Pneumococcal Virulence Factors Research Articles

The impact of pneumolysin on the macrophage response to Streptococcus pneumoniae is strain-dependent.

Streptococcus pneumoniae is the world's leading cause of pneumonia, bacteremia, meningitis and otitis media. A major pneumococcal virulence factor is the cholesterol-dependent cytolysin, which has the defining property of forming pores in cholesterol-containing membranes. In recent times a clinically significant and internationally successful serotype 1 ST306 clone has been found to express a non-cytolytic variant of Ply (Ply306). However, while the pneumococcus is a naturally transformable organism, strains of the ST306 clonal group have to date been virtually impossible to transform, severely restricting efforts to understand the role of non-cytolytic Ply in the success of this clone. In this study isogenic Ply mutants were constructed in the D39 background and for the first time in the ST306 background (A0229467) to enable direct comparisons between Ply variants for their impact on the immune response in a macrophage-like cell line. Strains that expressed cytolytic Ply were found to induce a significant increase in IL-1β release from macrophage-like cells compared to the non-cytolytic and Ply-deficient strains in a background-independent manner, confirming the requirement for pore formation in the Ply-dependent activation of the NLRP3 inflammasome. However, cytolytic activity in the D39 background was found to induce increased expression of the genes encoding GM-CSF (CSF2), p19 subunit of IL-23 (IL23A) and IFNβ (IFNB1) compared to non-cytolytic and Ply-deficient D39 mutants, but had no effect in the A0229467 background. The impact of Ply on the immune response to the pneumococcus is highly dependent on the strain background, thus emphasising the importance of the interaction between specific virulence factors and other components of the genetic background of this organism.

Progress of streptococcus pneumoniae infection and immunity

Streptococcus pneumoniae（ SP） is the leading pathogenic bacteria of invasive bacterial infections in children. It can cause some life-threatening diseases such as pneumonia,meningitis and sepsis. Streptococcus pneumoniae frequently colonizes the upper respiratory tract. It is essential to know the host immune response during the infection. This paper reviews antigenic structure of SP,pneumococcal conjugate vaccine and pneumococcal virulence factors,especially focuses on the immune response including the effect of innate immunity,macrophage,neutrophil and T-cell. Key words: Streptococcus pneumoniae; Pneumococcal pneumonia; Pneumococcal disease; Immunity

Improved capsular polysaccharide production by Streptococcus pneumoniae serotype 14 using continuous cultivation

The capsular polysaccharide (PS) is the most important pneumococcal virulence factor and is currently used as antigen in all pneumococcal vaccines. Despite its physiological and epidemiological importance, meager studies have been devoted to improve PS production and understand its relationship with pneumococcal central metabolism. In this study, kinetics of growth and production of PS by Streptococcus pneumoniae serotype 14 (PS14) in batch and continuous cultivation were investigated. Strong cell lysis was observed in batch cultivation, while accumulation of organic acids and autolysis was avoided in continuous cultivation. In the continuous cultivation was possible to achieve higher concentration of biomass and PS14. Calculation of kinetic parameters demonstrated that PS14 is a cell-associated product. The coefficients for growth-associated stoichiometric true yield and maintenance were determined as 0.25gglucosegbiomass−1 and 1.24gglucose(gbiomassh)−1, respectively. The maximum productivity of PS14 released in the supernatant (PS14R) and cell-bound PS14 (PS14C) were obtained at a dilution rate of 0.8h−1, respectively, 85 and 122mg (gbiomassh)−1. Compared to batch fermentation, both PS14R and PS14C productivities were increased by about 300% in the continuous process. These findings demonstrate that continuous cultivation is a promising strategy for PS production to be used in pneumococcal vaccines.

Mucosal and systemic immunization with a novel attenuated pneumococcal vaccine candidate confer serotype independent protection against Streptococcus pneumoniae in mice

Despite the availability of effective vaccines, Streptococcus pneumoniae is still one of the major infectious diseases causing substantial morbidity and mortality in children under 5 years old. In this study, we demonstrate the protective efficacy of S. pneumoniae SPY1, a novel live attenuated vaccine strain against pneumococcal infection in murine models. This strain was characterized by defects in three important pneumococcal virulence factors including capsule, teichoic acids and pneumolysin. The lactate dehydrogenase assays and in vivo animal experiments demonstrated a significantly attenuated virulence and a reduced nasopharyngeal colonization for the SPY1 strain. We also show that mucosal and systemic immunization with the live SPY1 strain induced protective immune responses against pneumococci. Mucosal immunization with SPY1 offered better protection against colonization challenge with strains TIGR4 and serotype 19F than systemic SPY1 immunization. In invasive infection models, mucosal vaccination with the SPY1 strain conferred complete protection against D39 and clinical serotype 6B and 3 strains. Notably, intranasal vaccination with the SPY1 strain conferred superior protection against pneumococcal invasive disease compared with the commercial available vaccines. SPY1 strain was shown to elicit high levels of serotype-independent antibodies and a mixed cellular immune response. Besides, the SPY1 serum was able to passively protect mice against invasive challenge with D39 strain, indicating the protective effect of the antibody-mediated responses. Together, the SPY1 strain may be a promising live vaccine strain to protect pneumococcal infection.

Following in Real Time the Impact of Pneumococcal Virulence Factors in an Acute Mouse Pneumonia Model Using Bioluminescent Bacteria

Following in Real Time the Impact of Pneumococcal Virulence Factors in an Acute Mouse Pneumonia Model Using Bioluminescent Bacteria

Following in Real Time the Impact of Pneumococcal Virulence Factors in an Acute Mouse Pneumonia Model Using Bioluminescent Bacteria

Pneumonia is one of the major health care problems in developing and industrialized countries and is associated with considerable morbidity and mortality. Despite advances in knowledge of this illness, the availability of intensive care units (ICU), and the use of potent antimicrobial agents and effective vaccines, the mortality rates remain high(1). Streptococcus pneumoniae is the leading pathogen of community-acquired pneumonia (CAP) and one of the most common causes of bacteremia in humans. This pathogen is equipped with an armamentarium of surface-exposed adhesins and virulence factors contributing to pneumonia and invasive pneumococcal disease (IPD). The assessment of the in vivo role of bacterial fitness or virulence factors is of utmost importance to unravel S. pneumoniae pathogenicity mechanisms. Murine models of pneumonia, bacteremia, and meningitis are being used to determine the impact of pneumococcal factors at different stages of the infection. Here we describe a protocol to monitor in real-time pneumococcal dissemination in mice after intranasal or intraperitoneal infections with bioluminescent bacteria. The results show the multiplication and dissemination of pneumococci in the lower respiratory tract and blood, which can be visualized and evaluated using an imaging system and the accompanying analysis software.

TLR4 mediates pneumolysin-induced ATF3 expression through the JNK/p38 pathway in Streptococcus pneumoniae-infected RAW 264.7 cells.

Activating transcription factor-3 (ATF3) acts as a negative regulator of cytokine production during Gram-negative bacterial infection. A recent study reported that ATF3 provides protection from Streptococcus pneumoniae infection by activating cytokines. However, the mechanism by which S. pneumoniae induces ATF3 after infection is still unknown. In this study, we show that ATF3 was upregulated via Toll-like receptor (TLR) pathways in response to S. pneumoniae infection in vitro. Induction was mediated by TLR4 and TLR2, which are in the TLR family. The expression of ATF3 was induced by pneumolysin (PLY), a potent pneumococcal virulence factor, via the TLR4 pathway. Furthermore, ATF3 induction is mediated by p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK). Thus, this study reveals a potential role of PLY in modulating ATF3 expression, which is required for the regulation of immune responses against pneumococcal infection in macrophages.

Contribution of different pneumococcal virulence factors to experimental meningitis in mice

BackgroundPneumococcal meningitis (PM) is a life-threatening disease with a high case-fatality rate and elevated risk for serious neurological sequelae. In this study, we investigated the contribution of three major virulence factors of Streptococcus pneumoniae, the capsule, pneumococcal surface protein A (PspA) and C (PspC), to the pathogenesis of experimental PM.MethodsMice were challenged by the intracranial route with the serotype 4 TIGR4 strain (wt) and three isogenic mutants devoid of PspA, PspC, and the capsule. Survival, bacterial counts, and brain histology were carried out. To study the interaction between S. pneumoniae mutants and microglia, phagocytosis and survival experiments were performed using the BV2 mouse microglial cell line.ResultsVirulence of the PspC mutant was comparable to that of TIGR4. In contrast, survival of animals challenged with the PspA mutant was significantly increased compared with the wt, and the mutant was also impaired at replicating in the brain and blood of infected mice. Brain histology indicated that all strains, except for the unencapsulated mutant, caused PM. Analysis of inflammation and damage in the brain of mice infected with TIGR4 or its unencapsulated mutant demonstrated that the rough strain was unable to induce inflammation and neuronal injury, even at high challenge doses. Results with BV2 cells showed no differences in phagocytic uptake between wt and mutants. In survival assays, however, the PspA mutant showed significantly reduced survival in microglia compared with the wt.ConclusionsPspA contributed to PM pathogenesis possibly by interacting with microglia at early infection stages, while PspC had limited importance in the disease. The rough mutant did not cause brain inflammation, neuronal damage or mouse death, strengthening the key role of the capsule in PM.

Multivalent Choline Dendrimers Increase Phagocytosis of Streptococcus pneumoniae R6 by Microglial Cells

Background: Pneumococcal virulence factors common to all serotypes, such as choline-binding proteins (CBPs), are promising therapeutic targets in pneumococcal infections. We studied the effect of a choline dendrimer with maximized binding affinity/specificity for CBPs on microglia-mediated pneumococcal phagocytosis. Methods: Pneumoccocal cultures were exposed to dendrimers containing 8 choline end groups or amino groups as controls, either from the beginning of bacterial growth or at the late exponential phase. The effect of long/short co-incubation was assessed in terms of bacterial morphological changes and increase in bacterial uptake by primary microglial cultures. Results: Inhibiting CBPs by micromolar concentrations of a choline dendrimer caused the formation of long pneumococcal chains that were readily phagocytosed by microglia. Enhanced phagocytosis was dendrimer dose-dependent. Long bacteria-dendrimer co-incubation (14 h) resulted in a higher bacterial uptake than short co-incubation (2 h; p < 0.001). Conclusions: Multivalent dendrimers containing choline end groups are promising antimicrobial agents for the management of pneumococcal diseases.

Evolution and molecular characterization of macrolide-resistant Streptococcus pneumoniae in Canada between 1998 and 2008

Studies were performed to assess resistance mechanisms, multidrug resistance (MDR), genetic relatedness, serotype distribution, heptavalent pneumococcal conjugate vaccine (PCV7) coverage and pili virulence factors among macrolide-resistant Streptococcus pneumoniae (MRSP) isolated from respiratory samples submitted to hospital laboratories across Canada from 1998 to 2008. Isolates of MRSP (n = 1518) collected by the national surveillance studies CROSS (Canadian Respiratory Organism Susceptibility Study; 1998-2006) and CANWARD (Canadian Ward Surveillance Study; 2007-08) were tested using the CLSI broth microdilution method to establish antimicrobial susceptibilities. PCR was used to detect macrolide resistance genes [mef(A) and erm(B)] and pili virulence factors (type 1 pili and type 2 pili), the Quellung reaction was used to identify serotypes and PFGE was used to determine genetic relatedness. The prevalence of MRSP increased from 8% in 1998 to 22% in 2008 (P = 0.0001). MRSP were 51% mef(A) positive, 36% erm(B) positive, 8% dual mef(A) and erm(B) positive and 5% mef(A) and erm(B) negative. Dual mef(A)- and erm(B)-positive isolates increased in prevalence from 3% in 1998 to 19% in 2008 (P = 0.001). The prevalence of PCV7 serotypes (4, 6B, 9V, 14, 18C, 19F and 23F) decreased from 67% in 1998 to 31% in 2008 (P = 0.0072). The prevalence of serotype 19A, a non-PCV7 serotype, increased by 15% from 1998 to 2008; isolates of serotype 19A were MDR, dual mef(A) and erm(B) positive, genetically related by PFGE and associated with the presence of pili virulence factors. From 1998 to 2008, respiratory isolates of MRSP in Canada increased significantly due primarily to the emergence and spread of serotypes 6A, 19A and other non-PCV7 serotypes.

Synthesis of 4-methylumbelliferyl α-d-mannopyranosyl-(1→6)-β-d-mannopyranoside and development of a coupled fluorescent assay for GH125 exo-α-1,6-mannosidases

Certain bacterial pathogens possess a repertoire of carbohydrate processing enzymes that process host N-linked glycans and many of these enzymes are required for full virulence of harmful human pathogens such as Clostridium perfringens and Streptococcus pneumoniae. One bacterial carbohydrate processing enzyme that has been studied is the pneumococcal virulence factor SpGH125 from S. pneumoniae and its homologue, CpGH125, from C. perfringens. These exo-α-1,6-mannosidases from glycoside hydrolase family 125 show poor activity toward aryl α-mannopyranosides. To circumvent this problem, we describe a convenient synthesis of the fluorogenic disaccharide substrate 4-methylumbelliferone α-d-mannopyranosyl-(1→6)-β-d-mannopyranoside. We show this substrate can be used in a coupled fluorescent assay by using β-mannosidases from either Cellulomonas fimi or Helix pomatia as the coupling enzyme. We find that this disaccharide substrate is processed much more efficiently than aryl α-mannopyranosides by CpGH125, most likely because inclusion of the second mannose residue makes this substrate more like the natural host glycan substrates of this enzyme, which enables it to bind better. Using this sensitive coupled assay, the detailed characterization of these metal-independent exo-α-mannosidases GH125 enzymes should be possible, as should screening chemical libraries for inhibitors of these virulence factors.

Streptococcus pneumoniae ClpP protease induces apoptosis via caspase-independent pathway in human neuroblastoma cells: Cytoplasmic relocalization of p53

Streptococcus pneumoniae causes the most severe form of the bacterial meningitis which is the major cause of bacterial meningitis. Virulence factors produced by S. pneumoniae have been known to contribute significantly to the disease process. ClpP protease (ClpP) which is essential for virulence and survival under stress conditions in S. pneumoniae was examined for the ability to induce apoptosis and the mechanism of the induction of apoptosis in human neuron-like cells, SK-N-SH neuroblastoma cells. ClpP inhibited cell growth and induced apoptosis in SK-N-SH cells. Treatment with ClpP resulted in hypodiploid DNA contents, increased Bax/Bcl-2 ratio and induction of reactive oxygen species (ROS) production. The release of cytochrome c from mitochondria into the cytosol, which is an initiator of the activation of caspase cascades, was not observed in ClpP-treated cells. In addition, pretreatment with Z-Val–Ala–Asp–fluoromethylketone (Z-VAD-fmk), a broad spectrum caspase inhibitor, could not rescue apoptotic cells from ClpP toxicity. Coincidently, caspase-3 and -8 activation and cleavage of PARP were not detected. Moreover, caspase independent apoptosis-inducing factor (AIF) was released from mitochondria and translocated to the nucleus in response to ClpP. We also found that ClpP treatment resulted in the increase of p53 activity and cytoplasmic p53 levels were increased by ClpP, suggesting that functional activation of p53 is intact despite increased cytoplasmic accumulation. Taken together, these data suggest that ClpP contributes to neuronal damage in meningitis and provide further insight into the mechanisms underlying action of pneumococcal virulence factors during bacterial pathogenesis.

Pneumolysin-mediated expression of β-defensin 2 is coordinated by p38 MAP kinase-MKP1 in human airway cells

Antimicrobial peptides act as important innate immune defense mediators against invading microbes such as Streptococcus pneumoniae. Among a number of antimicrobial peptides, β-defensin 2 (BD2) has strong antimicrobial activity against S. pneumoniae. However, little is known about the molecular signaling mechanisms leading to the BD2 expression. Here, we report that BD2 is strongly induced by S. pneumoniae in human airway cells including human middle-ear cells. Among diverse pneumococcal virulence factors, pneumolysin is required for inducing BD2 whose expression is under the control of p38 mitogen-activated protein kinase (MAPK). Pneumolysin also selectively regulates the expression of MAPK phosphatase 1 (MKP1), which inhibits the p38 signaling pathway, thereby leading to upregulation of BD2 to mount an effective defense against S. pneumoniae infection. These results provide novel insights into the molecular mechanisms underlying the coordinative regulation of BD2 expression via p38-MKP1 in the pathogenesis of airway infectious diseases.

CRISPR Interference Can Prevent Natural Transformation and Virulence Acquisition during In Vivo Bacterial Infection

Pathogenic bacterial strains emerge largely due to transfer of virulence and antimicrobial resistance genes between bacteria, a process known as horizontal gene transfer (HGT). Clustered, regularly interspaced, short palindromic repeat (CRISPR) loci of bacteria and archaea encode a sequence-specific defense mechanism against bacteriophages and constitute a programmable barrier to HGT. However, the impact of CRISPRs on the emergence of virulence is unknown. We programmed the human pathogen Streptococcus pneumoniae with CRISPR sequences that target capsule genes, an essential pneumococcal virulence factor, and show that CRISPR interference can prevent transformation of nonencapsulated, avirulent pneumococci into capsulated, virulent strains during infection in mice. Further, at low frequencies bacteria can lose CRISPR function, acquire capsule genes, and mount a successful infection. These results demonstrate that CRISPR interference can prevent the emergence of virulence in vivo and that strong selective pressure for virulence or antibiotic resistance can lead to CRISPR loss in bacterial pathogens.

Pneumococcal sepsis and nasopharyngeal carriage

Streptococcus pneumoniae (the pneumococcus) remains an important cause of invasive disease including bacteraemia. This review highlights recent findings related to pneumococcal bacteraemia, virulence factors, and multiple colonization, including strain competition, biofilm formation, and competence. Countries with no vaccination programmes see vaccine serotypes still prevalent in disease, whereas the emergence of nonvaccine serotypes in nasopharyngeal carriage and invasive disease is seen in countries with conjugate vaccination in place. Co-colonizing strains are being uncovered with more sensitive methods, and may act synergistically or compete with each other for survival. Several factors such as iron uptake, quorum signalling and the luxS gene, involved in colonization and virulence, are discussed. The role of quorum sensing signalling molecules and formation of biofilms are being explored. Epidemiological data suggest that the latest serotype-based conjugate vaccines should provide heightened protection, although serotype replacement is now being seen. Much remains to be elucidated about its biology during multiple colonization, when evolution and adaptation to its host take place. The modes of colonization (biofilm, intracellular or surface adherence to the mucosal epithelium), and whether organisms that cause invasive disease have attenuated ability to colonize the nasopharynx remain to be elucidated.

Heterologous expression of pneumococcal virulence factor PspC on the surface of Lactococcus lactis confers adhesive properties

Lactococcus lactis is a non-pathogenic bacterium that is used in the food industry but is also used as a heterologous host to reveal protein functions of pathogenic bacteria. The adhesin PspC from Streptococcus pneumoniae is a choline-binding protein that is non-covalently anchored to the bacterial cell wall. To assess the exclusive impact of pneumococcal surface protein C (PspC) on the interplay with its host we generated recombinant L. lactis producing a nisin-inducible and covalently anchored variant of PspC on the lactococcal cell surface. A translational fusion of the 5'-end of pspC3.4 with the 3'-end of hic (pspC11.4) was designed to decorate the surface of L. lactis with a chimeric PspC. The PspC3.4 part comprises the first 281 aa residues of PspC3.4, while the Hic sequence consists of the proline-rich and sortase-anchored domain. The results demonstrated that PspC is sufficient for adhesion and subsequent invasion of host epithelial cells expressing the human polymeric Ig receptor (hpIgR). Moreover, invasion via hpIgR was even more pronounced when the chimeric PspC was produced by lactococci compared with pneumococci. This study shows also for the first time that PspC plays no significant role during phagocytosis by macrophages. In contrast, recruitment of Factor H via the PspC chimer has a dramatic effect on phagocytosis of recombinant but not wild-type lactococci, as Factor H interacts specifically with the amino-terminal part of PspC and mediates the contact with phagocytes. Furthermore, L. lactis expressing PspC increased intracellular calcium levels in pIgR-expressing epithelial cells, thus resembling the effect of pneumococci, which induced release of Ca(2+) from intracellular stores via the PspC-pIgR mechanism. In conclusion, expression of the chimeric PspC confers adhesive properties to L. lactis and indicates the potential of L. lactis as a suitable host to study the impact of individual bacterial factors on their capacity to interfere with the host and manipulate eukaryotic epithelial cells.

Inhibition of the Pneumococcal Virulence Factor StrH and Molecular Insights into N-Glycan Recognition and Hydrolysis

The complete degradation of N-linked glycans by the pathogenic bacterium Streptococcus pneumoniae is facilitated by the large multimodular cell wall-attached exo-β-D-N-acetylglucosaminidase StrH. Structural dissection of this virulence factor using X-ray crystallography showed it to have two structurally related glycoside hydrolase family 20 catalytic domains, which displayed the expected specificity for complex N-glycans terminating in N-acetylglucosamine but exhibited unexpected differences in their preferences for the substructures present in these glycans. The structures of the two catalytic domains in complex with unhydrolyzed substrates, including an N-glycan possessing a bisecting N-acetylglucosamine residue, revealed the specific architectural features in the active sites that confer their differential specificities. Inhibitors of StrH are demonstrated to be effective tools in modulating the interaction of StrH with components of the host, such as the innate immune system. Overall, new structural and functional insight into a carbohydrate-mediated component of the pneumococcus-host interaction is provided.

Distribution and clonal relationship of cell surface virulence genes among Streptococcus pneumoniae isolates in Japan

Streptococcus pneumoniae resides on mucosal surfaces in the nasopharynx, where selection for horizontal transfer of antimicrobial resistance genes and virulence factors may provide a survival advantage. We investigated the distribution of genes for pneumococcal cell surface proteins and their correlations with multilocus sequence typing (MLST), Pneumococcal Molecular Epidemiology Network (PMEN) clones and antimicrobial resistance, to identify pneumococcal virulence factors predicting prevalent clones from 156 pneumococcal isolates recovered from adult patients with community-acquired pneumonia in Japan. Pneumococcal eno, pavA, piuA, cbpA and cbpG were present in all isolates, and hyl and piaA were distributed among the clinical isolates. In contrast, pneumococcal rlrA, pclA, psrP, nanC and pspA family 1-type genes were variably distributed and significantly associated with MLST (Wallace coefficients (W) were over 84%). Serotype was a weaker predictor of sequence type (W, 0.75) than vice versa (W, 0.97). A multiple logistic regression analysis adjusted to the presence of virulence genes, pspA family 1 genes and carriage serotypes revealed that pclA and rlrA correlated with PMEN clones and antimicrobial resistance, and are likely to contribute to the selection of prevalent clones.

Inhibition of Competence Development, Horizontal Gene Transfer and Virulence in Streptococcus pneumoniae by a Modified Competence Stimulating Peptide

Competence stimulating peptide (CSP) is a 17-amino acid peptide pheromone secreted by Streptococcus pneumoniae. Upon binding of CSP to its membrane-associated receptor kinase ComD, a cascade of signaling events is initiated, leading to activation of the competence regulon by the response regulator ComE. Genes encoding proteins that are involved in DNA uptake and transformation, as well as virulence, are upregulated. Previous studies have shown that disruption of key components in the competence regulon inhibits DNA transformation and attenuates virulence. Thus, synthetic analogues that competitively inhibit CSPs may serve as attractive drugs to control pneumococcal infection and to reduce horizontal gene transfer during infection. We performed amino acid substitutions on conserved amino acid residues of CSP1 in an effort to disable DNA transformation and to attenuate the virulence of S. pneumoniae. One of the mutated peptides, CSP1-E1A, inhibited development of competence in DNA transformation by outcompeting CSP1 in time and concentration-dependent manners. CSP1-E1A reduced the expression of pneumococcal virulence factors choline binding protein D (CbpD) and autolysin A (LytA) in vitro, and significantly reduced mouse mortality after lung infection. Furthermore, CSP1-E1A attenuated the acquisition of an antibiotic resistance gene and a capsule gene in vivo. Finally, we demonstrated that the strategy of using a peptide inhibitor is applicable to other CSP subtype, including CSP2. CSP1-E1A and CSP2-E1A were able to cross inhibit the induction of competence and DNA transformation in pneumococcal strains with incompatible ComD subtypes. These results demonstrate the applicability of generating competitive analogues of CSPs as drugs to control horizontal transfer of antibiotic resistance and virulence genes, and to attenuate virulence during infection by S. pneumoniae.

Factors affecting the development of systemic inflammatory response syndrome in pneumococcal infections

Streptococcus pneumoniae continues to be responsible for significant mortality and morbidity worldwide. A better understanding of the inflammatory response generated by the interaction of this microorganism with the host and antimicrobial therapy will improve the management of patients with pneumococcal infection. On the side of the microorganism, recent studies have identified virulence factors such as capsular polysaccharides, surface protein, pili and pneumolysin, among others, that are able to trigger a complex inflammatory network. A misbalance in this network will precipitate a specific response that generates the systemic inflammatory response syndrome. Some of these virulence factors could be used as antigens for the production of vaccines with a broader spectrum than the currently used ones. On the host side, many single-nucleotide polymorphisms in genes controlling the immune response have been associated with specific clinical presentations. Finally, some antimicrobials or adjunctive therapies have recently been evaluated as inmunomodulatory agents. Systemic inflammatory response syndrome is the result of an anomalous activation of the inflammatory network triggered by S. pneumoniae. Pneumococcal virulence factors, host comorbidities, the genetic background and the concomitant activity of antimicrobials and adjuvant therapies modulate the magnitude of this response.