| 1. |
- Karlsson, Christofer A.Q., et al.
(författare)
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Streptococcus pyogenes Infection and the Human Proteome with a Special Focus on the Immunoglobulin G-cleaving Enzyme IdeS
- 2018
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Ingår i: Molecular and Cellular Proteomics. - 1535-9476. ; 17:6, s. 1097-1111
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Tidskriftsartikel (refereegranskat)abstract
- Infectious diseases are characterized by a complex interplay between host and pathogen, but how these interactions impact the host proteome is unclear. Here we applied a combined mass spectrometry-based proteomics strategy to investigate how the human proteome is transiently modified by the pathogen Streptococcus pyogenes, with a particular focus on bacterial cleavage of IgG in vivo. In invasive diseases, S. pyogenes evokes a massive host response in blood, whereas superficial diseases are characterized by a local leakage of several blood plasma proteins at the site of infection including IgG. S. pyogenes produces IdeS, a protease cleaving IgG in the lower hinge region and we find highly effective IdeS-cleavage of IgG in samples from local IgG poor microenvironments. The results show that IdeS contributes to the adaptation of S. pyogenes to its normal ecological niches. Additionally, the work identifies novel clinical opportunities for in vivo pathogen detection.
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| 2. |
- Koymans, Kirsten J, et al.
(författare)
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The TLR2 Antagonist Staphylococcal Superantigen-Like Protein 3 Acts as a Virulence Factor to Promote Bacterial Pathogenicity in vivo
- 2017
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Ingår i: Journal of Innate Immunity. - : S. Karger AG. - 1662-811X .- 1662-8128. ; 9, s. 561-573
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Tidskriftsartikel (refereegranskat)abstract
- Toll-like receptor (TLR) signaling is important in the initiation of immune responses and subsequent instigation of adaptive immunity. TLR2 recognizes bacterial lipoproteins and plays a central role in the host defense against bacterial infections, including those caused by Staphylococcus aureus. Many studies have demonstrated the importance of TLR2 in murine S. aureus infection. S. aureus evades TLR2 activation by secreting two proteins, staphylococcal superantigen-like protein 3 (SSL3) and 4 (SSL4). In this study, we demonstrate that antibodies against SSL3 and SSL4 are found in healthy individuals, indicating that humans are exposed to these proteins during S. aureus colonization or infection. To investigate the TLR2-antagonistic properties of SSL3 and SSL4, we compared the infection with wild-type and SSL3/4 knockout S. aureus strains in an intravenous murine infection model. Direct evaluation of the contribution of SSL3/4 to infection pathogenesis was hindered by the fact that the SSLs were not expressed in the murine system. To circumvent this limitation, an SSL3-overproducing strain (pLukM-SSL3) was generated, resulting in constitutive expression of SSL3. pLukM-SSL3 exhibited increased virulence compared to the parental strain in a murine model that was found to be TLR2 dependent. Altogether, these data indicate that SSL3 contributes to S. aureus virulence in vivo.
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| 3. |
- Mohanty, Tirthankar, et al.
(författare)
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A pharmacoproteomic landscape of organotypic intervention responses in Gram-negative sepsis
- 2023
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Ingår i: Nature Communications. - 2041-1723. ; 14, s. 1-17
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Tidskriftsartikel (refereegranskat)abstract
- Sepsis is the major cause of mortality across intensive care units globally, yet details of accompanying pathological molecular events remain unclear. This knowledge gap has resulted in ineffective biomarker development and suboptimal treatment regimens to prevent and manage organ dysfunction/damage. Here, we used pharmacoproteomics to score time-dependent treatment impact in a murine Escherichia coli sepsis model after administering beta-lactam antibiotic meropenem (Mem) and/or the immunomodulatory glucocorticoid methylprednisolone (Gcc). Three distinct proteome response patterns were identified, which depended on the underlying proteotype for each organ. Gcc enhanced some positive proteome responses of Mem, including superior reduction of the inflammatory response in kidneys and partial restoration of sepsis-induced metabolic dysfunction. Mem introduced sepsis-independent perturbations in the mitochondrial proteome that Gcc counteracted. We provide a strategy for the quantitative and organotypic assessment of treatment effects of candidate therapies in relationship to dosing, timing, and potential synergistic intervention combinations during sepsis.
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| 4. |
- Mohanty, Tirthankar, et al.
(författare)
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Neutrophil extracellular traps in the central nervous system hinder bacterial clearance during pneumococcal meningitis
- 2019
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 1667-1667
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Tidskriftsartikel (refereegranskat)abstract
- Neutrophils are crucial mediators of host defense that are recruited to the central nervous system (CNS) in large numbers during acute bacterial meningitis caused by Streptococcus pneumoniae. Neutrophils release neutrophil extracellular traps (NETs) during infections to trap and kill bacteria. Intact NETs are fibrous structures composed of decondensed DNA and neutrophil-derived antimicrobial proteins. Here we show NETs in the cerebrospinal fluid (CSF) of patients with pneumococcal meningitis, and their absence in other forms of meningitis with neutrophil influx into the CSF caused by viruses, Borrelia and subarachnoid hemorrhage. In a rat model of meningitis, a clinical strain of pneumococci induced NET formation in the CSF. Disrupting NETs using DNase I significantly reduces bacterial load, demonstrating that NETs contribute to pneumococcal meningitis pathogenesis in vivo. We conclude that NETs in the CNS reduce bacterial clearance and degrading NETs using DNase I may have significant therapeutic implications.
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| 5. |
- Tanner, Lloyd, et al.
(författare)
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Citrullination of extracellular histone H3.1 reduces antibacterial activity and exacerbates its proteolytic degradation
- 2021
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Ingår i: Journal of Cystic Fibrosis. - : Elsevier BV. - 1873-5010 .- 1569-1993. ; 20:2, s. 346-355
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Cystic fibrosis (CF), involves excessive airway accumulation of neutrophils, often in parallel with severe infection caused by Pseudomonas aeruginosa. Free histones are known to possess bactericidal properties, but the degree of antibacterial activity exerted on specific lung-based pathogens is largely unknown. Neutrophils have a high content of peptidyl deiminase 4 (PADI4), which citrullinate cationic peptidyl-arginines. In histone H3.1, several positions in the NH2-terminal tail are subject to citrullination.METHODS: Full-length and segmented histone subunit H3.1 was investigated for bactericidal activity towards P. aeruginosa (strain PAO1). PADI4-induced citrullination of histone H3.1 was assessed for antibacterial activity towards P. aeruginosa. Next, the effect of neutrophil elastase (NE)-mediated proteolysis of histone H3.1 was investigated. Finally, PADI4, H3.1, and citrullinated H3.1 were examined in healthy control and CF patient lung tissues.RESULTS: Full-length histone H3.1 and sections of the histone H3.1 tail, displayed bactericidal activity towards P. aeruginosa. These antibacterial effects were reduced following citrullination by PADI4 or proteolysis by NE. Interestingly, citrullination of histone H3.1 exacerbated NE-mediated degradation. In CF lung tissue, citrullinated histone H3.1 and PADI4 immunoreactivity was abundant. Degraded histone H3.1 was detected in the sputum of CF patients but was absent in the sputum of healthy controls.CONCLUSIONS: Citrullination impairs the antibacterial activity of histone H3.1 and exacerbates its proteolytic degradation by NE. Citrullination is likely to play an important role during resolution of acute inflammation. However, in chronic inflammation akin to CF, citrullination may dampen host defense and promote pathogen survival, as exemplified by P. aeruginosa.
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