 

  92. Henriques, B. et al. Molecular epidemiology of Streptococcus pneumoniae causing invasive disease in 5 countries. J. Infect. Dis. 182, 833–839 (2000).

    CAS  PubMed  Google Scholar 

  93. Browall, S. et al. Intraclonal variations among Streptococcus pneumoniae isolates influence the likelihood of invasive disease in children. J. Infect. Dis. 209, 377–388 (2014).

    CAS  PubMed  Google Scholar 

  94. Browall, S. et al. Clinical manifestations of invasive pneumococcal disease by vaccine and non-vaccine types. Eur. Respir. J. 44, 1646–1657 (2014).

    PubMed  Google Scholar 

  95. Galanis, I. et al. Effects of PCV7 and PCV13 on invasive pneumococcal disease and carriage in Stockholm, Sweden. Eur. Respir. J. 47, 1208–1218 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Lindstrand, A. et al. Unaltered pneumococcal carriage prevalence due to expansion of non-vaccine types of low invasive potential 8 years after vaccine introduction in Stockholm, Sweden. Vaccine 34, 4565–4571 (2016).

    PubMed  Google Scholar 

  97. Panagiotou, S. et al. Hypervirulent pneumococcal serotype 1 harbours two pneumolysin variants with differential haemolytic activity. Sci. Rep. 10, 17313 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Chaguza, C., Yang, M., Jacques, L. C., Bentley, S. D. & Kadioglu, A. Serotype 1 pneumococcus: epidemiology, genomics, and disease mechanisms. Trends Microbiol. 30, 581–592 (2022).

    CAS  PubMed  Google Scholar 

  99. Jacques, L. C. et al. Increased pathogenicity of pneumococcal serotype 1 is driven by rapid autolysis and release of pneumolysin. Nat. Commun. 11, 1892 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Iovino, F., Seinen, J., Henriques-Normark, B. & van Dijl, J. M. How does Streptococcus pneumoniae invade the brain? Trends Microbiol. 24, 307–315 (2016).

    CAS  PubMed  Google Scholar 

  101. Iovino, F. et al. Pneumococcal meningitis is promoted by single cocci expressing pilus adhesin RrgA. J. Clin. Invest. 126, 2821–2826 (2016).

    PubMed  PubMed Central  Google Scholar 

  102. Doran, K. S. et al. Host–pathogen interactions in bacterial meningitis. Acta Neuropathol. 131, 185–209 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Jim, K. K. et al. Pneumolysin promotes host cell necroptosis and bacterial competence during pneumococcal meningitis as shown by whole-animal dual RNA-seq. Cell Rep. 41, 111851 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Block, N., Naucler, P., Wagner, P., Morfeldt, E. & Henriques-Normark, B. Bacterial meningitis: aetiology, risk factors, disease trends and severe sequelae during 50 years in Sweden. J. Intern. Med. 292, 350–364 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Jefferies, J. M. et al. Presence of nonhemolytic pneumolysin in serotypes of Streptococcus pneumoniae associated with disease outbreaks. J. Infect. Dis. 196, 936–944 (2007).

    CAS  PubMed  Google Scholar 

  106. Muller, A. et al. Meningitis-associated pneumococcal serotype 8, ST 53, strain is hypervirulent in a rat model and has non-haemolytic pneumolysin which can be attenuated by liposomes. Front. Cell Infect. Microbiol. 12, 1106063 (2022).

    CAS  PubMed  Google Scholar 

  107. Lock, R. A., Zhang, Q. Y., Berry, A. M. & Paton, J. C. Sequence variation in the Streptococcus pneumoniae pneumolysin gene affecting haemolytic activity and electrophoretic mobility of the toxin. Microb. Pathog. 21, 71–83 (1996).

    CAS  PubMed  Google Scholar 

  108. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Iovino, F., Thorsdottir, S. & Henriques-Normark, B. Receptor blockade: a novel approach to protect the brain from pneumococcal invasion. J. Infect. Dis. 218, 476–484 (2018).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  111. Tabusi, M. et al. Neuronal death in pneumococcal meningitis is triggered by pneumolysin and RrgA interactions with β-actin. PLoS Pathog. 17, e1009432 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Zhang, Z., Clarke, T. B. & Weiser, J. N. Cellular effectors mediating TH17-dependent clearance of pneumococcal colonization in mice. J. Clin. Invest. 119, 1899–1909 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Ritchie, N. D., Ijaz, U. Z. & Evans, T. J. IL-17 signalling restructures the nasal microbiome and drives dynamic changes following Streptococcus pneumoniae colonization. BMC Genomics 18, 807 (2017).

    PubMed  PubMed Central  Google Scholar 

  114. 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).

    CAS  PubMed  Google Scholar 

  115. Jochems, S. P. et al. Innate and adaptive nasal mucosal immune responses following experimental human pneumococcal colonization. J. Clin. Invest. 129, 4523–4538 (2019).

    PubMed  PubMed Central  Google Scholar 

  116. Aberdein, J. D., Cole, J., Bewley, M. A., Marriott, H. M. & Dockrell, D. H. Alveolar macrophages in pulmonary host defence the unrecognized role of apoptosis as a mechanism of intracellular bacterial killing. Clin. Exp. Immunol. 174, 193–202 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Sun, K., Gan, Y. & Metzger, D. W. Analysis of murine genetic predisposition to pneumococcal infection reveals a critical role of alveolar macrophages in maintaining the sterility of the lower respiratory tract. Infect. Immun. 79, 1842–1847 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Verma, A. K., Bansal, S., Bauer, C., Muralidharan, A. & Sun, K. Influenza infection induces alveolar macrophage dysfunction and thereby enables noninvasive Streptococcus pneumoniae to cause deadly pneumonia. J. Immunol. 205, 1601–1607 (2020).

    CAS  PubMed  Google Scholar 

  119. Dockrell, D. H. et al. Alveolar macrophage apoptosis contributes to pneumococcal clearance in a resolving model of pulmonary infection. J. Immunol. 171, 5380–5388 (2003).

    CAS  PubMed  Google Scholar 

  120. Marriott, H. M. et al. Decreased alveolar macrophage apoptosis is associated with increased pulmonary inflammation in a murine model of pneumococcal pneumonia. J. Immunol. 177, 6480–6488 (2006).

    CAS  PubMed  Google Scholar 

  121. Winter, C. et al. Important role for CC chemokine ligand 2-dependent lung mononuclear phagocyte recruitment to inhibit sepsis in mice infected with Streptococcus pneumoniae. J. Immunol. 182, 4931–4937 (2009).

    CAS  PubMed  Google Scholar 

  122. Guilliams, M. & Svedberg, F. R. Does tissue imprinting restrict macrophage plasticity? Nat. Immunol. 22, 118–127 (2021).

    CAS  PubMed  Google Scholar 

  123. Aegerter, H. et al. Influenza-induced monocyte-derived alveolar macrophages confer prolonged antibacterial protection. Nat. Immunol. 21, 145–157 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Vissers, M. et al. Quantity and quality of naturally acquired antibody immunity to the pneumococcal proteome throughout life. J. Infect. Dis. https://doi.org/10.1093/infdis/jiae255 (2024).

  125. He, S. W. J. et al. Serological profiling of pneumococcal proteins reveals unique patterns of acquisition, maintenance and waning of antibodies throughout life. J. Infect. Dis. https://doi.org/10.1093/infdis/jiae216 (2024).

  126. Gil, E., Noursadeghi, M. & Brown, J. S. Streptococcus pneumoniae interactions with the complement system. Front. Cell Infect. Microbiol. 12, 929483 (2022).

    PubMed  PubMed Central  Google Scholar 

  127. Penaloza, H. F. et al. Interleukin-10 plays a key role in the modulation of neutrophils recruitment and lung inflammation during infection by Streptococcus pneumoniae. Immunology 146, 100–112 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Clark, S. E., Schmidt, R. L., Aguilera, E. R. & Lenz, L. L. IL-10-producing NK cells exacerbate sublethal Streptococcus pneumoniae infection in the lung. Transl. Res. 226, 70–82 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Camarasa, T. M. N., Torne, J., Chevalier, C., Rasid, O. & Hamon, M. A. Streptococcus pneumoniae drives specific and lasting natural killer cell memory. PLoS Pathog. 19, e1011159 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Van Maele, L. et al. Activation of type 3 innate lymphoid cells and Interleukin 22 secretion in the lungs during Streptococcus pneumoniae infection. J. Infect. Dis. 210, 493–503 (2014).

    PubMed  Google Scholar 

  131. Weiser, J. N., Ferreira, D. M. & Paton, J. C. Streptococcus pneumoniae: transmission, colonization and invasion. Nat. Rev. Microbiol. 16, 355–367 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Minhas, V. et al. In vivo dual RNA-seq reveals that neutrophil recruitment underlies differential tissue tropism of Streptococcus pneumoniae. Commun. Biol. 3, 293 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Johnson, M. O. et al. Distinct regulation of TH17 and TH1 cell differentiation by glutaminase-dependent metabolism. Cell 175, 1780–1795.e19 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Shapiro, E. D. et al. The protective efficacy of polyvalent pneumococcal polysaccharide vaccine. N. Engl. J. Med. 325, 1453–1460 (1991).

    CAS  PubMed  Google Scholar 

  135. Djennad, A. et al. Effectiveness of 23-valent polysaccharide pneumococcal vaccine and changes in invasive pneumococcal disease incidence from 2000 to 2017 in those aged 65 and over in England and Wales. eClinicalMedicine 6, 42–50 (2018).

    PubMed  Google Scholar 

  136. Essink, B. et al. Pivotal phase III randomized clinical trial of the safety, tolerability, and immunogenicity of 20-valent pneumococcal conjugate vaccine in adults aged ≥18 years. Clin. Infect. Dis. 75, 390–398 (2022).

    PubMed  Google Scholar 

  137. Kobayashi, M. et al. Use of 15-valent pneumococcal conjugate vaccine and 20-valent pneumococcal conjugate vaccine among U.S. adults: updated recommendations of the advisory committee on immunization practices — United States, 2022. MMWR Morb. Mortal. Wkly Rep. 71, 109–117 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Savulescu, C. et al. Effect of high-valency pneumococcal conjugate vaccines on invasive pneumococcal disease in children in SpIDnet countries: an observational multicentre study. Lancet Respir. Med. 5, 648–656 (2017).

    CAS  PubMed  Google Scholar 

  139. Hanquet, G. et al. Serotype replacement after introduction of 10-valent and 13-valent pneumococcal conjugate vaccines in 10 countries, Europe. Emerg. Infect. Dis. 28, 137–138 (2022).

    PubMed  Google Scholar 

  140. Naucler, P. et al. Comparison of the impact of pneumococcal conjugate vaccine 10 or pneumococcal conjugate vaccine 13 on invasive pneumococcal disease in equivalent populations. Clin. Infect. Dis. 65, 1780–1789 (2017).

    PubMed  PubMed Central  Google Scholar 

  141. Huang, S. S. et al. Continued impact of pneumococcal conjugate vaccine on carriage in young children. Pediatrics 124, e1–e11 (2009).

    PubMed  Google Scholar 

  142. Flasche, S. et al. Effect of pneumococcal conjugate vaccination on serotype-specific carriage and invasive disease in England: a cross-sectional study. PLoS Med. 8, e1001017 (2011).

    PubMed  PubMed Central  Google Scholar 

  143. Brueggemann, A. B. et al. Changes in the incidence of invasive disease due to Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis during the COVID-19 pandemic in 26 countries and territories in the Invasive Respiratory Infection Surveillance Initiative: a prospective analysis of surveillance data. Lancet Digit. Health 3, e360–e370 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Shaw, D. et al. Trends in invasive bacterial diseases during the first 2 years of the COVID-19 pandemic: analyses of prospective surveillance data from 30 countries and territories in the IRIS Consortium. Lancet Digit. Health 59, e582–e593 (2023).

    Google Scholar 

  145. Mitsi, E. et al. Streptococcus pneumoniae colonization associates with impaired adaptive immune responses against SARS-CoV-2. J. Clin. Invest. 132, e157124 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Naucler, P. et al. The changing epidemiology of community-acquired pneumonia: nationwide register-based study in Sweden. J. Intern. Med. 286, 689–701 (2019).

    CAS  PubMed  Google Scholar 

  147. Wateska, A. R. et al. Cost-effectiveness of an in-development adult-formulated pneumococcal vaccine in older U.S. adults. Vaccine 41, 4431–4437 (2023).

    PubMed  PubMed Central  Google Scholar 

  148. Chichili, G. R. et al. Phase I/II study of a novel 24-valent pneumococcal vaccine in healthy adults aged 18 to 64 years and in older adults aged 65 to 85 years. Vaccine 40, 4190–4198 (2022).

    CAS  PubMed  Google Scholar 

  149. Malley, R. et al. Intranasal immunization with killed unencapsulated whole cells prevents colonization and invasive disease by capsulated pneumococci. Infect. Immun. 69, 4870–4873 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Keech, C. A. et al. A phase I randomized, placebo-controlled, observer-blinded trial to evaluate the safety and immunogenicity of inactivated Streptococcus pneumoniae whole-cell vaccine in adults. Pediatr. Infect. Dis. J. 39, 345–351 (2020).

    PubMed  Google Scholar 

  151. Converso, T. R., Assoni, L., Andre, G. O., Darrieux, M. & Leite, L. C. C. The long search for a serotype independent pneumococcal vaccine. Expert Rev. Vaccines 19, 57–70 (2020).

    CAS  PubMed  Google Scholar 

  152. Talukdar, S., Zutshi, S., Prashanth, K. S., Saikia, K. K. & Kumar, P. Identification of potential vaccine candidates against Streptococcus pneumoniae by reverse vaccinology approach. Appl. Biochem. Biotechnol. 172, 3026–3041 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Moffitt, K. et al. TH17-mediated protection against pneumococcal carriage by a whole-cell vaccine is dependent on toll-like receptor 2 and surface lipoproteins. Clin. Vaccin. Immunol. 22, 909–916 (2015).

    CAS  Google Scholar 

  154. Moffitt, K. L. et al. TH17-based vaccine design for prevention of Streptococcus pneumoniae colonization. Cell Host Microbe 9, 158–165 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Liu, X. et al. A conserved antigen induces respiratory TH17-mediated broad serotype protection against pneumococcal superinfection. Cell Host Microbe 32, 304–314.e8 (2024).

    CAS  PubMed  Google Scholar 

  156. Sterrett, S. et al. Peripheral CD4 T follicular cells induced by a conjugated pneumococcal vaccine correlate with enhanced opsonophagocytic antibody responses in younger individuals. Vaccine 38, 1778–1786 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Karasartova, D. et al. Anti-pneumococcal vaccine-induced cellular immune responses in post-traumatic splenectomized individuals. J. Clin. Immunol. 37, 388–396 (2017).

    CAS  PubMed  Google Scholar 

  158. Gergova, R., Boyanov, V., Muhtarova, A. & Alexandrova, A. A review of the impact of streptococcal infections and antimicrobial resistance on human health. Antibiotics 13, 360 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Sempere, J. et al. Effect of pneumococcal conjugate vaccines and SARS-CoV-2 on antimicrobial resistance and the emergence of Streptococcus pneumoniae serotypes with reduced susceptibility in Spain, 2004–20: a national surveillance study. Lancet Microbe 3, e744–e752 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Reithuber, E. et al. THCz: small molecules with antimicrobial activity that block cell wall lipid intermediates. Proc. Natl Acad. Sci. USA 118, e2108244118 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Reithuber, E. et al. The bactericidal fatty acid mimetic 2CCA-1 selectively targets pneumococcal extracellular polyunsaturated fatty acid metabolism. mBio 11, e03027-20 (2020).

    PubMed  PubMed Central  Google Scholar 

  162. Wong, K. Y. et al. Endolysins against streptococci as an antibiotic alternative. Front. Microbiol. 13, 935145 (2022).

    PubMed  PubMed Central  Google Scholar 

  163. Southern, J. et al. Pneumococcal carriage in children and their household contacts six years after introduction of the 13-valent pneumococcal conjugate vaccine in England. PLoS ONE 13, e0195799 (2018).

    PubMed  PubMed Central  Google Scholar 

  164. Rybak, A. et al. Dynamics of antibiotic resistance of Streptococcus pneumoniae in france: a pediatric prospective nasopharyngeal carriage study from 2001 to 2022. Antibiotics 12, 1020 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Felix, S. et al. Impact of private use of the 13-valent pneumococcal conjugate vaccine (PCV13) on pneumococcal carriage among Portuguese children living in urban and rural regions. Vaccine 39, 4524–4533 (2021).

    CAS  PubMed  Google Scholar 

  166. Lee, G. M. et al. Impact of 13-valent pneumococcal conjugate vaccination on Streptococcus pneumoniae carriage in young children in Massachusetts. J. Pediatr. Infect. Dis. Soc. 3, 23–32 (2014).

    Google Scholar 

  167. Gonzales, B. E. et al. Pneumococcal serotypes and antibiotic resistance in healthy carriage children after introduction of PCV13 in Lima, Peru. Vaccine 41, 4106–4113 (2023).

    CAS  PubMed  Google Scholar 

  168. Chang, B. et al. Impact of thirteen-valent pneumococcal conjugate vaccine on nasopharyngeal carriage in healthy children under 24 months in Okinawa, Japan. J. Infect. Chemother. 26, 465–470 (2020).

    CAS  PubMed  Google Scholar 

  169. Chan, K. C. et al. Pneumococcal carriage in young children after introduction of PCV13 in Hong Kong. Vaccine 34, 3867–3874 (2016).

    PubMed  Google Scholar 

  170. Adamu, A. L. et al. The impact of introduction of the 10-valent pneumococcal conjugate vaccine on pneumococcal carriage in Nigeria. Nat. Commun. 14, 2666 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Aziz, U. B. A. et al. Targeted small molecule inhibitors blocking the cytolytic effects of pneumolysin and homologous toxins. Nat. Commun. 15, 3537 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Marangu, D. & Zar, H. J. Childhood pneumonia in low-and-middle-income countries: an update. Paediatr. Respir. Rev. 32, 3–9 (2019).

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Work in the authors’ laboratory was supported by grants from the Torsten Söderberg Foundation, the Swedish Research Council, Stockholm County Council, the Swedish Foundation for Strategic research, and the Knut and Alice Wallenberg foundation.

Author information

Authors and Affiliations

Authors

Contributions

B.H.-N. researched data for the article, substantially contributed to the discussion of the content, wrote a major part of the article, and reviewed and edited the article. A.R.N., R.D., P.N. and S.N. researched data for the article, wrote parts of the article, and reviewed and edited the article.

Corresponding author

Correspondence to Birgitta Henriques-Normark.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Microbiology thanks James Paton, Elaine Tuomanen and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Narciso, A.R., Dookie, R., Nannapaneni, P. et al. Streptococcus pneumoniae epidemiology, pathogenesis and control. Nat Rev Microbiol 23, 256–271 (2025). https://doi.org/10.1038/s41579-024-01116-z

Download citation

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41579-024-01116-z

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing