PMCCPMCCPMCC

Search tips
Search criteria 

Advanced


 
Formats
Article sections
Authors
Related links
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Respirology. Author manuscript; available in PMC 2011 October 1.
Published in final edited form as:
PMCID: PMC2956737
NIHMSID: NIHMS237471
Copyright notice and Disclaimer
Pneumococci: immunology of the innate host response
Gavin K. Paterson and Carlos J. Orihuela
Department of Microbiology and Immunology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900 U. S. A
Correspondence: Carlos J. Orihuela ; orihuela/at/uthscsa.edu fax: (210) 567-6612
Small right arrow pointing to: The publisher's final edited version of this article is available at Respirology
Small right arrow pointing to: See other articles in PMC that cite the published article.
Abstract
Despite the development of vaccines and antibiotics, Streptococcus pneumoniae (the pneumococcus) continues to be a major cause of human morbidity and mortality throughout the world. In recent years our understanding of how the host innate immune system recognizes and responds to pneumococcal infection has advanced significantly. Herein, we highlight some of the key features of the innate response to the pneumococcus.
Keywords: Streptococcus pneumoniae, infectious disease, innate immunity, toll-like receptors, pattern recognition receptors
The Gram-positive bacterium Streptococcus pneumoniae, the pneumococcus, is a common commensal of the human nasopharynx. However, it is also a significant pathogen, able to spread from the site of carriage to cause a range of infections, most notably: otitis media, pneumonia, bacteremia, and meningitis. The significance of S. pneumoniae as a human pathogen is highlighted by the estimate that among children under 5 years old there were 14.5 million episodes of serious pneumococcal disease in 2000 with 826,000 deaths 1. Other estimates suggest the pneumococcus to be responsible for a total of 1.6 million deaths annually 2. Shortcomings with the currently available vaccines (which cover only selected capsular serotypes) and the spread of antibiotic resistance suggest that the pneumococcus will remain an important human pathogen for some time to come.
The immune system consists of a diverse array of defense mechanisms including complement, mucociliary clearance, phagocytes, antibodies and effector T-cells. The non-specific early defenses of the innate immune system are critical for the prevention and slowing of infections; allowing time for the adaptive immune response to develop if needed. For a recent review on the adaptive immune response and vaccine development in the context of the pneumococcus see Malley3. Herein, we discuss recent advances in our understanding of the host innate immune response to the pneumococcus.
The complement system comprises over thirty serum and membrane proteins which, when activated, contribute to host defense by serving as chemotactic factors, opsonins, and bactericidal agents. Briefly, three pathways of complement activation exist: 1) The classical pathway which is activated by antibody binding to an antigen or other immune factors such as acute phase proteins. 2) The alternative pathway which is continuously activated at low levels but is only amplified on foreign surfaces due the absence of inhibitors present on host cells. 3) The lectin pathway, which is activated by mannose-binding lectin recognition of carbohydrates on microbial surfaces. Regardless of the activation pathway, the key functions of complement are: the opsonization of the microbial surface promoting phagocytosis, activation of neutrophil chemotaxis, and the direct killing of the microbe via formation of the membrane attack complex.
The importance of complement to host defense against the pneumococcus is shown by the severe infections suffered by those with genetic complement deficiencies. For instance patients genetically deficient for C3, the central complement component common to all three activation pathways, suffer recurrent pneumococcal (and other encapsulated bacterial) infections throughout their life. The essential role of complement is further supported by work in gene knock-out mice. Comparisons of mice lacking complement components specific to each activation pathway suggest that it is the classical pathway which is the dominant pathway for protection against the pneumococcus 4. Natural antibodies and the acute phase proteins, serum amyloid protein and C-reactive protein, have been found to be important in the activation of the classical pathway during pneumococcal infection 4–6. The alternative pathway also contributed to protection in these studies although its contribution was generally weaker in comparison to the classical pathway 4.
The importance of complement is further substantiated by the fact the pneumococcus processes a variety of complement-evasion mechanisms. All invasive clinical isolates of S. pneumoniae are encapsulated and the polysaccharide capsule is recognized to be the sine qua non virulence determinant. Capsule contributes to disease pathogenesis by protecting the pneumococcus from complement-mediated opsonophagocytosis, but also by preventing entrapment in mucus7 and neutrophil extracellular traps8 (see below). Capsule prevents opsonophagocytosis by multiple mechanisms including decreasing classical pathway activation by impairing C-reactive protein and IgG binding to the bacterial surface. Capsule also reduces alternative pathway activation, although the mechanism for this remains unclear, and decreases the degradation of C3b to iC3b on the bacterial surface. As a result of these combined effects the pneumococcal capsule impedes phagocytosis by Fcγ receptors, complement receptors, with evidence that it also protects against nonopsonic receptors 9.
Today, over 90 serologically distinct capsule serotypes are recognized and most have been isolated from individuals with disease. Importantly several serotypes, such as 1, 4, 5, 7 and 14, are overrepresented among invasive isolates while other serotypes less frequently cause disease. It is believed that the chemical composition and net charge of each serotype is central to these differences in virulence. However, considerable genetic diversity exists between strains thus making it difficult to assess the significance of capsule type versus other virulence factors. Recent studies using capsule swap pneumococcal mutants now clearly show that protection against complement-mediated immunity varies between capsular serotypes even when expressed in an otherwise isogenic background and that this effect correlates to observed differences in colonization and invasive potential 10, 11.
The capsule is not the only strategy the pneumococcus employs to avoid complement and phagocytosis. For example, the cytolysin pneumolysin is a key virulence factor produced by clinical isolates. It possesses a wide range of biological activities that contribute to carriage and disease (for review see 12, 13). With regards to complement, pneumolysin activates the classical pathway in the absence of antibodies specific to the toxin 14, 15. Deletion of the gene encoding pneumolysin results in increased opsonophagocytosis of pneumococci via the classical pathway and therefore suggests that complement activation by released toxin occurs distally leaving less available to deposit on the bacterial surface 16. In support of the latter, the contribution of pneumolysin to bacterial virulence in complement knockout mice is diminished 16.
The pneumococal surface protein CpbA (often referred to as PspC) recruits human but not mouse serum factor H, a negative regulator of the alternative pathway, to the bacterial surface 17. Likewise, certain CbpA alleles recruit the classical pathway inhibitor, C4-binding protein to the bacterial surface 18. PspA, the pneumococcal histidine triad proteins (PhtA, B, D and E), neuraminidase A, β-galactosidase and N-acetylglucosaminidase are additional pneumococcal surface proteins that act to reduce complement deposition on the bacterial surface and protect against opsonophagocytosis 19–21.
Pathogen recognition receptors (PPR) are a diverse collection of germ line-encoded host molecules that function to provide early recognition and initiate the inflammatory response to infection 22. This occurs via the recognition of conserved microbial features, so-called pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide (LPS) from Gram-negative bacteria, lipotechoic acids from Gram-positive bacteria, mannan from fungi, and double-stranded viral RNA. It is worth noting that host products may also be recognized and stimulate inflammation via PRRs. The toll-like receptor (TLR) family are one group of PRRs that have received much attention due to their central role in a variety of infectious and inflammatory diseases (for recent review see 23). There are at least 10 TLRs in humans and 13 in mice each recognizing a distinct repertoire of ligands with several implicated in the host response to the pneumococcus.
Among the diverse ligands recognized by TLR2 is bacterial, including pneumococcal, lipoteichoic acid (LTA) 24–27. This interaction involves LPS binding-protein and CD14 26. TLR2 −/− mice show heighted susceptibility in models of pneumococcal meningitis with increased disease severity and higher bacterial counts compared to wild type controls 28, 29. In models of pneumonia and sepsis TLR2 −/− mice show only a modest increase in susceptibility 30, 31 probably due to the compensatory affects of TLR4 recognition of pneumolysin (see below) 32. Finally, in a nasopharyngeal carriage model, TLR2−/− mice show impaired clearance of pneumococci 33. Structural differences in LTA between pneumococcal strains alter their ability to stimulate TLR2 in vitro which may contribute to differences in virulence 24.
TLR4 was the first TLR to be recognized and is widely studied due to its role in the response to LPS 34, but also recognizes other ligands including pneumolysin 35, 36. Although the structural basis of this interaction is unclear, it is independent of the pore-forming and complement-activating activity of pneumolysin 35. The role of pneumolysin-TLR4 recognition during nasopharyngeal carriage is ambiguous with one study finding TLR4 −/− mice to have increased colonization levels and heightened risk of invasive disease 35. In contrast other work described no difference between wild type and TLR4 −/− mice 33. The reason(s) for such differences remain unresolved but may relate to different experimental approaches including the use of different pneumococcal strains. Finally, TLR4 plays only a limited role in pneumonia, systemic infection or meningitis 37–40. As indicated, this is probably due in part to redundancy between different TLRs 32, 41.
Bacterial DNA has inflammatory activity due to the presence of unmethylated cytosine-phosphate-guanosine (CpG) motifs that are recognized by TLR9 42, 43. TLR 9 −/− mice display enhanced susceptibility to pneumococcal pneumonia, a phenotype more severe than that seen with mice lacking TLR2 or TLR4 40. Unlike TLRs 2 and 4, which are on the cell surface, TLR 9 is expressed within endosomal compartments, thus it may serve to amplify/modulate responses following phagocytosis. TLR1 and TLR6 are both implicated in the innate recognition of pneumococci in vitro although their significance has not yet been tested in an infection model 25, 44. Both of these TLRs dimerize with TLR2 and TLR2/6 heterodimers recognize diacylated lipoproteins, whereas TLR1/2 heterodimers recognize triacylated lipopeptides 45. Myeloid differentiation factor 88 (Myd88) is a key signaling adaptor protein during TLR as well as the Interleukin (IL)-1 family receptor signaling. In line with a role for different TLRs during pneumococcal recognition, Myd88 −/− mice show an increase in susceptibility in various infection models, although the contribution of IL-1 and IL-18 signaling may also contribute to this affect 31, 46, 47
Finally, supporting a role for TLRs and their signaling pathways during human infection, various polymorphisms in TLRs and their signaling molecules have been associated with susceptibility or resistance to pneumococal infection 48–52. Of particular note is the signaling adaptor Mal (also known as TIRAP), which functions following TLR2 and TLR4 activation. Interestingly, heterozygous carriage of a S180L variant of Mal is associated with resistance to invasive pneumococcal disease, malaria and tuberculosis 48. It is thought that the protective effect of S180L heterogeneity is mediated through the production of a reduced yet sufficient inflammatory response that confers protection while not inducing immunopathology. In contrast, a L181L variant of Mal which lacks signaling activity confers what appeared to be increased susceptibility to infection. However, the mutation was found so infrequently that any association could not be robustly assessed. The relative scarcity of L181L homozygote, especially in areas of high endemic disease is consistent with increased disease susceptibility and a strong selective pressure against such a genotype. This example highlights that while TLR signaling in humans is required for protection against pneumococcal disease it may also be detrimental if not properly regulated.
The elderly have an increased incidence of pneumococcal pneumonia that is associated with rapid-onset of severe disease with high mortality. Although there are likely to be several mechanisms underlying this heighted susceptibility, recent data from aged mice suggests reduced TLR function plays an important role. Compared to young mice, aged mice had reduced TLR1, 2 and 4 protein levels in their lungs, and were more susceptible to pneumococcal pneumonia 53. Consistent with decreased TLR function, aged mice showed a reduction in NFkB activation during infection and reduced pro-inflammatory cytokine production following intratracheal challenge with purified pneumococcal components 53.
In humans, elderly patients with pneumonia often present without one or more of the three classic symptoms of pneumonia (cough, fever and dyspnea) with ~10% showing no signs of infection other than confusion or delirium 54. Reduced TLR function is a possible explanation for such atypical presentations in the elderly. Prior to pneumococcal infection, age-associated inflammation also increases the expression of the pneumococcal ligands polymeric immunoglobulin receptor and platelet aggregating factor receptor53. Bacterial interaction with these proteins has been shown to initiate their uptake and translocation through the cell and binding to these proteins is thought to be important for development of bacteremia and meningitis 55, 56. TLR dysfunction and inflammation-mediated lung priming probably work simultaneously to heighten the susceptibility to pneumonia of aged animals and possibly human subjects as well.
NOD-like receptors (NLR) are intracellular PRRs acting in the cytosol to recognize and respond to microbial products. NOD1 and NOD2 recognize bacterial cell wall components containing D-glutamyl-meso-diaminopimelic acid and muramyl dipeptide, respectively. They function via activation of the inflammasome, a cytosolic multiprotein complex which activates caspase-1 which in turn promotes the cleavage and secretion of IL-1β and IL-18. They have also been found to induce pyroptosis, a caspase-1-dependent form of cell death that is highly inflammatory 57, 58. Although the pneumococcus stimulates the NLR NOD2 59 and activates caspase-1 in vitro 60 the significance in vivo is not clear given that caspase-1 −/− mice show no altered susceptibility to infection 40. On the other hand, Nod1−/− mice are more susceptible to pneumococcal sepsis due to the role of Nod1 recognition of the intestinal microbiota in priming the innate immune system 61.
Whilst the pneumococcal capsule is a key target of the adaptive immune system, forming the basis of current vaccines, its recognition by the innate immune system should not be overlooked. The C-type lectin SIGN-related 1 (SIGN-R1) is expressed by macrophages and binds purified capsular polysaccharide of different serotypes as well as to whole cells thus promoting their uptake 62. The significance of this recognition is shown by the increased susceptibly of SIGN-R1 knockout mice to systemic and pulmonary pneumococcal infection 63, 64. Absence of SIGN-R1 also reduces the levels of natural antibodies against the pneumococcus which most likely also impedes host defense Finally, SIGN-R1 activates the classical complement pathway by binding C1q and promoting complement disposition on SIGN-R1-bound pneumococci 65.
Scavenger receptors (SR) represent a large, diverse family of surface glycoproteins expressed predominantly on macrophages, dendritic cells and endothelial cells 66. Although first studied for their role in the clearance of oxidized low-density lipoproteins their function as PRRs is now appreciated, in particular as phagocytic receptors mediating direct non-opsonic phagocytosis of microbes 67. The scavenger receptors SR-A and MARCO both bind pneumococci, although the bacterial features that are recognized are not yet known, however, mice lacking either receptor have increased susceptibility to pneumococcal pneumonia 68, 69. In addition down-regulation of MARCO following influenza infection has been implicated in the the severity of secondary pneumococcal infections 70.
Pulmonary surfactant is a mixture of proteins and lipids that prevent alveoli from collapsing during expiration due to surface tension. In addition, the surfactant proteins (SPs) SPA and SP-D play a role in host defense against infection by binding to and opsonizing microbes and by modulating immune cell function 71, 72. In the case of S. pneumoniae, SP-D knockout mice show increased susceptibility to infection 73 while SP-A promotes phagocytosis of pneumococci in vitro 74. This latter effect is seemingly due to the up-regulation of SR-A (on macrophages) by SP-A rather than direct opsonization of the pneumococcus 75.
While the role of neutrophils in the phagocytotic uptake and intracellular killing of pathogens has long been recognized, more recently they have been shown to produce so-called neutrophil extracellular traps (NETs) to entrap and kill pathogens in the extracellular environment 76, 77. NETs consist of extruded DNA to which antimicrobial components, such as elastase, lactoferrin, bactericidal permeability increasing protein and myeloperoxide are attached. The pneumococcus is relatively resistant to NET-mediated killing due to D-alanylation of lipoteichoic acid 8. This results in a positive charge in the bacterial surface which generates an electrochemical repulsion against the antimicrobial peptides in the NETs. Furthermore, the pneumococcus produces an extracellular endonuclease, EndA, which facilitates pneumococcal escape from entrapment 78. Despite these evasion strategies it seems likely that entrapment by NETs may impede bacterial dissemination even if only transiently. Interestingly, strain to strain variation was observed for pneumococal extracellular nuclease activity, and this could contribute to the differences in virulence between strains and serotypes 78.
A variety of cytokines including IL-12 79, IL-17 79, IL-18 80–83 and IL-6 84 have all been shown to be important for the innate response to pneumococci. However, it appears the overlapping affects of TNF-α and IL-1 are of central importance during the early stages of infection being responsible for enhancing cytokine expression, neutrophil recruitment, and resultant bacterial killing via NFκB RelA activation 85–87. The importance of TNF-α during pneumococcal infection is substantiated in numerous experimental studies 87–90 showing that deletion or neutralization of TNF-α was detrimental and by the finding that human patients treated with anti-TNF-α therapies may have increased risk of invasive pneumococcal disease 91. However, while protective, TNF-α may also contribute to tissue damage and the up-regulation of pneumococcal receptors such as during chronic low-grade inflammation in the elderly 92, 53. The latter is substantiated by studies showing that the individuals with elevated levels of TNF-α and IL-6 were more likely to develop community-acquired pneumonia than those with lower levels 93.
Concluding remarks
The response to pneumococcal infection is multi-faceted and involves almost all aspects of the innate immune system in the lungs, many of which could not be discussed due to space limitations. These interactions are key for preventing severe disease, as is often demonstrated by the severe infections observed in individuals or animals that with deficiencies in various components. It may be possible to augment the host-defense through targeting of specific innate components, however, such an approach carries considerable risk as the immune system can be a double-edged sword that can protect or inflict damage to the host.
Acknowledgments
This review is supported by NIH grant AG033274.
Biographies
•
Gavin Paterson earned his PhD from the University of Glasgow in 2004 for work on pneumococcal-host interactions. Positions at the Defence Science Technology Laboratory (DSTL), Porton Down and the Department of Veterinary Medicine, University of Cambridge followed before his current post of Postdoctoral Fellow in the Orihuela Laboratory.
•
Carlos Orihuela has worked on pneumococcal host-pathogen interactions since entering graduate school in 1996. He received his PhD from the University of Texas Medical Branch in Galveston in 2001 and completed his postdoctoral training at St. Jude Children’s Research Hospital in 2005. He is currently an Assistant Professor at the University of Texas Health Science Center in San Antonio.
Footnotes
Conflict of interest statement: C. J. O. has received funding for research unrelated to this review from Novartis Pharmaceuticals.
References
1. O’Brien KL, Wolfson LJ, Watt JP, Henkle E, Deloria-Knoll M, et al. Burden of disease caused by Streptococcus pneumoniae in children younger than 5 years: global estimates. Lancet. 2009;374:893–902. [PubMed]
2. Lynch JP, Zhanel GG. Streptococcus pneumoniae: Epidemiology, Risk Factors, and Strategies for Prevention. Seminars in Respiratory and Critical Care Medicine. 2009;30:189–209. [PubMed]
3. Malley R. Antibody and cell-mediated immunity to Streptococcus pneumoniae: implications for vaccine development. J Mol Med. 2010;88:135–42. [PubMed]
4. Brown JS, Hussell T, Gilliland SM, Holden DW, Paton JC, et al. The classical pathway is the dominant complement pathway required for innate immunity to Streptococcus pneumoniae infection in mice. Proceedings of the National Academy of Sciences of the United States of America. 2002;99:16969–74. [PubMed]
5. Yuste J, Botto M, Bottoms SE, Brown JS. Serum amyloid P aids complement-mediated immunity to Streptococcus pneumoniae. Plos Pathogens. 2007;3:1208–19. [PMC free article] [PubMed]
6. Mold C, Du Clos TW. C-reactive protein increases cytokine responses to Streptococcus pneumoniae through interactions with Fc gamma receptors. Journal of Immunology. 2006;176:7598–604. [PubMed]
7. Nelson AL, Roche AM, Gould JM, Chim K, Ratner AJ, et al. Capsule enhances pneumococcal colonization by limiting mucus-mediated clearance. Infect Immun. 2007;75:83–90. [PMC free article] [PubMed]
8. Wartha F, Beiter K, Albiger B, Fernebro J, Zychlinsky A, et al. Capsule and D-alanylated lipoteichoic acids protect Streptococcus pneumoniae against neutrophil extracellular traps. Cellular Microbiology. 2007;9:1162–71. [PubMed]
9. Hyams C, Camberlein E, Cohen JM, Bax K, Brown JS. The Streptococcus pneumoniae Capsule Inhibits Complement Activity and Neutrophil Phagocytosis by Multiple Mechanisms. Infection and Immunity. 2010;78:704–15. [PMC free article] [PubMed]
10. Hyams C, Yuste J, Bax K, Camberlein E, Weiser JN, et al. Streptococcus pneumoniae Resistance to Complement-Mediated Immunity Is Dependent on the Capsular Serotype. Infection and Immunity. 2010;78:716–25. [PMC free article] [PubMed]
11. Weinberger DM, Trzcinski K, Lu YJ, Bogaert D, Brandes A, et al. Pneumococcal Capsular Polysaccharide Structure Predicts Serotype Prevalence. Plos Pathogens. 2009;5:9. [PMC free article] [PubMed]
12. Hirst RA, Kadioglu A, O’Callaghan C, Andrew PW. The role of pneumolysin in pneumococcal pneumonia and meningitis. Clinical and Experimental Immunology. 2004;138:195–201. [PubMed]
13. Marriott HM, Mitchell TJ, Dockrell DH. Pneumolysin: A double-edged sword during the host-pathogen interaction. Current Molecular Medicine. 2008;8:497–509. [PubMed]
14. Mitchell TJ, Andrew PW, Saunders FK, Smith AN, Boulnois GJ. Complement activationand antibody-binding by pneumolysin via a region of the toxin homologous to a human acute-phase protein. Molecular Microbiology. 1991;5:1883–8. [PubMed]
15. Rossjohn J, Gilbert RJC, Crane D, Morgan PJ, Mitchell TJ, et al. The molecular mechanism of pneumolysin, a virulence factor from Streptococcus pneumoniae. J Mol Biol. 1998;284:449–61. [PubMed]
16. Yuste J, Botto M, Paton JC, Holden DW, Brown JS. Additive inhibition of complement deposition by pneumolysin and PspA facilitates Streptococcus pneumoniae septicemia. Journal of Immunology. 2005;175:1813–9. [PubMed]
17. Lu L, Ma Z, Jokiranta TS, Whitney AR, DeLeo FR, et al. Species-Specific Interaction of Streptococcus pneumoniae with Human Complement Factor H. Journal of Immunology. 2008;181:7138–46. [PMC free article] [PubMed]
18. Dieudonne-Vatran A, Krentz S, Blom AM, Meri S, Henriques-Normark B, et al. Clinical Isolates of Streptococcus pneumoniae Bind the Complement Inhibitor Cob-Binding Protein in a PspC Allele-Dependent Fashion. Journal of Immunology. 2009;182:7865–77. [PubMed]
19. Dalia AB, Standish AJ, Weiser JN. Three Surface Exoglycosidases from Streptococcus pneumoniae, NanA, BgaA, and StrH, Promote Resistance to Opsonophagocytic Killing by Human Neutrophils. Infection and Immunity. 2010;78:2108–16. [PMC free article] [PubMed]
20. Tu AHT, Fulgham RL, McCrory MA, Briles DE, Szalai AJ. Pneumococcal surface protein A inhibits complement activation by Streptococcus pneumoniae. Infection and Immunity. 1999;67:4720–4. [PMC free article] [PubMed]
21. Melin M, Di Paolo E, Tikkanen L, Jarva H, Neyt C, et al. Interaction of Pneumococcal Histidine Triad Proteins with Human Complement. Infection and Immunity. 2010;78:2089–98. [PMC free article] [PubMed]
22. Janeway CA, Medzhitov R. Innate immune recognition. Annual Review of Immunology. 2002;20:197–216. [PubMed]
23. O’Neill LA, Bryant CE, Doyle SL. Therapeutic targeting of Toll-like receptors for infectious and inflammatory diseases and cancer. Pharmacol Rev. 2009;61:177–97. [PubMed]
24. Draing C, Pfitzenmaier M, Zummo S, Mancuso G, Geyer A, et al. Comparison of lipoteichoic acid from different serotypes of Streptococcus pneumoniae. Journal of Biological Chemistry. 2006;281:33849–59. [PubMed]
25. Han SH, Kim JH, Martin M, Michalek SM, Nahm MH. Pneumococcal lipoteichoic acid (LTA) is not as potent as staphylococcal LTA in stimulating toll-like receptor 2. Infection and Immunity. 2003;71:5541–8. [PMC free article] [PubMed]
26. Schroder NWJ, Morath S, Alexander C, Hamann L, Hartung T, et al. Lipoteichoic acid (LTA) of Streptococcus pneumoniae and Staphylococcus aureus activates immune cells via toll-like receptor (TLR)-2, lipopolysaccharide-binding protein (LBP), and CD14, whereas TLR-4 and MD-2 are not involved. Journal of Biological Chemistry. 2003;278:15587–94. [PubMed]
27. Yoshimura A, Lien E, Ingalls RR, Tuomanen E, Dziarski R, et al. Cutting edge: Recognition of gram-positive bacterial cell wall components by the innate immune system occurs via toll-like receptor 2. Journal of Immunology. 1999;163:1–5. [PubMed]
28. Echchannaoui H, Frei K, Schnell C, Leib SL, Zimmerli W, et al. Toll-like receptor 2-deficient mice are highly susceptible to Streptococcus pneumoniae meningitis because of reduced bacterial clearing and enhanced inflammation. Journal of Infectious Diseases. 2002;186:798–806. [PubMed]
29. Koedel U, Angele B, Rupprecht T, Wagner H, Roggenkamp A, et al. Toll-like receptor 2 participates in mediation of immune response in experimental pneumococcal meningitis. Journal of Immunology. 2003;170:438–44. [PubMed]
30. Knapp S, Wieland CW, van ‘t Veer C, Takeuchi O, Akira S, et al. Toll-like receptor 2 plays a role in the early inflammatory response to murine pneumococcal pneumonia but does not contribute to antibacterial defense. Journal of Immunology. 2004;172:3132–8. [PubMed]
31. Khan AQ, Chen QY, Wu ZQ, Paton JC, Snapper CM. Both innate immunity and type 1 humoral immunity to Streptococcus pneumoniae are mediated by MyD88 but differ in their relative levels of dependence on Toll-like receptor 2. Infection and Immunity. 2005;73:298–307. [PMC free article] [PubMed]
32. Dessing MC, Florquin S, Paton JC, Poll TD. Toll-like receptor 2 contributes to antibacterial defence against pneumolysin-deficient pneumococci. Cellular Microbiology. 2008;10:237–46. [PMC free article] [PubMed]
33. van Rossum AMC, Lysenko ES, Weiser JN. Host and bacterial factors contributing to the clearance of colonization by Streptococcus pneumoniae in a murine model. Infection and Immunity. 2005;73:7718–26. [PMC free article] [PubMed]
34. Medzhitov R, Preston Hurlburt P, Janeway CA. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature. 1997;388:394–7. [PubMed]
35. Malley R, Henneke P, Morse SC, Cieslewicz MJ, Lipsitch M, et al. Recognition of pneumolysin by toll-like receptor 4 confers resistance to pneumococcal infection. Proceedings of the National Academy of Sciences of the United States of America. 2003;100:1966–71. [PubMed]
36. Srivastava A, Henneke P, Visintin A, Morse SC, Martin V, et al. The apoptotic response to pneumolysin is toll-like receptor 4 dependent and protects against pneumococcal disease. Infection and Immunity. 2005;73:6479–87. [PMC free article] [PubMed]
37. Klein M, Obermaier B, Angele B, Pfister HW, Wagner H, et al. Innate immunity to pneumococcal infection of the central nervous system depends on Toll-like receptor (TLR) 2 and TLR4. Journal of Infectious Diseases. 2008;198:1028–36. [PubMed]
38. Benton KA, Paton JC, Briles DE. The hemolytic and complement-activating properties of pneumolysin do not contribute individually to virulence in a pneumococcal bacteremia model. Microbial Pathogenesis. 1997;23:201–9. [PubMed]
39. Branger J, Knapp S, Weijer S, Leemans JC, Pater JM, et al. Role of toll-like receptor 4 in gram-positive and gram-negative pneumonia in mice. Infection and Immunity. 2004;72:788–94. [PMC free article] [PubMed]
40. Albiger B, Dahlberg S, Sandgren A, Wartha F, Beiter K, et al. Toll-like receptor 9 acts at an early stage in host defence against pneumococcal infection. Cellular Microbiology. 2007;9:633–44. [PubMed]
41. Lee KS, Scanga CA, Bachelder EM, Chen QY, Snapper CM. TLR2 synergizes with both TLR4 and TLR9 for induction of the MyD88-dependent splenic cytokine and chemokine response to Streptococcus pneumoniae. Cellular Immunology. 2007;245:103–10. [PMC free article] [PubMed]
42. Ishii KJ, Akira S. Innate immune recognition of, and regulation by, DNA. Trends Immunol. 2006;27:525–32. [PubMed]
43. Krieg AM. The role of CpG motifs in innate immunity. Current Opinion in Immunology. 2000;12:35–43. [PubMed]
44. Ozinsky A, Underhill DM, Fontenot JD, Hajjar AM, Smith KD, et al. The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between Toll-like receptors. Proceedings of the National Academy of Sciences of the United States of America. 2000;97:13766–71. [PubMed]
45. Schenk M, Belisle JT, Modlin RL. TLR2 looks at lipoproteins. Immunity. 2009;31:847–9. [PubMed]
46. Koedel U, Rupprecht T, Angele B, Heesemann J, Wagner H, et al. MyD88 is required for mounting a robust host immune response to Streptococcus pneumoniae in the CNS. Brain. 2004;127:1437–45. [PubMed]
47. Albiger B, Sandgren A, Katsuragi H, Meyer-Hoffert U, Beiter K, et al. Myeloid differentiation factor 88-dependent signalling controls bacterial growth during colonization and systemic pneumococcal disease in mice. Cellular Microbiology. 2005;7:1603–15. [PubMed]
48. Khor CC, Chapman SJ, Vannberg FO, Dunne A, Murphy C, et al. A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis. Nature Genet. 2007;39:523–8. [PMC free article] [PubMed]
49. Yuan FF, Marks K, Wong M, Watson S, de Leon E, et al. Clinical relevance of TLR2, TLR4, CD14 and Fc gamma RIIA genepolymorphisms in Streptococcus pneumoniae infection. Immunol Cell Biol. 2008;86:268–70. [PubMed]
50. Picard C, Puel A, Bonnet M, Ku CL, Bustamante J, et al. Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science. 2003;299:2076–9. [PubMed]
51. Currie AJ, Davidson DJ, Reid GSD, Bharya S, MacDonald KL, et al. Primary immunodeficiency to pneumococcal infection due to a defect in toll-like receptor signaling. Journal of Pediatrics. 2004;144:512–8. [PubMed]
52. Ku C-L, Picard C, Erdos M, Jeurissen A, Bustamante J, et al. IRAK4 and NEMO mutations in otherwise healthy children with recurrent invasive pneumococcal disease. Journal of Medical Genetics. 2007;44:16–23. [PMC free article] [PubMed]
53. Hinojosa E, Boyd AR, Orihuela CJ. Age-Associated Inflammation and Toll-Like Receptor Dysfunction Prime the Lungs for Pneumococcal Pneumonia. Journal of Infectious Diseases. 2009;200:546–54. [PMC free article] [PubMed]
54. Fein AM. Pneumonia in the elderly -Special Diagnostic and therapeutic considerations. Medical Clinics of North America. 1994;78:1015–33. [PubMed]
55. Cundell DR, Gerard NP, Gerard C, Idanpaan-Heikkila I, Tuomanen EI. Streptococcus pneumoniae anchor to activated human cells by the receptor for platelet-activating factor. Nature. 1995;377:435–8. [PubMed]
56. Zhang JR, Mostov KE, Lamm ME, Nanno M, Shimida S, et al. The polymeric immunoglobulin receptor translocates pneumococci across human nasopharyngeal epithelial cells. Cell. 2000;102:827–37. [PubMed]
57. Bryant C, Fitzgerald KA. Molecular mechanisms involved in inflammasome activation. Trends in Cell Biology. 2009;19:455–64. [PubMed]
58. Chen G, Shaw MH, Kim YG, Nunez G. NOD-Like Receptors: Role in Innate Immunity and Inflammatory Disease. Annual Review of Pathology-Mechanisms of Disease. 2009;4:365–98. [PubMed]
59. Opitz B, Puschel A, Schmeck B, Hocke AC, Rosseau S, et al. Nucleotide-binding oligomerization domain proteins are innate immune receptors for internalized Streptococcus pneumoniae. Journal of Biological Chemistry. 2004;279:36426–32. [PubMed]
60. Shoma S, Tsuchiya K, Kawamura I, Nomura T, Hara H, et al. Critical Involvement of pneumolysin in production of interleukin-1 alpha and caspase-1-dependent cytokines in infection with Streptococcus pneumoniae in vitro: a novel function of pneumolysin in caspase-1 activation. Infection and Immunity. 2008;76:1547–57. [PMC free article] [PubMed]
61. Clarke TB, Davis KM, Lysenko ES, Zhou AY, Yu Y, et al. Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity. Nat Med. 16:228–31. [PubMed]
62. Kang YS, Kim JY, Bruening SA, Pack M, Charalambous A, et al. The C-type lectin SIGN-R1 mediates uptake of the capsular polysaccharide of Streptococcus pneumoniae in the marginal zone of mouse spleen. Proc Natl Acad Sci U S A. 2004;101:215–20. [PubMed]
63. Koppel EA, Wieland CW, van den Berg VC, Litjens M, Florquin S, et al. Specific ICAM-3 grabbing nonintegrin-related 1 (SIGNR1) expressed by marginal zone macrophages is essential for defense against pulmonary Streptococcus pneumoniae infection. Eur J Immunol. 2005;35:2962–9. [PubMed]
64. Lanoue A, Chatworthy MR, Smith P, Green S, Townsend MJ, et al. SIGN-R1 contributes to protection against lethal pneumococcal infection in mice. Journal of Experimental Medicine. 2004;200:1383–93. [PMC free article] [PubMed]
65. Kang YS, Do YY, Lee HK, Park SH, Cheong C, et al. A dominant complement fixation pathway for pneumococcal polysaccharides initiated by SIGN-R1 interacting with C1q. Cell. 2006;125:47–58. [PubMed]
66. Murphy JE, Tedbury PR, Homer-Vanniasinkam S, Walker JH, Ponnambalam S. Biochemistry and cell biology of mammalian scavenger receptors. Atherosclerosis. 2005;182:1–15. [PubMed]
67. Areschoug T, Gordon S. Scavenger receptors: role in innate immunity and microbial pathogenesis. Cellular Microbiology. 2009;11:1160–9. [PubMed]
68. Arredouani M, Yang ZP, Ning YY, Qin GZ, Soininen R, et al. The scavenger receptor MARCO is required for lung defense against pneumococcal pneumonia and inhaled particles. Journal of Experimental Medicine. 2004;200:267–72. [PMC free article] [PubMed]
69. Arredouani MS, Yang ZP, Imrich A, Ning YY, Qin GZ, et al. The macrophage scavenger receptor SR-AI/II and lung defense against pneumococci and particles. American Journal of Respiratory Cell and Molecular Biology. 2006;35:474–8. [PMC free article] [PubMed]
70. Sun K, Metzger DW. Inhibition of pulmonary antibacterial defense by interferon-gamma during recovery from influenza infection. Nature Medicine. 2008;14:558–64. [PubMed]
71. Crouch E, Wright JR. Surfactant proteins A and D and pulmonary host defense. Annual Review of Physiology. 2001;63:521–54. [PubMed]
72. Whitsett JA. Surfactant proteins in innate host defense of the lung. Biology of the Neonate. 2005;88:175–80. [PubMed]
73. Jounblat R, Clark H, Eggleton P, Hawgood S, Andrew PW, et al. The role of surfactant protein D in the colonisation of the respiratory tract and onset of bacteraemia during pneumococcal pneumonia. Respir Res. 2005;6:12. [PMC free article] [PubMed]
74. Kuronuma K, Sano H, Kato K, Kudo K, Hyakushima N, et al. Pulmonary surfactant protein A augments the phagocytosis of Streptococcus pneumoniae by alveolar macrophages through a casein kinase 2-dependent increase of cell surface localization of scavenger receptor A. Journal of Biological Chemistry. 2004;279:21421–30. [PubMed]
75. Sano H, Kuronuma K, Kudo K, Mitsuzawa H, Sato M, et al. Regulation of inflammation and bacterial clearance by lung collectins. Respirology. 2006;11:S46–S50. [PubMed]
76. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, et al. Neutrophil extracellular traps kill bacteria. Science. 2004;303:1532–5. [PubMed]
77. Wartha F, Beiter K, Normark S, Henriques-Normark B. Neutrophil extracellular traps: casting the NET over pathogenesis. Curr Opin Microbiol. 2007;10:52–6. [PubMed]
78. Beiter K, Wartha F, Albiger B, Normark S, Zychlinsky A, et al. An endonuclease allows Streptococcus pneumoniae to escape from neutrophil extracellular traps. Current Biology. 2006;16:401–7. [PubMed]
79. Zhang Z, Clarke TB, Weiser JN. Cellular effectors mediating Th17-dependent clearance of pneumococcal colonization in mice. J Clin Invest. 2009;119:1899–909. [PMC free article] [PubMed]
80. Lauw FN, Branger J, Florquin S, Speelman P, van Deventer SJH, et al. IL-18 improves the early antimicrobial host response to pneumococcal pneumonia. Journal of Immunology. 2002;168:372–8. [PubMed]
81. Paterson GK, Bluet CE, Mitchell TJ. Role of interleukin-18 in experimental infections with Streptococcus pneumoniae. Journal of Medical Microbiology. 2005;54:323–6. [PubMed]
82. Zwijnenburg PJG, van der Poll T, Florquin S, Akira S, Takeda K, et al. Interleukin-18 gene-deficient mice show enhanced defense and reduced inflammation during pneumococcal meningitis. Journal of Neuroimmunology. 2003;138:31–7. [PubMed]
83. Yamamoto N, Kawakami K, Kinjo Y, Miyagi K, Kinjo T, et al. Essential role for the p40 subunit of interleukin-12 in neutrophil-mediated early host defense against pulmonary infection with Streptococcus pneumoniae: involvement of interferon-gamma. Microbes and Infection. 2004;6:1241–9. [PubMed]
84. vanderPoll T, Keogh CV, Guirao X, Buurman WA, Kopf M, et al. Interleukin-6 gene-deficient mice show impaired defense against pneumococcal pneumonia. Journal of Infectious Diseases. 1997;176:439–44. [PubMed]
85. Jones MR, Simms BT, Lupa MM, Kogan MS, Mizgerd JP. Lung NF-kappaB activation and neutrophil recruitment require IL-1 and TNF receptor signaling during pneumococcal pneumonia. J Immunol. 2005;175:7530–5. [PMC free article] [PubMed]
86. Quinton LJ, Jones MR, Simms BT, Kogan MS, Robson BE, et al. Functions and regulation of NF-kappaB RelA during pneumococcal pneumonia. J Immunol. 2007;178:1896–903. [PMC free article] [PubMed]
87. Rijneveld AW, Florquin S, Branger J, Speelman P, Van Deventer SJH, et al. TNF-alpha compensates for the impaired host defense of IL-1 type I receptor-deficient mice during pneumococcal pneumonia. Journal of Immunology. 2001;167:5240–6. [PubMed]
88. O’Brien DP, Briles DE, Szalai AJ, Tu AH, Sanz I, et al. Tumor necrosis factor alpha receptor I is important for survival from Streptococcus pneumoniae infections. Infection and Immunity. 1999;67:595–601. [PMC free article] [PubMed]
89. Takashima K, Tateda K, Matsumoto T, Iizawa Y, Nakao M, et al. Role of tumor necrosis factor alpha in pathogenesis of pneumococcal pneumonia in mice. Infection and Immunity. 1997;65:257–60. [PMC free article] [PubMed]
90. Wellmer A, Gerber J, Ragheb J, Zysk G, Kunst T, et al. Effect of deficiency of tumor necrosis factor alpha or both of its receptors on Streptococcus pneumoniae central nervous system infection and peritonitis. Infection and Immunity. 2001;69:6881–6. [PMC free article] [PubMed]
91. Colombel JF, Loftus EV, Tremaine WJ, Egan LJ, Harmsen WS, et al. The safety profile of infliximab in patients with Crohn’s disease: The Mayo Clinic experience in 500 patients. Gastroenterology. 2004;126:19–31. [PubMed]
92. Cundell DR, Gerard NP, Gerard C, Idanpaanheikkila I, Tuomanen EI. Streptococcus pneumoniae anchor to activated human cells by the receptor for platelet-activating factor. Nature. 1995;377:435–8. [PubMed]
93. Yende S, Tuomanen EI, Wunderink R, Kanaya A, Newman AB, et al. Preinfection systemic inflammatory markers and risk of hospitalization due to pneumonia. Am J Respir Crit Care Med. 2005;172:1440–6. [PMC free article] [PubMed]