scholarly journals The Capsular Serotype of Streptococcus pneumoniae Is More Important than the Genetic Background for Resistance to Complement

2010 ◽  
Vol 78 (12) ◽  
pp. 5262-5270 ◽  
Author(s):  
Merit Melin ◽  
Krzysztof Trzciński ◽  
Seppo Meri ◽  
Helena Käyhty ◽  
Merja Väkeväinen
Keyword(s):  
Streptococcus Pneumoniae ◽  
Invasive Disease ◽  
Relative Effect ◽  
Clinical Isolates ◽  
Complement C3 ◽  
Bacterial Surface ◽  
Complement Resistance ◽  
Opsonophagocytic Killing ◽  
Complement Deposition ◽  
Phagocytic Killing

ABSTRACT The polysaccharide capsule of Streptococcus pneumoniae inhibits phagocytic killing by innate immune mechanisms. Certain serotypes are associated with invasive disease while others with a nasopharyngeal carriage. The invasiveness of serotypes may partly be explained by ability to resist deposition of complement (C3) on the bacterial surface and consequent opsonophagocytic killing. In our previous studies, we observed that clinical isolates of serotypes 1 and 5, which are rarely detected in asymptomatic carriage, were resistant to complement deposition and opsonophagocytosis, whereas serotypes 6B and 23F, both common in carriage, were more sensitive to deposition of C3 and opsonophagocytic killing. However, presence of significant variation in C3 deposition between isolates of the same serotype indicated that factors other than the capsule also affect complement resistance. To distinguish the relative effect of the capsular serotype and other virulence factors on C3 deposition, we compared capsule-switched mutants prepared in genetic backgrounds of pneumococcal strains TIGR4, 603, and 618. Clinical isolates which had the same multilocus sequence type but expressed different serotypes were also compared. We found that the serotype had a significant impact on complement resistance and that the more resistant the strain was to complement, the higher was the concentration of polysaccharide-specific antibodies required for opsonophagocytic killing. Comparison of strains expressing the same capsular polysaccharides in the different genetic backgrounds and various capsular mutants of the same strain suggests that while the genotype affects complement resistance, the serotype is the most important determinant. Differences between serotypes were more significant than the differences between strains.

scholarly journals Serotype-Related Variation in Susceptibility to Complement Deposition and Opsonophagocytosis among Clinical Isolates of Streptococcus pneumoniae

2010 ◽  
Vol 78 (12) ◽  
pp. 5252-5261 ◽  
Author(s):  
Merit Melin ◽  
Krzysztof Trzciński ◽  
Martin Antonio ◽  
Seppo Meri ◽  
Richard Adegbola ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Severe Disease ◽  
Invasive Disease ◽  
Clinical Isolates ◽  
Complement C3 ◽  
Complement Resistance ◽  
Common Causes ◽  
Serotype 1 ◽  
Opsonophagocytic Killing ◽  
Healthy Carriers

ABSTRACT The polysaccharide capsule is a major virulence factor of Streptococcus pneumoniae; it affects complement resistance and shields the bacterium from phagocytes. Certain capsular serotypes appear to be better able to cause invasive disease than others. Serotypes 1 and 5 are common causes of invasive disease but are rarely isolated from healthy carriers, whereas serotypes 6B and 23F are more frequently isolated from carriage than invasive disease. We have recently shown that serotypes 6B and 19F differ in resistance to complement C3 deposition and opsonophagocytic killing. In this study we assessed the complement resistance and susceptibility to opsonophagocytosis of several other serotypes targeted by the pneumococcal conjugate vaccines. Clinical isolates of serotypes 1, 4, 5, 14, 18C, and 23F were tested along reference strains of corresponding capsular types. The concentration of anticapsular antibodies required for opsonophagocytic killing correlated inversely with C3 deposition on the serotype. Serotype 1 was the most resistant of the clinical isolates to C3 deposition and, along with serotypes 5 and 19F, required the highest concentration of capsule antibodies for opsonophagocytic killing, whereas serotype 23F was the most sensitive to opsonophagocytosis. Sensitivity to C3 deposition and opsonophagocytosis was associated with serotype-specific mortality of invasive pneumococcal disease, suggesting that the primary pathogens, such as serotypes 1 and 5, are more resistant to complement and require a higher concentration of capsule antibodies for opsonophagocytic killing than the opportunistic serotypes such as 6B and 23F, which are associated with a more severe disease outcome.

scholarly journals Three Surface Exoglycosidases from Streptococcus pneumoniae, NanA, BgaA, and StrH, Promote Resistance to Opsonophagocytic Killing by Human Neutrophils

2010 ◽  
Vol 78 (5) ◽  
pp. 2108-2116 ◽  
Author(s):  
Ankur B. Dalia ◽  
Alistair J. Standish ◽  
Jeffrey N. Weiser
Keyword(s):  
Streptococcus Pneumoniae ◽  
Human Serum ◽  
Ex Vivo ◽  
Human Neutrophils ◽  
Human Pathogen ◽  
Complement Component C3 ◽  
Genomic Approach ◽  
Opsonophagocytic Killing ◽  
Complement Deposition ◽  
Phagocytic Killing

ABSTRACT Streptococcus pneumoniae (the pneumococcus) is a major human pathogen and a leading cause of inflammatory infections such as pneumonia and otitis media. An important mechanism for host defense against S. pneumoniae is opsonophagocytic killing by neutrophils. To persist in the human host, the pneumococcus has developed strategies to evade opsonization and subsequent neutrophil-mediated killing. Utilizing a genomic approach, we identified NanA, the major pneumococcal neuraminidase, as a factor important for resistance to opsonophagocytic killing in ex vivo killing assays using human neutrophils. The effect of NanA was shown using both type 4 (TIGR4) and type 6A clinical isolates. NanA promotes this resistance by acting in conjunction with two other surface-associated exoglycosidases, BgaA, a β-galactosidase, and StrH, an N-acetylglucosaminidase. Experiments using human serum showed that these exoglycosidases reduced deposition of complement component C3 on the pneumococcal surface, providing a mechanism for this resistance. Additionally, we have shown that antibodies in human serum do not contribute to this phenotype. These results demonstrate that deglycosylation of a human serum glycoconjugate(s) by the combined effects of NanA, BgaA, and StrH, is important for resistance to complement deposition and subsequent phagocytic killing of S. pneumoniae.

scholarly journals NontypeableHaemophilus influenzaeInvasive Blood Isolates Are Mainly Phosphorylcholine Negative and Show Decreased Complement-Mediated Killing That Is Associated with Lower Binding of IgM and CRP in Comparison to Colonizing Isolates from the Oropharynx

2018 ◽  
Vol 87 (2) ◽  
Author(s):  
Jeroen D. Langereis ◽  
Amelieke J. H. Cremers ◽  
Marloes Vissers ◽  
Josine van Beek ◽  
Jacques F. Meis ◽  
...  
Keyword(s):  
Human Serum ◽  
Invasive Disease ◽  
Complement C3 ◽  
Classical Pathway ◽  
Nasopharyngeal Colonization ◽  
Content Type ◽  
Specific Antibodies ◽  
Bacterial Surface ◽  
Reactive Protein ◽  
Serum Killing

ABSTRACTNontypeableHaemophilus influenzae(NTHi) bacteria express various molecules that contribute to their virulence. The presence of phosphocholine (PCho) on NTHi lipooligosaccharide increases adhesion to epithelial cells and is an advantage for the bacterium, enabling nasopharyngeal colonization, as measured in humans and animal models. However, when PCho is expressed on the lipooligosaccharide, it is also recognized by the acute-phase protein C-reactive protein (CRP) and PCho-specific antibodies, both of which are potent initiators of the classical pathway of complement activation. In this study, we show that blood isolates, which are exposed to CRP and PCho-specific antibodies in the bloodstream, have a higher survival in serum than oropharyngeal isolates, which was associated with a decreased presence of PCho. PCholowstrains showed decreased IgM, CRP, and complement C3 deposition, which was associated with increased survival in human serum. Consistent with the case for the PCholowstrains, removal of PCho expression bylicAgene deletion decreased IgM, CRP, and complement C3 deposition, which increased survival in human serum. Complement-mediated killing of PChohighstrains was mainly dependent on binding of IgM to the bacterial surface. These data support the hypothesis that a PCholowphenotype was selected in blood during invasive disease, which increased resistance to serum killing, mainly due to lowered IgM and CRP binding to the bacterial surface.

scholarly journals Streptococcus pneumoniae Resistance to Complement-Mediated Immunity Is Dependent on the Capsular Serotype

2009 ◽  
Vol 78 (2) ◽  
pp. 716-725 ◽  
Author(s):  
Catherine Hyams ◽  
Jose Yuste ◽  
Katie Bax ◽  
Emilie Camberlein ◽  
Jeffrey N. Weiser ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Streptococcus Pneumoniae ◽  
Mouse Model ◽  
Immunoglobulin G ◽  
Invasive Disease ◽  
Genetic Differences ◽  
Host Immunity ◽  
Clinical Isolates ◽  
Mutant Strains ◽  
Phase Variants

ABSTRACT Streptococcus pneumoniae strains vary considerably in the ability to cause invasive disease in humans, and this is partially associated with the capsular serotype. The S. pneumoniae capsule inhibits complement- and phagocyte-mediated immunity, and differences between serotypes in these effects on host immunity may cause some of the variation in virulence between strains. However, the considerable genetic differences between S. pneumoniae strains independent of the capsular serotype prevent an unambiguous assessment of the effects of the capsular serotype on immunity using clinical isolates. We have therefore used capsular serotype-switched TIGR4 mutant strains to investigate the effects of the capsular serotype on S. pneumoniae interactions with complement. Flow cytometry assays demonstrated large differences in C3b/iC3b deposition on opaque-phase variants of TIGR4(−)+4, +6A, +7F, and +23F strains even though the thicknesses of the capsule layers were similar. There was increased C3b/iC3b deposition on TIGR4(−)+6A and +23F strains compared to +7F and +4 strains, and these differences persisted even in serum depleted of immunoglobulin G. Neutrophil phagocytosis of the TIGR4(−)+6A and +23F strains was also increased, but only in the presence of complement, showing that the effects of the capsular serotype on C3b/iC3b deposition are functionally significant. In addition, the virulence of the TIGR4(−)+6A and +23F strains was reduced in a mouse model of sepsis. These data demonstrate that resistance to complement-mediated immunity can vary with the capsular serotype independently of antibody and of other genetic differences between strains. This might be one mechanism by which the capsular serotype can affect the relative invasiveness of different S. pneumoniae strains.

scholarly journals Transformation of nonencapsulated Streptococcus pneumoniae during systemic infection

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Jessica L. Bradshaw ◽  
Iftekhar M. Rafiqullah ◽  
D. Ashley Robinson ◽  
Larry S. McDaniel
Keyword(s):  
Streptococcus Pneumoniae ◽  
Systemic Infection ◽  
Dna Uptake ◽  
Pathogenic Potential ◽  
Bacterial Surface ◽  
Capsule Production ◽  
Virulent Strains ◽  
Capsule Locus ◽  
Ear Infections ◽  
Complement Deposition

Abstract Streptococcus pneumoniae (pneumococcus) is a principal cause of bacterial middle ear infections, pneumonia, and meningitis. Capsule-targeted pneumococcal vaccines have likely contributed to increased carriage of nonencapsulated S. pneumoniae (NESp). Some NESp lineages are associated with highly efficient DNA uptake and transformation frequencies. However, NESp strains lack capsule that may increase disease severity. We tested the hypothesis that NESp could acquire capsule during systemic infection and transform into more virulent pneumococci. We reveal that NESp strains MNZ67 and MNZ41 are highly transformable and resistant to multiple antibiotics. Natural transformation of NESp when co-administered with heat-killed encapsulated strain WU2 in a murine model of systemic infection resulted in encapsulation of NESp and increased virulence during bacteremia. Functional capsule production increased the pathogenic potential of MNZ67 by significantly decreasing complement deposition on the bacterial surface. However, capsule acquisition did not further decrease complement deposition on the relatively highly pathogenic strain MNZ41. Whole genome sequencing of select transformants demonstrated that recombination of up to 56.7 kbp length occurred at the capsule locus, along with additional recombination occurring at distal sites harboring virulence-associated genes. These findings indicate NESp can compensate for lack of capsule production and rapidly evolve into more virulent strains.

scholarly journals Streptococcus pneumoniae Capsular Serotype 19F Is More Resistant to C3 Deposition and Less Sensitive to Opsonophagocytosis than Serotype 6B

2008 ◽  
Vol 77 (2) ◽  
pp. 676-684 ◽  
Author(s):  
Merit Melin ◽  
Hanna Jarva ◽  
Lotta Siira ◽  
Seppo Meri ◽  
Helena Käyhty ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Conjugate Vaccine ◽  
Middle Ear ◽  
Complement Activation ◽  
Capsular Polysaccharide ◽  
Immune Defense ◽  
Pneumococcal Serotypes ◽  
Vaccine Trials ◽  
Opsonophagocytic Killing ◽  
Complement Deposition

ABSTRACT The polysaccharide capsule is a major virulence mechanism of Streptococcus pneumoniae, shielding the bacterium from phagocytes. Capsule types may differ in their abilities to resist immune defense. Antibody-mediated complement activation and opsonophagocytosis are crucial in protection against pneumococcus. Conjugate vaccine trials suggest imperfect protection against 19F. We have previously shown that significantly more anti-19F than anti-6B antibody is needed for killing in the opsonophagocytic assay (OPA). In this study, we explored whether the amount of C3 deposited on serotype 6B and 19F pneumococcal strains reflects their sensitivity to opsonophagocytosis. We compared clinical 6B and 19F nasopharyngeal, middle ear, and blood isolates as well as reference OPA strains (n = 16) for their sensitivity to opsonophagocytosis and C3 deposition. Sixfold anticapsular antibody concentrations were required for 50% opsonophagocytic killing of 19F compared to that of 6B strains. Serotype 19F was more resistant to C3 deposition than 6B. Complement deposition and opsonophagocytosis were dependent on the concentration of anticapsular antibodies. Differences between pneumococcal serotypes in antibody-mediated protection may partly be explained by the abilities of the capsules to resist complement deposition. These findings support previous studies suggesting that higher antibody concentrations to the capsular polysaccharide are needed for protection against disease caused by serotype 19F than that caused by 6B.

scholarly journals Zinc metalloproteinase genes in clinical isolates of Streptococcus pneumoniae: association of the full array with a clonal cluster comprising serotypes 8 and 11A

Microbiology ◽  
2006 ◽  
Vol 152 (2) ◽  
pp. 313-321 ◽  
Author(s):  
Romina Camilli ◽  
Elena Pettini ◽  
Maria Del Grosso ◽  
Gianni Pozzi ◽  
Annalisa Pantosti ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Matrix Metalloproteinase ◽  
Molecular Typing ◽  
Invasive Disease ◽  
Matrix Metalloproteinase 9 ◽  
Hinge Region ◽  
Clinical Isolates ◽  
Genes Encoding ◽  
Metalloproteinase 9 ◽  
Iga Protease

Pneumococci display large zinc metalloproteinases on the surface, including the IgA protease, which cleaves human IgA1 in the hinge region, the ZmpC proteinase, which cleaves human matrix metalloproteinase 9 (MMP-9), and two other proteinases, ZmpB and ZmpD, whose substrates have not yet been identified. Surface metalloproteinases are antigenic and have been linked to virulence. The genes encoding these proteinases reside in three distinct loci: two loci specific for zmpB and zmpC, and a third, the iga locus, containing iga and zmpD. Data obtained by this and other groups have shown that pneumococcal metalloproteinase genes are transcribed and yield mature and enzymatically active proteins. Since the presence of the four proteinase genes is variable in the pneumococcal strains whose genomes have been sequenced, the presence of these genes in a collection of 218 pneumococcal isolates, mostly from invasive disease, was investigated. The data showed that zmpB and iga were present in all the isolates examined, while zmpC and zmpD were present in a variable proportion of the isolates (in 18 and 49 %, respectively). Interestingly, isolates carrying both zmpC and zmpD were found to belong mainly to two serotypes (sts), 8 and 11A. By molecular typing, st 8 and st 11A isolates appeared to belong to the same clonal cluster. The presence of these two additional metalloproteinases could contribute to the fitness of particular pneumococcal clones.

scholarly journals Role of Complement in Host Defense against Pneumococcal Otitis Media

2009 ◽  
Vol 77 (3) ◽  
pp. 1121-1127 ◽  
Author(s):  
Vishakha Sabharwal ◽  
Sanjay Ram ◽  
Marisol Figueira ◽  
In Ho Park ◽  
Stephen I. Pelton
Keyword(s):  
Animal Model ◽  
Otitis Media ◽  
Critical Role ◽  
Invasive Disease ◽  
Complement C3 ◽  
Low Level ◽  
Fluorescence Binding ◽  
High Level ◽  
Complement Deposition

ABSTRACT Strategies to limit complement deposition on Streptococcus pneumoniae are established as virulence features for invasive disease, but their role in respiratory tract infection requires further analysis. We evaluated complement C3 protein deposition on discordant S. pneumoniae isolates of the same serotype (6A) and their capacity to cause nasopharyngeal (NP) colonization and experimental otitis media (EOM) in an animal model. We compared C3 binding to five 6A isolates from asymptomatic NP carriers with five 6A strains that caused invasive disease, and we observed less C3 (∼10-fold less fluorescence) binding to invasive isolates. We selected two high-level C3-binding carriage and two low-level C3-binding invasive 6A isolates for further study. In the EOM model, 11/12 (92%) ears challenged with a low-level C3-binding 6A strain became infected. Only 2/8 (25%) ears challenged with the discordant high-level C3-binding 6A isolate developed disease (P = 0.005). Results with the second discordant 6A isolate pair were comparable. Cobra venom factor (CoVF) treatment, which depletes C3 and consumes complement, restored virulence of the high-level C3-binding strain; 8/8 (100%) ears in CoVF-treated animals developed EOM compared to only 25% of ears in naïve animals (P = 0.007). These studies demonstrate the critical role for complement evasion in pneumococcal EOM. Colonization with carriage isolates that bound high levels of C3 caused EOM in fewer animals compared to low-level C3-binding invasive strains. Thus, limiting C3 deposition on the surface of S. pneumoniae correlates with increased incidence of EOM following NP colonization and barotrauma in the animal model.

scholarly journals Streptococcus pneumoniaePspC Subgroup Prevalence in Invasive Disease and Differences in Contribution to Complement Evasion

2018 ◽  
Vol 86 (4) ◽  
Author(s):  
Erika van der Maten ◽  
Bryan van den Broek ◽  
Marien I. de Jonge ◽  
Kim J. W. Rensen ◽  
Marc J. Eleveld ◽  
...  
Keyword(s):  
Surface Protein ◽  
Invasive Disease ◽  
Factor H ◽  
Complement Factor ◽  
Content Type ◽  
Complement Resistance ◽  
Functional Differences ◽  
Subgroup Ii ◽  
Virulence Protein ◽  
Complement Deposition

ABSTRACTThe pneumococcal capsular serotype is an important determinant of complement resistance and invasive disease potential, but other virulence factors have also been found to contribute. Pneumococcal surface protein C (PspC), a highly variable virulence protein that binds complement factor H to evade C3 opsonization, is divided into two subgroups: choline-bound subgroup I and LPxTG-anchored subgroup II. The prevalence of different PspC subgroups in invasive pneumococcal disease (IPD) and functional differences in complement evasion are unknown. The prevalence of PspC subgroups in IPD isolates was determined in a collection of 349 sequenced strains ofStreptococcus pneumoniaeisolated from adult patients.pspCdeletion mutants and isogenicpspCswitch mutants were constructed to study differences in factor H binding and complement evasion in relation to capsule thickness. Subgroup IpspCwas far more prevalent in IPD isolates than subgroup IIpspC. The presence of capsule was associated with a greater ability of bound factor H to reduce complement opsonization. Pneumococcal subgroup I PspC bound significantly more factor H and showed more effective complement evasion than subgroup II PspC in isogenic encapsulated pneumococci. We conclude that variation in the PspC subgroups, independent of capsule serotypes, affects pneumococcal factor H binding and its ability to evade complement deposition.

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