Immunization with pneumococcal elongation factor Tu enhances serotype-independent protection against Streptococcus pneumoniae infection

Nagai, Koichi; Domon, Hisanori; Maekawa, Tomoki; Hiyoshi, Takumi; Tamura, Hikaru; Yonezawa, Daisuke; Habuka, Rie; Saitoh, Akihiko; Terao, Yutaka

doi:10.1016/j.vaccine.2018.11.015

Cited by 16 publications

(15 citation statements)

References 52 publications

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“…EF-Tu can be anchored to the bacterial cell surface, adhere to extracellular components including complement factors (Mohan et al, 2014), chaperone bacterial virulence proteins to the cell surface in membrane vesicles (Olaya-Abril et al, 2014), promote adhesion and invasion of host cells, and alter bacterial shape via post-translational modification of bacterial proteins (Harvey et al, 2019). S. pneumoniae EF-Tu can bind complement factors H and related proteins Factor HL1 and CFHR1, and plasminogen, has effects on autolysis even provides potent antigen stimulation in an experimental pneumococcal vaccine (Mohan et al, 2014;Nagai et al, 2018;Thofte et al, 2018;Harvey et al, 2019;Nagai et al, 2019). We investigated whether EF-Tu levels in the CSF correlated with complement proteins, proteins associated with BBB breakdown or neutrophil proteins found in the human CSF proteome.…”

Section: Discussionmentioning

confidence: 99%

“…These were Q8CWR9 (a ribosomal protein) and Elongation Factor Tu (EF-Tu, P64031) ( Figure 3C). EF-Tu is an immunogenic surface expressed S. pneumoniae protein (Thofte et al, 2018;Nagai et al, 2019), involved in the transport of amino acylated tRNA components to ribosomes and is thought to be essential. Recent data suggests that it may also assist S. pneumoniae evasion of complement-mediated immunity (Mohan et al, 2014).…”

Section: Poor Outcome Was Associated With Higher Levels Of the Streptmentioning

confidence: 99%

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CSF Levels of Elongation Factor Tu Is Associated With Increased Mortality in Malawian Adults With Streptococcus pneumoniae Meningitis

Wall

Brownridge

Laing

et al. 2020

Front. Cell. Infect. Microbiol.

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BackgroundMortality from bacterial meningitis, predominately caused by Streptococcus pneumoniae, exceeds 50% in sub-Saharan African countries with high HIV prevalence. Underlying causes of high mortality are poorly understood. We examined the host and pathogen proteome in the CSF of adults with proven pneumococcal meningitis (PM), testing if there was an association between differentially expressed proteins and outcome.Materials/MethodsCSF proteomes were analyzed by quantitative Mass-Spectrometry. Spectra were identified using the Swissprot human and TIGR4 pneumococcal protein libraries. Proteins were quantitated and analyzed against mortality. Unique proteins in PM were identified against published normal CSF proteome. Random-Forest models were used to test for protein signatures discriminating outcome. Proteins of interest were tested for their effects on growth and neutrophil opsonophagocytic killing of S. pneumoniae.ResultsCSF proteomes were available for 57 Adults with PM (median age 32 years, 60% male, 70% HIV-1 co-infected, mortality 63%). Three hundred sixty individual human and 23 pneumococcal proteins were identified. Of the human protein hits, 30% were not expressed in normal CSF, and these were strongly associated with inflammation and primarily related to neutrophil activity. No human protein signature predicted outcome. However, expression of the essential S. pneumoniae protein Elongation Factor Tu (EF-Tu) was significantly increased in CSF of non-survivors [False Discovery Rate (q) <0.001]. Expression of EF-Tu was negatively co-correlated against expression of Neutrophil defensin (r 0.4 p p < 0.002), but not against complement proteins C3 or Factor H. In vitro, addition of EF-Tu protein impaired S. pneumoniae neutrophil killing in CSF.ConclusionsExcessive S. pneumoniae EF-Tu protein in CSF was associated with reduced survival in meningitis in a high HIV prevalence population. We show EF-Tu may inhibit neutrophil mediated killing of S. pneumoniae in CSF. Further mechanistic work is required to better understand how S. pneumoniae avoids essential innate immune responses during PM through production of excess EF-Tu.

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Section: Discussionmentioning

confidence: 99%

Section: Poor Outcome Was Associated With Higher Levels Of the Streptmentioning

confidence: 99%

CSF Levels of Elongation Factor Tu Is Associated With Increased Mortality in Malawian Adults With Streptococcus pneumoniae Meningitis

Wall

Brownridge

Laing

et al. 2020

Front. Cell. Infect. Microbiol.

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“…Research on a subunit anti-GBS vaccine based on EF Tu revealed the capability of the indication of the immunity and protection of tilapia against infection caused by Streptococcus agalactiae, however vaccination with the subunit EF Tu vaccine generated moderate immune protection with RPS equal 70% [136]. Mouse vaccination against EF Tu of Streptococcus pneumoniae resulted in the animals' protection against lethal challenges, and on the molecular level, increased cytokine, IgG1 and IgG2a, and CD4+ T-cell production was observed [137]. Promising results of rEF-Tu vaccination was obtained for fish as well [136].…”

Section: Elongation Factor Tumentioning

confidence: 99%

Immunogenic Proteins of Group B Streptococcus—Potential Antigens in Immunodiagnostic Assay for GBS Detection

Dobrut

Brzychczy-Włoch

2021

Pathogens

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Streptococcus agalactiae (Group B Streptococcus, GBS) is an opportunistic pathogen, which asymptomatically colonizes the gastrointestinal and genitourinary tract of up to one third of healthy adults. Nevertheless, GBS carriage in pregnant women may lead to several health issues in newborns causing life threatening infection, such as sepsis, pneumonia or meningitis. Recommended GBS screening in pregnant women significantly reduced morbidity and mortality in infants. Nevertheless, intrapartum antibiotic prophylaxis, recommended following the detection of carriage or in case of lack of a carriage test result for pregnant women who demonstrate certain risk factors, led to the expansion of the adverse phenomenon of bacterial resistance to antibiotics. In our paper, we reviewed some immunogenic GBS proteins, i.e., Alp family proteins, β protein, Lmb, Sip, BibA, FsbA, ScpB, enolase, elongation factor Tu, IMPDH, and GroEL, which possess features characteristic of good candidates for immunodiagnostic assays for GBS carriage detection, such as immunoreactivity and specificity. We assume that they can be used as an alternative diagnostic method to the presently recommended bacteriological cultivation and MALDI.

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“…Immunization with rEF-Tu elicited both Th1 and Th2-type responses against Streptococcus suis and anti-rEF-Tu sera reduced viable load detection in porcine blood (Feng et al, 2018). Mice immunized with rEF-Tu demonstrated significant protection against lethal challenges with S. pneumoniae and increased cytokine, IgG1 and IgG2a, and CD4 + T-cell production (Nagai et al, 2019). rEF-Tu mediated protection against S. pneumoniae has also been demonstrated in fish (Yang et al, 2018), and partial protection against H. influenzae was achieved in mice (Thofte et al, 2018).…”

Section: Moonlighting Proteins In Bacteriamentioning

confidence: 99%

The Diverse Functional Roles of Elongation Factor Tu (EF-Tu) in Microbial Pathogenesis

Harvey

Jarocki

Charles³

et al. 2019

Front. Microbiol.

141

103

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Elongation factor thermal unstable Tu (EF-Tu) is a G protein that catalyzes the binding of aminoacyl-tRNA to the A-site of the ribosome inside living cells. Structural and biochemical studies have described the complex interactions needed to effect canonical function. However, EF-Tu has evolved the capacity to execute diverse functions on the extracellular surface of both eukaryote and prokaryote cells. EF-Tu can traffic to, and is retained on, cell surfaces where can interact with membrane receptors and with extracellular matrix on the surface of plant and animal cells. Our structural studies indicate that short linear motifs (SLiMs) in surface exposed, non-conserved regions of the molecule may play a key role in the moonlighting functions ascribed to this ancient, highly abundant protein. Here we explore the diverse moonlighting functions relating to pathogenesis of EF-Tu in bacteria and examine putative SLiMs on surface-exposed regions of the molecule.

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Immunization with pneumococcal elongation factor Tu enhances serotype-independent protection against Streptococcus pneumoniae infection

Cited by 16 publications

References 52 publications

CSF Levels of Elongation Factor Tu Is Associated With Increased Mortality in Malawian Adults With Streptococcus pneumoniae Meningitis

CSF Levels of Elongation Factor Tu Is Associated With Increased Mortality in Malawian Adults With Streptococcus pneumoniae Meningitis

Immunogenic Proteins of Group B Streptococcus—Potential Antigens in Immunodiagnostic Assay for GBS Detection

The Diverse Functional Roles of Elongation Factor Tu (EF-Tu) in Microbial Pathogenesis

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