Streptococcus pneumoniae exerts oxidative stress, subverts antioxidant signaling and autophagy in human corneal epithelial cells that is alleviated by tert-Butylhydroquinone

Sharma, Prerana; Roy, Sanhita

doi:10.1007/s00430-022-00731-y

Cited by 6 publications

(1 citation statement)

References 53 publications

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“…Research has shown that autophagy can degrade tight junction proteins (TJ proteins) and increase epithelial barrier permeability in the intestines [ 21 , 22 ] and respiratory tracts [ 23 ]. It has also been reported that S. pneumoniae infection can induce autophagy activation in human alveolar epithelial cells (AECs) [ 24 ], human corneal epithelial cells [ 25 ], and mouse bone-marrow-derived neutrophils [ 26 ]. Intracellular S. pneumoniae can be recognized by bactericidal autophagy, and certain S. pneumoniae -derived proteins have been considered autophagy activators, such as surface-exposed choline-binding protein CbpC [ 27 ], pore-forming toxin pneumolysin PLY [ 28 , 29 ], and S. pneumoniae endopeptidase O PepO [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

Streptococcus pneumoniae extracellular vesicles aggravate alveolar epithelial barrier disruption via autophagic degradation of OCLN (occludin)

Cui,

Yang,

Huo

et al. 2024

Autophagy

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Streptococcus pneumoniae ( S. pneumoniae ) represents a major human bacterial pathogen leading to high morbidity and mortality in children and the elderly. Recent research emphasizes the role of extracellular vesicles (EVs) in bacterial pathogenicity. However, the contribution of S. pneumoniae EVs (pEVs) to host-microbe interactions has remained unclear. Here, we observed that S. pneumoniae infections in mice led to severe lung injuries and alveolar epithelial barrier (AEB) dysfunction. Infections of S. pneumoniae reduced the protein expression of tight junction protein OCLN (occludin) and activated macroautophagy/autophagy in lung tissues of mice and A549 cells. Mechanically, S. pneumoniae induced autophagosomal degradation of OCLN leading to AEB impairment in the A549 monolayer. S. pneumoniae released the pEVs that could be internalized by alveolar epithelial cells. Through proteomics, we profiled the cargo proteins inside pEVs and found that these pEVs contained many virulence factors, among which we identified a eukaryotic-like serine-threonine kinase protein StkP. The internalized StkP could induce the phosphorylation of BECN1 (beclin 1) at Ser93 and Ser96 sites, initiating autophagy and resulting in autophagy-dependent OCLN degradation and AEB dysfunction. Finally, the deletion of stkP in S. pneumoniae completely protected infected mice from death, significantly alleviated OCLN degradation in vivo , and largely abolished the AEB disruption caused by pEVs in vitro . Overall, our results suggested that pEVs played a crucial role in the spread of S. pneumoniae virulence factors. The cargo protein StkP in pEVs could communicate with host target proteins and even hijack the BECN1 autophagy initiation pathway, contributing to AEB disruption and bacterial pathogenicity. Abbreviations : AEB: alveolarepithelial barrier; AECs: alveolar epithelial cells; ATG16L1: autophagy related 16 like 1; ATP:adenosine 5’-triphosphate; BafA 1 : bafilomycin A 1 ; BBB: blood-brain barrier; CFU: colony-forming unit; co-IP: co-immunoprecipitation; CQ:chloroquine; CTRL: control; DiO: 3,3′-dioctadecylox-acarbocyanineperchlorate; DOX: doxycycline; DTT: dithiothreitol; ECIS: electricalcell-substrate impedance sensing; eGFP: enhanced green fluorescentprotein; erm R : erythromycin-resistance expression cassette; Ery: erythromycin; eSTKs: eukaryotic-like serine-threoninekinases; EVs: extracellular vesicles; HA: hemagglutinin; H&E: hematoxylin and eosin; HsLC3B: human LC3B; hpi: hours post-infection; IP: immunoprecipitation; KD: knockdown; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LC/MS: liquid chromatography-mass spectrometry; MAP1LC3/LC3: micro...

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