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Pathogenesis

Capsule Type and Amount Affect Shedding and Transmission of Streptococcus pneumoniae.

MBio. 2017 Aug 22;8(4). pii: e00989-17. doi: 10.1128/mBio.00989-17.

Capsule Type and Amount Affect Shedding and Transmission of Streptococcus pneumoniae.

Zafar MA1, Hamaguchi S1, Zangari T1, Cammer M2, Weiser JN3.

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Abstract

The capsular polysaccharide (CPS) of Streptococcus pneumoniae is characterized by its diversity, as it has over 95 known serotypes, and the variation in its thickness as it surrounds an organism. While within-host effects of CPS have been studied in detail, there is no information about its contribution to host-to-host transmission. In this study, we used an infant mouse model of intralitter transmission, together with isogenic capsule switch and cps promoter switch constructs, to explore the effects of CPS type and amount. The determining factor in the transmission rate in this model is the number of pneumococci shed in nasal secretions by colonized hosts. Two of seven capsule switch constructs showed reduced shedding. These constructs were unimpaired in colonization and expressed capsules similar in size to those of the wild-type strain. A cps promoter switch mutant expressing ~50% of wild-type amounts of CPS also displayed reduced shedding without a defect in colonization. Since shedding from the mucosal surface may require escape from mucus entrapment, a mucin-binding assay was used to compare capsule switch and cps promoter switch mutants. The CPS type or amount constructs that shed poorly were bound more robustly by immobilized mucin. These capsule switch and cps promoter switch constructs with increased mucin-binding affinity and reduced shedding also had lower rates of pup-to-pup transmission. Our results demonstrate that CPS type and amount affect transmission dynamics and may contribute to the marked differences in prevalence among pneumococcal types.IMPORTANCEStreptococcus pneumoniae, a leading cause of morbidity and mortality, is readily transmitted, especially among young children. Its structurally and antigenically diverse capsular polysaccharide is the target of currently licensed pneumococcal vaccines. Epidemiology studies show that only a subset of the >95 distinct serotypes are prevalent in the human population, suggesting that certain capsular polysaccharide types might be more likely to be transmitted within the community. Herein, we used an infant mouse model to show that both capsule type and amount are important determinants in the spread of pneumococci from host to host. Transmission rates correlate with those capsule types that are better at escaping mucus entrapment, a key step in exiting the host upper respiratory tract. Hence, our study provides a better mechanistic understanding of why certain pneumococcal serotypes are more common in the human population.

Copyright © 2017 Zafar et al.

KEYWORDS:

Streptococcus pneumoniae; bacterial shedding; capsular polysaccharide; host-pathogen interactions; influenza A; pneumococcus; transmission

PMID: 28830943 DOI: 10.1128/mBio.00989-17

Acanthamoeba castellanii interactions with Streptococcus pneumoniae and Streptococcus pyogenes.

Exp Parasitol. 2017 Aug 17. pii: S0014-4894(17)30278-3. doi: 10.1016/j.exppara.2017.08.005. [Epub ahead of print]

Acanthamoeba castellanii interactions with Streptococcus pneumoniae and Streptococcus pyogenes.

Siddiqui R1, Yee Ong TY1, Jung SY2, Khan NA3.

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Abstract

Among the genus Streptococcus, S. pyogenes and S. pneumoniae are the major causes of pharyngitis, impetigo, pneumonia and meningitis in humans. Streptococcus spp. are facultative anaerobes that are nutritionally fastidious, yet survive in the environment and target the predisposed population. Antibacterial disinfectants have been partially effective only, indicating the need for novel preventative measures and to understand mechanisms of bacterial resistance. Acanthamoeba is a free-living protist that is known to harbour microbial pathogens, provide shelter, and assist in their transmission to susceptible population. The overall aim of this study was to determine whether S. pyogenes and S. pneumoniae can interact with A. castellanii by associating, invading, and surviving inside trophozoites and cysts. It was observed that both S. pyogenes and S. pneumoniae were able to associate as well as invade and/or taken up by the phagocytic A. castellanii trophozoite. Notably, S. pyogenes and S. pneumoniae survived encystation process, avoided phagocytosis, multiplied, and exhibited higher recovery from the mature cysts, compared with the trophozoite stage (approximately 2 bacteria per amoebae ratio for cyst stage versus 0.02 bacteria per amoeba ration for trophozoite stage). As Acanthamoeba cysts are resilient and can disperse through the air, A. castellanii can act as a vector in providing shelter, facilitating growth and possibly genetic exchanges. In addition, these interactions may contribute to S. pyogenes and S. pneumoniae survival in harsh environments, and transmission to susceptible population and possibly affecting their virulence. Future studies will determine the molecular mechanisms associated with Acanthamoeba interactions with Streptococcus and the evolution of pathogenic bacteria and in turn expedite discovery of novel therapeutic and/or preventative measures.

Copyright © 2017. Published by Elsevier Inc.

KEYWORDS:

Acanthamoeba; Association; Encystation; Invasion; Streptococcus; Survival

PMID: 28823705 DOI: 10.1016/j.exppara.2017.08.005

Cytosolic phospholipase A2α promotes pulmonary inflammation and systemic disease during Streptococcus pneumoniae infection.

Infect Immun. 2017 Aug 14. pii: IAI.00280-17. doi: 10.1128/IAI.00280-17. [Epub ahead of print]

Cytosolic phospholipase A2α promotes pulmonary inflammation and systemic disease during Streptococcus pneumoniae infection.

Bhowmick R1, Clark S2, Bonventre JV3, Leong JM4, McCormick BA5.

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Abstract

Pulmonary infection by Streptococcus pneumoniae is characterized by a robust alveolar infiltration of neutrophils (polymorphonuclear cells or PMNs) that can promote systemic spread of the infection if not resolved. We previously showed that 12-lipoxygenase (12-LOX), which is required to generate the PMN chemoattractant hepoxilin A3 (HXA3) from arachidonic acid (AA), promotes acute pulmonary inflammation and systemic infection after lung challenge with S. pneumoniae As phospholipase A2 (PLA2) promotes the release of AA, we investigated the role of PLA2 in local and systemic disease during S. pneumoniae infection. The Group IVA cytosolic isoform of PLA2 (cPLA2α) was activated upon S. pneumoniae infection of cultured lung epithelial cells and was critical for AA release from membrane phospholipids. Pharmacological inhibition of this enzyme blocked S. pneumoniae-induced PMN transepithelial migration in vitro Genetic ablation of the cPLA2 isoform cPLA2α dramatically reduced lung inflammation in mice upon high-dose pulmonary challenge with S. pneumoniae The cPLA2α-deficient mice also suffered no bacteremia and survived a pulmonary challenge that was lethal to wild type mice. Our data suggest that cPLA2α plays a crucial role in eliciting pulmonary inflammation during pneumococcal infection and is required for lethal systemic infection following S. pneumoniaelung challenge.

Copyright © 2017 American Society for Microbiology.

PMID: 28808157 DOI: 10.1128/IAI.00280-17

Streptococcus pneumoniae and lytic antibiotic therapy: are we adding insult to injury during invasive pneumococcal disease and sepsis?

J Med Microbiol. 2017 Aug 10. doi: 10.1099/jmm.0.000545. [Epub ahead of print]

Streptococcus pneumoniae and lytic antibiotic therapy: are we adding insult to injury during invasive pneumococcal disease and sepsis?

Brown LA1, Mitchell AM2, Mitchell TJ2.

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Abstract

Streptococcus pneumoniae (S. pneumoniae), otherwise known as 'the pneumococcus', is a fascinating microbe that continues to pose a significant problem to public health. Currently there are no specific National Institute for Clinical Excellence (NICE) or British Thoracic Society (BTS) clinical guidelines referring to the treatment of invasive pneumococcal infection. NICE clinical guidelines suggest the use of lytic β-lactam antibiotic regimens for the management of community-acquired pneumonia and bacterial meningitis; infections for which S. pneumoniae is a likely causative organism. Lytic antibiotics have been shown to increase the release of pneumolysin (the highly inflammatory and damaging toxin of the pneumococcus), thus theoretically increasing host damage, which may lead to a decline of clinical outcomes in vulnerable patients. In light of this information, should the use of non-lytic antibiotics, such as quinolones, rifamycins and macrolides, be considered for the treatment of invasive pneumococcal disease?

PMID: 28792379 DOI: 10.1099/jmm.0.000545

Brain-derived neurotrophic factor reduces inflammation and hippocampal apoptosis in experimental Streptococcus pneumoniae meningitis.

J Neuroinflammation. 2017 Aug 4;14(1):156. doi: 10.1186/s12974-017-0930-6.

Brain-derived neurotrophic factor reduces inflammation and hippocampal apoptosis in experimental Streptococcus pneumoniae meningitis.

Xu D1, Lian D1, Wu J1, Liu Y2, Zhu M3, Sun J3, He D1, Li L4.

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Abstract

BACKGROUND:

Streptococcus pneumoniae meningitis is a serious inflammatory disease of the central nervous system (CNS) and is associated with high morbidity and mortality rates. The inflammatory processes initiated by recognition of bacterial components contribute to apoptosis in the hippocampal dentate gyrus. Brain-derived neurotrophic factor (BDNF) has long been recommended for the treatment of CNS diseases due to its powerful neuro-survival properties, as well as its recently reported anti-inflammatory and anti-apoptotic effects in vitro and in vivo.

METHODS:

In this study, we investigated the effects of BDNF-related signaling on the inflammatory response and hippocampal apoptosis in experimental models of pneumococcal meningitis. Pretreatment with exogenous BDNF or the tropomyosin-receptor kinase B (TrkB) inhibitor k252a was performed to assess the activation or inhibition of the BDNF/TrkB-signaling axis prior to intracisternal infection with live S. pneumoniae. At 24 h post-infection, rats were assessed for clinical severity and sacrificed to harvest the brains. Paraffin-embedded brain sections underwent hematoxylin and eosin staining to evaluate pathological severity, and cytokine and chemokine levels in the hippocampus and cortex were evaluated by enzyme-linked immunosorbent assay. Additionally, apoptotic neurons were detected in the hippocampal dentate gyrus by terminal deoxynucleotidyl transferase dUTP-nick-end labeling, key molecules associated with the related signaling pathway were analyzed by real-time polymerase chain reaction and western blot, and the DNA-binding activity of nuclear factor kappa B (NF-κB) was measured by electrophoretic mobility shift assay.

RESULTS:

Rats administered BDNF exhibited reduced clinical impairment, pathological severity, and hippocampal apoptosis. Furthermore, BDNF pretreatment suppressed the expression of inflammatory factors, including tumor necrosis factor α, interleukin (IL)-1β, and IL-6, and increased the expression of the anti-inflammatory factor IL-10. Moreover, BDNF pretreatment increased TrkB expression, activated downstream phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling, and inhibited the myeloid differentiation primary response gene 88 (MyD88)/NF-κB-signaling pathway.

CONCLUSIONS:

These data suggested that BDNF administration exerted anti-inflammatory and anti-apoptotic effects on an experimental pneumococcal meningitis model via modulation of MyD88/NF-κB- and PI3K/AKT-signaling pathways. Our results indicated that treatment with exogenous BDNF might constitute a potential therapeutic strategy for the treatment of bacterial meningitis.

KEYWORDS:

Brain-derived neurotrophic factor; Hippocampal apoptosis; Neuroinflammation; Streptococcus pneumoniae meningitis

PMID: 28778220 PMCID: PMC5545027 DOI: 10.1186/s12974-017-0930-6

Streptococcus pneumoniae colonization is required to alter the nasal microbiota in cigarette smoke-exposed mice.

Infect Immun. 2017 Jul 31. pii: IAI.00434-17. doi: 10.1128/IAI.00434-17. [Epub ahead of print]

Streptococcus pneumoniae colonization is required to alter the nasal microbiota in cigarette smoke-exposed mice.

Shen P1, Whelan FJ2,3, Schenck LP2,3, McGrath JJC1, Vanderstocken G4, Bowdish DME3,4, Surette MG2,3,5,6, Stämpfli MR7,8.

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Abstract

Smokers have nasal microbiota dysbiosis, with an increased frequency of colonizing bacterial pathogens. It is possible that cigarette smoke increases pathogen acquisition by perturbing the microbiota and decreasing colonization resistance. However, it is difficult to disentangle microbiota dysbiosis due to cigarette smoke exposure from microbiota changes caused by increased pathogen acquisition in human smokers. Utilizing an experimental mouse model, we investigated the impact of cigarette smoke on the nasal microbiota in the absence and presence of nasal pneumococcal colonization. We observed that cigarette smoke exposure alone did not alter nasal microbiota composition. Microbiota composition was also unchanged at 12 hours following low dose nasal pneumococcal inoculation, suggesting the ability of the microbiota to resist initial nasal pneumococcal acquisition was not impaired in smoke-exposed mice. However, nasal microbiota dysbiosis occurred as a consequence of established high dose nasal pneumococcal colonization at day 3 in smoke-exposed mice. Similar to clinical reports in human smokers, we observed an enrichment of potentially pathogenic bacterial genera such as Fusobacterium, Gemella, and Neisseria Our findings suggest that cigarette smoke exposure predisposes to pneumococcal colonization independent of changes to the nasal microbiota, and microbiota dysbiosis observed in smokers may occur as a consequence of established pathogen colonization.

Copyright © 2017 American Society for Microbiology.

PMID: 28760931 DOI: 10.1128/IAI.00434-17

Mathematical modeling of postcoinfection with influenza A virus and Streptococcus pneumoniae, with implications for pneumonia and COPD-risk assessment.

Int J Chron Obstruct Pulmon Dis. 2017 Jul 5;12:1973-1988. doi: 10.2147/COPD.S138295. eCollection 2017.

Mathematical modeling of postcoinfection with influenza A virus and Streptococcus pneumoniae, with implications for pneumonia and COPD-risk assessment.

Cheng YH1, You SH2, Lin YJ3, Chen SC4,5, Chen WY6, Chou WC2, Hsieh NH7, Liao CM3.

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Abstract

BACKGROUND:

The interaction between influenza and pneumococcus is important for understanding how coinfection may exacerbate pneumonia. Secondary pneumococcal pneumonia associated with influenza infection is more likely to increase respiratory morbidity and mortality. This study aimed to assess exacerbated inflammatory effects posed by secondary pneumococcal pneumonia, given prior influenza infection.

MATERIALS AND METHODS:

A well-derived mathematical within-host dynamic model of coinfection with influenza A virus and Streptococcus pneumoniae (SP) integrated with dose-response relationships composed of previously published mouse experimental data and clinical studies was implemented to study potentially exacerbated inflammatory responses in pneumonia based on a probabilistic approach.

RESULTS:

We found that TNFα is likely to be the most sensitive biomarker reflecting inflammatory response during coinfection among three explored cytokines. We showed that the worst inflammatory effects would occur at day 7 SP coinfection, with risk probability of 50% (likely) to develop severe inflammatory responses. Our model also showed that the day of secondary SP infection had much more impact on the severity of inflammatory responses in pneumonia compared to the effects caused by initial virus titers and bacteria loads.

CONCLUSION:

People and health care workers should be wary of secondary SP infection on day 7 post-influenza infection for prompt and proper control-measure implementation. Our quantitative risk-assessment framework can provide new insights into improvements in respiratory health especially, predominantly due to chronic obstructive pulmonary disease (COPD).

KEYWORDS:

chronic obstructive pulmonary disease; coinfection; influenza; modeling; pneumonia; risk assessment

PMID: 28740377 PMCID: PMC5505164 DOI: 10.2147/COPD.S138295

Effect of decreased BCAA synthesis through disruption of ilvC gene on the virulence of Streptococcus pneumoniae.

Arch Pharm Res. 2017 Jul 22. doi: 10.1007/s12272-017-0931-0. [Epub ahead of print]

Effect of decreased BCAA synthesis through disruption of ilvC gene on the virulence of Streptococcus pneumoniae.

Kim GL1, Lee S1, Luong TT1, Nguyen CT1, Park SS1, Pyo S1, Rhee DK2.

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Abstract

Streptococcus pneumoniae (pneumococcus) is responsible for significant morbidity and mortality worldwide. It causes a variety of life-threatening infections such as pneumonia, bacteremia, and meningitis. In bacterial physiology, the metabolic pathway of branched-chain amino acids (BCAAs) plays an important role in virulence. Nonetheless, the function of IlvC, one of the enzymes involved in the biosynthesis of BCAAs, in S. pneumoniae remains unclear. Here, we demonstrated that downregulation of BCAA biosynthesis by ilvC ablation can diminish BCAA concentration and expression of pneumolysin (Ply) and LytA, and subsequently attenuate virulence. Infection with an ilvC mutant showed significantly reduced mortality and colonization in comparison with strain D39 (serotype 2, wild type), suggesting that ilvC can potentiate S. pneumoniae virulence due to adequate BCAA synthesis. Taken together, these results suggest that the function of ilvC in BCAA synthesis is essential for virulence factor and could play an important role in the pathogenesis of respiratory infections.

KEYWORDS:

BCAA; Colonization; Streptococcus pneumoniae; Virulence; ilvC

PMID: 28735462 DOI: 10.1007/s12272-017-0931-0

 

 

CRH Affects the Phenotypic Expression of Sepsis-Associated Virulence Factors by Streptococcus pneumoniae Serotype 1 In vitro.

Front Cell Infect Microbiol. 2017 Jun 22;7:263. doi: 10.3389/fcimb.2017.00263. eCollection 2017.

CRH Affects the Phenotypic Expression of Sepsis-Associated Virulence Factors by Streptococcus pneumoniae Serotype 1 In vitro.

Ngo Ndjom CG1, Kantor LV2, Jones HP1.

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Abstract

Sepsis is a life-threatening health condition caused by infectious pathogens of the respiratory tract, and accounts for 28-50% of annual deaths in the US alone. Current treatment regimen advocates the use of corticosteroids as adjunct treatment with antibiotics, for their broad inhibitory effect on the activity and production of pro-inflammatory mediators. However, despite their use, corticosteroids have not proven to be able to reverse the death incidence among septic patients. We have previously demonstrated the potential for neuroendocrine factors to directly influence Streptococcus pneumoniae virulence, which may in turn mediate disease outcome leading to sepsis and septic shock. The current study investigated the role of Corticotropin-releasing hormone (CRH) in mediating key markers of pneumococcal virulence as important phenotypic determinants of sepsis and septic shock risks. In vitro cultures of serotype 1 pneumococcal strain with CRH promoted growth rate, increased capsule thickness and penicillin resistance, as well as induced pneumolysin gene expression. These results thus provide significant insights of CRH-pathogen interactions useful in understanding the underlying mechanisms of neuroendocrine factor's role in the onset of community acquired pneumonias (CAP), sepsis and septic shock.

KEYWORDS:

Streptococcus pneumoniae; corticotropin releasing hormone; phenotype; sepsis virulence; serotypes

PMID: 28690980 PMCID: PMC5479890 DOI: 10.3389/fcimb.2017.00263

Increased Zinc Availability Enhances Initial Aggregation and Biofilm Formation of Streptococcus pneumoniae.

Front Cell Infect Microbiol. 2017 Jun 7;7:233. doi: 10.3389/fcimb.2017.00233. eCollection 2017.

Increased Zinc Availability Enhances Initial Aggregation and Biofilm Formation of Streptococcus pneumoniae.

Brown LR1, Caulkins RC1, Schartel TE1, Rosch JW2, Honsa ES2, Schultz-Cherry S2, Meliopoulos VA2, Cherry S2, Thornton JA1.

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Abstract

Bacteria growing within biofilms are protected from antibiotics and the immune system. Within these structures, horizontal transfer of genes encoding virulence factors, and promoting antibiotic resistance occurs, making biofilms an extremely important aspect of pneumococcal colonization and persistence. Identifying environmental cues that contribute to the formation of biofilms is critical to understanding pneumococcal colonization and infection. Iron has been shown to be essential for the formation of pneumococcal biofilms; however, the role of other physiologically important metals such as copper, zinc, and manganese has been largely neglected. In this study, we investigated the effect of metals on pneumococcal aggregation and early biofilm formation. Our results show that biofilms increase as zinc concentrations increase. The effect was found to be zinc-specific, as altering copper and manganese concentrations did not affect biofilm formation. Scanning electron microscopy analysis revealed structural differences between biofilms grown in varying concentrations of zinc. Analysis of biofilm formation in a mutant strain lacking the peroxide-generating enzyme pyruvate oxidase, SpxB, revealed that zinc does not protect against pneumococcal H2O2. Further, analysis of a mutant strain lacking the major autolysin, LytA, indicated the role of zinc as a negative regulator of LytA-dependent autolysis, which could affect biofilm formation. Additionally, analysis of cell-cell aggregation via plating and microscopy revealed that high concentrations of zinc contribute to intercellular interaction of pneumococci. The findings from this study demonstrate that metal availability contributes to the ability of pneumococci to form aggregates and subsequently, biofilms.

KEYWORDS:

biofilms; cell-cell interactions; colonization; pneumococcus; zinc

PMID: 28638805 PMCID: PMC5461340 DOI: 10.3389/fcimb.2017.00233

Structure of the competence pilus major pilin ComGC in Streptococcus pneumoniae.

J Biol Chem. 2017 Jun 28. pii: jbc.M117.787671. doi: 10.1074/jbc.M117.787671. [Epub ahead of print]

Structure of the competence pilus major pilin ComGC in Streptococcus pneumoniae.

Muschiol S1, Erlendsson S2, Aschtgen MS1, Oliveira V1, Schmieder P3, de Lichtenberg C2, Teilum K2, Boesen T4, Akbey U4, Henriques-Normark B5.

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Abstract

Type IV pili are important virulence factors on the surface of many pathogenic bacteria and have been implicated in a wide range of diverse functions including attachment, twitching motility, biofilm formation and horizontal gene transfer. The respiratory pathogen Streptococcus pneumoniae deploys type IV pili to take up DNA during transformation. These "competence pili" are composed of the major pilin protein ComGC and exclusively assembled during bacterial competence, but their biogenesis remains unclear. Here, we report the high resolution NMR structure of N-terminal truncated ComGC revealing a highly flexible and structurally divergent type IV pilin. It consists of only three α-helical segments forming a well-defined electronegative cavity and confined electronegative and hydrophobic patches. The structure is particularly flexible between the first and second α-helix with the first helical part exhibiting slightly slower dynamics than the rest of the pilin, suggesting that the first helix is involved in forming the pilus structure core and that parts of helices two and three are primarily surface exposed. Taken together, our results provide the first structure of a type IV pilin protein involved in the formation of competence-induced pili in Gram-positive bacteria and corroborate the remarkable structural diversity among type IV pilin proteins.

Copyright © 2017, The American Society for Biochemistry and Molecular Biology.

KEYWORDS:

Streptococcus pneumoniae; horizontal gene transfer; major pilin; microbiology; nuclear magnetic resonance (NMR); pneumococci; protein structure; transformation; type IV pili

PMID: 28659339 DOI: 10.1074/jbc.M117.787671

Proteomic comparisons of opaque and transparent variants of Streptococcus pneumoniae by two dimensional-differential gel electrophoresis.

Sci Rep. 2017 May 26;7(1):2453. doi: 10.1038/s41598-017-02465-x.

Proteomic comparisons of opaque and transparent variants of Streptococcus pneumoniae by two dimensional-differential gel electrophoresis.

Chai MH1, Weiland F2,3,4, Harvey RM1, Hoffmann P2,3, Ogunniyi AD5,6, Paton JC1.

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Abstract

Streptococcus pneumoniae (the pneumococcus) is a human pathogen, accounting for massive global morbidity and mortality. Although asymptomatic colonization of the nasopharynx almost invariably precedes disease, the critical determinants enabling pneumococcal progression from this niche to cause invasive disease are poorly understood. One mechanism proposed to be central to this transition involves opacity phase variation, whereby pneumococci harvested from the nasopharynx are typically transparent, while those simultaneously harvested from the blood are opaque. Here, we used two dimensional-differential gel electrophoresis (2D-DIGE) to compare protein expression profiles of transparent and opaque variants of 3 pneumococcal strains, D39 (serotype 2), WCH43 (serotype 4) and WCH16 (serotype 6A) in vitro. One spot comprising a mixture of capsular polysaccharide biosynthesis protein and other proteins was significantly up-regulated in the opaque phenotype in all 3 strains; other proteins were differentially regulated in a strain-specific manner. We conclude that pneumococcal phase variation is a complex and multifactorial process leading to strain-specific pathogenicity.

PMID: 28550292 PMCID: PMC5446427 DOI: 10.1038/s41598-017-02465-x