The impact of the ancillary pilus‐1 protein RrgA of <i>Streptococcus pneumoniae</i> on colonization and disease

Iovino, Federico; Nannapaneni, Priyanka; Henriques‐Normark, Birgitta; Normark, Staffan

doi:10.1111/mmi.14451

Cited by 14 publications

(11 citation statements)

References 65 publications

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“…The importance of RrgA for brain infection is also supported by previous studies demonstrating that RrgA promotes bacterial entry into the brain from the blood-stream by interacting with the two endothelial receptors PECAM-1 and pIgR, and at autopsy, after a fatal pneumococcal meningitis, five out of six brains studied contained RrgA expressing pneumococci (Iovino et al, 2017). However, only about 20-30% of clinical pneumococcal isolates harbour the pilus-1 islet (Moschioni et al, 2010;Iovino et al, 2020).…”

Section: Discussionsupporting

confidence: 66%

Neuronal death in pneumococcal meningitis is triggered by pneumolysin and pilus-1 interactions with β-actin

Tabusi

Thorsdottir

Lysandrou

et al. 2020

Preprint

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Neuronal damage is a major consequence of bacterial meningitis, but little is known about mechanisms that lead to neuronal death. Streptococcus pneumoniae (pneumococcus) is a leading cause of bacterial meningitis and many survivors develop neurological sequelae after the acute infection has resolved, possibly due to neuronal damage. Here, we studied mechanisms for pneumococcal interactions with neurons. Using human primary neurons and co-immunoprecipitation assays, we showed that pneumococci interact with the cytoskeleton protein β-actin through the pilus-1 adhesin RrgA and the cytotoxin pneumolysin (Ply), thereby promoting adhesion and uptake into neurons and neuronal death. Using our bacteremia-derived meningitis mouse model, we observed that RrgA- and Ply-expressing pneumococci co-localize with neuronal β-actin. We found that pneumococcal-infected neurons show increased intracellular Ca2+ levels depending on RrgA and mainly Ply which likely cause actin cytoskeleton disassembly leading to neuronal damage. Finally, neuronal death caused by pneumococcal infection could be inhibited using antibody against β-actin.

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Section: Discussionsupporting

confidence: 66%

Neuronal death in pneumococcal meningitis is triggered by pneumolysin and pilus-1 interactions with β-actin

Tabusi

Thorsdottir

Lysandrou

et al. 2020

Preprint

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“…It was recently shown that Ply might facilitate the internalization of the pneumococcus into neurons together with the pilus-1, a protein complex with adhesin activity, exposed outside the cell wall, which has been associated with the capacity of pneumococci to interact with and invade different types of host cells (Iovino et al, 2020 ). More specifically, both the pilus-1 component RrgA and Ply interact with β-actin exposed on the neuronal plasma membrane.…”

Section: Neuronal Damage In Bacterial Meningitismentioning

confidence: 99%

Neuronal Damage and Neuroinflammation, a Bridge Between Bacterial Meningitis and Neurodegenerative Diseases

Farmen

Tofiño-Vian

Iovino

2021

Front. Cell. Neurosci.

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Bacterial meningitis is an inflammation of the meninges which covers and protects the brain and the spinal cord. Such inflammation is mostly caused by blood-borne bacteria that cross the blood-brain barrier (BBB) and finally invade the brain parenchyma. Pathogens such as Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae are the main etiological causes of bacterial meningitis. After trafficking across the BBB, bacterial pathogens in the brain interact with neurons, the fundamental units of Central Nervous System, and other types of glial cells. Although the specific molecular mechanism behind the interaction between such pathogens with neurons is still under investigation, it is clear that bacterial interaction with neurons and neuroinflammatory responses within the brain leads to neuronal cell death. Furthermore, clinical studies have shown indications of meningitis-caused dementia; and a variety of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease are characterized by the loss of neurons, which, unlike many other eukaryotic cells, once dead or damaged, they are seldom replaced. The aim of this review article is to provide an overview of the knowledge on how bacterial pathogens in the brain damage neurons through direct and indirect interactions, and how the neuronal damage caused by bacterial pathogen can, in the long-term, influence the onset of neurodegenerative disorders.

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“…However, pneumococcal proteins capable of binding collagen type VI have not been identified. In pneumococci, the presence of type‐1 pili has been associated with virulence and enhanced the ability to interact with epithelial and endothelial cells (Iovino et al, 2020). Proteins RrgA and RrgB were shown to be expressed along the entire pilus‐1 surface (Hilleringmann et al, 2008) and to consecutively interlock with collagen type I fibrils, as shown using atomic force microscopy (Becke et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Streptococcus pneumoniae binds collagens and C1q via the SSURE repeats of the PfbB adhesin

Gaetano

Coppolino

Lentini

et al. 2022

Molecular Microbiology

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The binding of Streptococcus pneumoniae to collagen is likely an important step in the pathogenesis of pneumococcal infections, but little is known of the underlying molecular mechanisms. Streptococcal surface repeats (SSURE) are highly conserved protein domains present in cell wall adhesins from different Streptococcus species. We find here that SSURE repeats of the pneumococcal adhesin plasminogen and fibronectin binding protein B (PfbB) bind to various types of collagen. Moreover, deletion of the pfbB gene resulted in a significant impairment of the ability of encapsulated or unencapsulated pneumococci to bind collagen. Notably, a PfbB SSURE domain is also bound to the complement component C1q that bears a collagen‐like domain and promotes adherence of pneumococci to host cells by acting as a bridge between bacteria and epithelial cells. Accordingly, deletion of PfbB or pre‐treatment with anti‐SSURE antibodies markedly decreased pneumococcal binding to C1q as well as C1q‐dependent adherence to epithelial and endothelial cells. Further data indicated that C1q promotes pneumococcal adherence by binding to integrin α2β1. In conclusion, our results indicate that the SSURE domains of the PfbB protein promote interactions of pneumococci with various types of collagen and with C1q. These repeats may be useful targets in strategies to control S. pneumoniae infections.

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The impact of the ancillary pilus‐1 protein RrgA of Streptococcus pneumoniae on colonization and disease

Cited by 14 publications

References 65 publications

Neuronal death in pneumococcal meningitis is triggered by pneumolysin and pilus-1 interactions with β-actin

Neuronal death in pneumococcal meningitis is triggered by pneumolysin and pilus-1 interactions with β-actin

Neuronal Damage and Neuroinflammation, a Bridge Between Bacterial Meningitis and Neurodegenerative Diseases

Streptococcus pneumoniae binds collagens and C1q via the SSURE repeats of the PfbB adhesin

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