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- Horst, SA, et al.
(författare)
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Prognostic value and therapeutic potential of TREM-1 in Streptococcus pyogenes- induced sepsis
- 2013
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Ingår i: Journal of innate immunity. - : S. Karger AG. - 1662-8128 .- 1662-811X. ; 5:6, s. 581-590
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Tidskriftsartikel (refereegranskat)abstract
- TREM-1 (triggering receptor expressed on myeloid cells) is a surface molecule expressed on neutrophils and macrophages which has been implicated in the amplification of inflammatory responses triggered during infection. In the present study, we have investigated the clinical significance of TREM-1 in <i>Streptococcus pyogenes</i>-induced severe sepsis in both experimentally infected mice as well as in patients with streptococcal toxic shock. We found that <i>S. pyogenes</i> induced a dose-dependent upregulation of TREM-1 in in vitro cultured phagocytic cells and in the organs of <i>S. pyogenes-</i>infected mice. Furthermore, we reported a positive correlation between serum levels of soluble TREM-1 (sTREM-1) and disease severity in infected patients as well as in experimentally infected mice. Hence, sTREM-1 may represent a useful surrogate marker for streptococcal sepsis. We found that modulation of TREM-1 by administration of the TREM-1 decoy receptor rTREM-1/Fc substantially attenuated the synthesis of inflammatory cytokines. More importantly, treatment of <i>S. pyogenes</i>-infected septic mice with rTREM-1/Fc or the synthetically produced conserved extracellular domain LP17 significantly improved disease outcome. In summary, our data suggest that TREM-1 may not only represent a valuable marker for <i>S. pyogenes</i> infection severity but it may also be an attractive target for the treatment of streptococcal sepsis.
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- Thanert, R, et al.
(författare)
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Molecular profiling of tissue biopsies reveals unique signatures associated with streptococcal necrotizing soft tissue infections
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 3846-
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Tidskriftsartikel (refereegranskat)abstract
- Necrotizing soft tissue infections (NSTIs) are devastating infections caused by either a single pathogen, predominantly Streptococcus pyogenes, or by multiple bacterial species. A better understanding of the pathogenic mechanisms underlying these different NSTI types could facilitate faster diagnostic and more effective therapeutic strategies. Here, we integrate microbial community profiling with host and pathogen(s) transcriptional analysis in patient biopsies to dissect the pathophysiology of streptococcal and polymicrobial NSTIs. We observe that the pathogenicity of polymicrobial communities is mediated by synergistic interactions between community members, fueling a cycle of bacterial colonization and inflammatory tissue destruction. In S. pyogenes NSTIs, expression of specialized virulence factors underlies infection pathophysiology. Furthermore, we identify a strong interferon-related response specific to S. pyogenes NSTIs that could be exploited as a potential diagnostic biomarker. Our study provides insights into the pathophysiology of mono- and polymicrobial NSTIs and highlights the potential of host-derived signatures for microbial diagnosis of NSTIs.
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- Hansen, MB, et al.
(författare)
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Association between cytokine response, the LRINEC score and outcome in patients with necrotising soft tissue infection: a multicentre, prospective study
- 2017
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7, s. 42179-
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Tidskriftsartikel (refereegranskat)abstract
- Early assessment of necrotising soft tissue infection (NSTI) is challenging. Analysis of inflammatory markers could provide important information about disease severity and guide decision making. For this purpose, we investigated the association between cytokine levels and the Laboratory Risk Indicator for Necrotising Fasciitis (LRINEC)-score, disease severity and mortality in NSTI patients. In 159 patients, plasma was analysed for IL-1β, IL-6, IL-10 and TNF-α upon admission. The severity of NSTI was assessed by SAPS, SOFA score, septic shock, microbial aetiology, renal replacement therapy and amputation. We found no significant difference in cytokine levels according to a LRINEC- score above or below 6 (IL-1β: 3.0 vs. 1.3; IL-6: 607 vs. 289; IL-10: 38.4 vs. 38.8; TNF-α: 15.1 vs. 7.8 pg/mL, P > 0.05). Patients with β-haemolytic streptococcal infection had higher level of particularly IL-6. There was no difference in mortality between patients with a LRINEC-score above or below 6. In the adjusted analysis assessing 30-day mortality, the association was strongest for IL-1β (OR 3.86 [95% CI, 1.43-10.40], P = 0.008) and IL-10 (4.80 [1.67-13.78], P = 0.004). In conclusion, we found no significant association between the LRINEC-score and cytokine levels on admission. IL-6 was consistently associated with disease severity, whereas IL-1β had the strongest association with 30-day mortality.
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- Linner, A, et al.
(författare)
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Reply to Arends and Harkisoen
- 2015
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Ingår i: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. - : Oxford University Press (OUP). - 1537-6591. ; 60:2, s. 324-5
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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- Palma Medina, LM, et al.
(författare)
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Targeted plasma proteomics reveals signatures discriminating COVID-19 from sepsis with pneumonia
- 2023
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Ingår i: Respiratory research. - : Springer Science and Business Media LLC. - 1465-993X. ; 24:1, s. 62-
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundCOVID-19 remains a major public health challenge, requiring the development of tools to improve diagnosis and inform therapeutic decisions. As dysregulated inflammation and coagulation responses have been implicated in the pathophysiology of COVID-19 and sepsis, we studied their plasma proteome profiles to delineate similarities from specific features.MethodsWe measured 276 plasma proteins involved in Inflammation, organ damage, immune response and coagulation in healthy controls, COVID-19 patients during acute and convalescence phase, and sepsis patients; the latter included (i) community-acquired pneumonia (CAP) caused by Influenza, (ii) bacterial CAP, (iii) non-pneumonia sepsis, and (iv) septic shock patients.ResultsWe identified a core response to infection consisting of 42 proteins altered in both COVID-19 and sepsis, although higher levels of cytokine storm-associated proteins were evident in sepsis. Furthermore, microbiologic etiology and clinical endotypes were linked to unique signatures. Finally, through machine learning, we identified biomarkers, such as TRIM21, PTN and CASP8, that accurately differentiated COVID-19 from CAP-sepsis with higher accuracy than standard clinical markers.ConclusionsThis study extends the understanding of host responses underlying sepsis and COVID-19, indicating varying disease mechanisms with unique signatures. These diagnostic and severity signatures are candidates for the development of personalized management of COVID-19 and sepsis.
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- Shambat, SM, et al.
(författare)
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A point mutation in AgrC determines cytotoxic or colonizing properties associated with phenotypic variants of ST22 MRSA strains
- 2016
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6, s. 31360-
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Tidskriftsartikel (refereegranskat)abstract
- Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of skin and soft tissue infections. One of the highly successful and rapidly disseminating clones is MRSA ST22 commonly associated with skin tropism. Here we show that a naturally occurring single amino acid substitution (tyrosine to cysteine) at position 223 of AgrC determines starkly different ST22 S. aureus virulence phenotypes, e.g. cytotoxic or colonizing, as evident in both in vitro and in vivo skin infections. Y223C amino acid substitution destabilizes AgrC-AgrA interaction leading to a colonizing phenotype characterized by upregulation of bacterial surface proteins. The colonizing phenotype strains cause less severe skin tissue damage, show decreased susceptibility towards the antimicrobial LL-37 and induce autophagy. In contrast, cytotoxic strains with tyrosine at position 223 of AgrC cause infections characterized by inflammasome activation and severe skin tissue pathology. Taken together, the study demonstrates how a single amino acid substitution in the histidine kinase receptor AgrC of ST22 strains determines virulence properties and infection outcome.
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- Siemens, N, et al.
(författare)
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Prothrombotic and Proinflammatory Activities of the β-Hemolytic Group B Streptococcal Pigment
- 2020
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Ingår i: Journal of innate immunity. - : S. Karger AG. - 1662-8128 .- 1662-811X. ; 12:4, s. 291-303
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Tidskriftsartikel (refereegranskat)abstract
- A prominent feature of severe streptococcal infections is the profound inflammatory response that contributes to systemic toxicity. In sepsis the dysregulated host response involves both immunological and nonimmunological pathways. Here, we report a fatal case of an immunocompetent healthy female presenting with toxic shock and purpura fulminans caused by group B streptococcus (GBS; serotype III, CC19). The strain (LUMC16) was pigmented and hyperhemolytic. Stimulation of human primary cells with hyperhemolytic LUMC16 and STSS/NF-HH strains and pigment toxin resulted in a release of proinflammatory mediators, including tumor necrosis factor, interleukin (IL)-1β, and IL-6. In addition, LUMC16 induced blood clotting and showed factor XII activity on its surface, which was linked to the presence of the pigment. The expression of pigment was not linked to a mutation within the CovR/S region. In conclusion, our study shows that the hemolytic lipid toxin contributes to the ability of GBS to cause systemic hyperinflammation and interferes with the coagulation system.
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- Alpkvist, H, et al.
(författare)
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High HMGB1 levels in sputum are related to pneumococcal bacteraemia but not to disease severity in community-acquired pneumonia
- 2018
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1, s. 13428-
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Tidskriftsartikel (refereegranskat)abstract
- During bacterial infections, damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) activate immune cells. Here, we investigated whether plasma and sputum levels of High Mobility Group Box 1 (HMGB1), a prototypic DAMP, are associated with disease severity and aetiology in community-acquired pneumonia (CAP). In addition, in patients with pneumococcal CAP, the impact of the level of sputum lytA DNA load, a PAMP, was investigated. We studied patients hospitalised for bacterial CAP (n = 111), and samples were collected at admission. HMGB1 was determined by enzyme-linked immunosorbent assays, and pneumococcal lytA DNA load was determined by quantitative polymerase chain reaction. Plasma and sputum HMGB1 levels did not correlate to disease severity (pneumonia severity index or presence of sepsis), but high sputum HMGB1 level was correlated to pneumococcal aetiology (p = 0.002). In pneumococcal pneumonia, high sputum lytA DNA load was associated with respiratory failure (low PaO2/FiO2 ratio; p = 0.019), and high sputum HMGB1 level was associated with bacteraemia (p = 0.006). To conclude, high sputum HMGB1 was not associated with severe disease, but with pneumococcal bacteraemia, indicating a potential role for HMGB1 in bacterial dissemination. High sputum lytA was associated with severe disease.
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