Intracellular replication of Streptococcus pneumoniae inside splenic macrophages serves as a reservoir for septicaemia

Ercoli, Giuseppe; Fernandes, Vitor E.; Chung, Wen Yuan; Wanford, Joseph J.; Thomson, Sarah; Bayliss, Christopher D.; Straatman, K.R.; Crocker, Paul R.; Dennison, Ashley R.; Martı́nez-Pomares, Luisa; Andrew, Peter W.; Moxon, E. Richard; Oggioni, Marco R.

doi:10.1038/s41564-018-0147-1

Cited by 116 publications

(172 citation statements)

References 62 publications

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“…However, this raises the important question of how the pneumococcus causes septicemia despite clearance from the bloodstream by splenic macrophages. Ercoli et al () investigated this phenomenon and found that CD169 + splenic macrophages serve as a reservoir for intracellular replication of internalised pneumococci. Using a 1:1 inoculation of mice with D39 strains expressing green or red fluorescent proteins, they showed that bacterial foci within the spleen consisted entirely of single labelled bacteria.…”

Section: Replication Within the Spleenmentioning

confidence: 99%

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Emerging concepts in the pathogenesis of theStreptococcus pneumoniae: From nasopharyngeal colonizer to intracellular pathogen

Subramanian

Henriques‐Normark

Normark

2019

Cellular Microbiology

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Streptococcus pneumoniae (the pneumococcus) is a human respiratory tract pathogen and a major cause of morbidity and mortality globally. Although the pneumococcus is a commensal bacterium that colonizes the nasopharynx, it also causes lethal diseases such as meningitis, sepsis, and pneumonia, especially in immunocompromised patients, in the elderly, and in young children. Due to the acquisition of antibiotic resistance and the emergence of nonvaccine serotypes, the pneumococcus has been classified as one of the priority pathogens for which new antibacterials are urgently required by the World Health Organization, 2017. Understanding molecular mechanisms behind the pathogenesis of pneumococcal infections and bacterial interactions within the host is crucial to developing novel therapeutics. Previously considered to be an extracellular pathogen, it is becoming evident that pneumococci may also occasionally establish intracellular niches within the body to escape immune surveillance and spread within the host. Intracellular survival within host cells also enables pneumococci to resist many antibiotics. Within the host cell, the bacteria exist in unique vacuoles, thereby avoiding degradation by the acidic lysosomes, and modulate the expression of its virulence genes to adapt to the intracellular environment. To invade and survive intracellularly, the pneumococcus utilizes a combination of virulence factors such as pneumolysin (PLY), pneumococcal surface protein A (PspA), pneumococcal adhesion and virulence protein B (PavB), the pilus‐1 adhesin RrgA, pyruvate oxidase (SpxB), and metalloprotease (ZmpB). In this review, we discuss recent findings showing the intracellular persistence of Streptococcus pneumoniae and its underlying mechanisms.

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Section: Replication Within the Spleenmentioning

confidence: 99%

“…However, this raises the important question of how the pneumococcus causes septicemia despite clearance from the bloodstream by splenic macrophages. Ercoli et al (2018) investigated this phenomenon and found that CD169 + splenic macrophages serve as a reservoir for intracellular replication of internalised pneumococci.…”

Section: Replication Within the Spleenmentioning

confidence: 99%

Emerging concepts in the pathogenesis of theStreptococcus pneumoniae: From nasopharyngeal colonizer to intracellular pathogen

Subramanian

Henriques‐Normark

Normark

2019

Cellular Microbiology

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“…Gerlini and Colleagues () demonstrated that this bottleneck can be extremely narrow (10–100 cells), and in some cases can even result in clonal expansion from a single surviving bacterium. Very recently, Ercoli and Colleagues () utilised microscopy to connect this systemic bottleneck with permissiveness for pneumococcal replication in a subset of CD169+ splenic macrophages. Infection and bacterial replication within these cells was essential for disease, as evidenced by survival of mice treated with an anti‐CD169 monoclonal antibody, however, infection of these cells did not impose selection for a particular genotype but was instead stochastic for isogenic genotypes.…”

Section: Selective and Non‐selective Bottlenecks Influence Bacterial mentioning

confidence: 99%

Selective and non‐selective bottlenecks as drivers of the evolution of hypermutable bacterial loci

Croix

Holmes

Wanford

et al. 2020

Molecular Microbiology

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Bottlenecks reduce the size of the gene pool within populations of all life forms with implications for their subsequent survival. Here, we examine the effects of bottlenecks on bacterial commensal‐pathogens during transmission between, and dissemination within, hosts. By reducing genetic diversity, bottlenecks may alter individual or population‐wide adaptive potential. A diverse range of hypermutable mechanisms have evolved in infectious agents that allow for rapid generation of genetic diversity in specific genomic loci as opposed to the variability arising from increased genome‐wide mutation rates. These localised hypermutable mechanisms include multi‐gene phase variation (PV) of outer membrane components, multi‐allele PV of restriction systems and recombination‐driven antigenic variation. We review selected experimental and theoretical (mathematical) models pertaining to the hypothesis that localised hypermutation (LH) compensates for fitness losses caused by bottlenecks and discuss whether bottlenecks have driven the evolution of hypermutable loci.

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“… —Immunogenicity of the capsular serotype of the pneumococcus, magnitude of bacteraemia and impact on rate of clearance of the pathogen —Propensity to produce pneumolysin and intramyocardial biofilm, enabling persistence in cardiomyocytes, cardiac fibroblasts and macrophages ; —Propensity to survive intracellularly in CD169 + splenic macrophages, M2‐polarized macrophages and dendritic cells ; —Persistence of pneumococcal antigens in pathogen‐derived extracellular vesicles ; —Persistence due to capsular switching . …”

Section: Persistent Inflammation Following Clinical Recovery From Pnementioning

confidence: 99%

Pathogenesis and prevention of risk of cardiovascular events in patients with pneumococcal community‐acquired pneumonia

et al. 2019

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It is now well recognized that cardiovascular events (CVE) occur quite commonly, both in the acute phase and in the long‐term, in patients with community‐acquired pneumonia (CAP). CVE have been noted in up to 30% of patients hospitalized with all‐cause CAP. One systematic review and meta‐analysis of hospitalized patients with all‐cause CAP noted that the incidence rates for overall cardiac events were 17.7%, for incident heart failure were 14.1%, for acute coronary syndromes were 5.3% and for incident cardiac arrhythmias were 4.7%. In the case of pneumococcal CAP, almost 20% of patients studied had one or more of these cardiac events. Recent research has provided insights into the pathogenesis of the acute cardiac events occurring in pneumococcal infections. With respect to the former, key involvements of the major pneumococcal protein virulence factor, pneumolysin, are now well documented, whilst systemic platelet‐driven neutrophil activation may also contribute. However, events involved in the pathogenesis of the long‐term cardiovascular sequelae remain largely unexplored. Emerging evidence suggests that persistent antigenaemia may predispose to the development of a systemic pro‐inflammatory/prothrombotic phenotype underpinning the risk of future cardiovascular events. The current manuscript briefly reviews the occurrence of cardiovascular events in patients with all‐cause CAP, as well as in pneumococcal and influenza infections. It highlights the close interaction between influenza and pneumococcal pneumonia. It also includes a brief discussion of mechanisms of the acute cardiac events in CAP. However, the primary focus is on the prevalence, pathogenesis and prevention of the longer‐term cardiac sequelae of severe pneumococcal disease, particularly in the context of persistent antigenaemia and associated inflammation.

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Intracellular replication of Streptococcus pneumoniae inside splenic macrophages serves as a reservoir for septicaemia

Cited by 116 publications

References 62 publications

Emerging concepts in the pathogenesis of theStreptococcus pneumoniae: From nasopharyngeal colonizer to intracellular pathogen

Emerging concepts in the pathogenesis of theStreptococcus pneumoniae: From nasopharyngeal colonizer to intracellular pathogen

Selective and non‐selective bottlenecks as drivers of the evolution of hypermutable bacterial loci

Pathogenesis and prevention of risk of cardiovascular events in patients with pneumococcal community‐acquired pneumonia

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