scholarly journals Early-Stage Staphylococcus aureus Bloodstream Infection Causes Changes in the Concentrations of Lipoproteins and Acute-Phase Proteins and Is Associated with Low Antibody Titers against Bacterial Virulence Factors

mSystems ◽  
2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Stephan Michalik ◽  
Nandakumar Sundaramoorthy ◽  
Annette Murr ◽  
Maren Depke ◽  
Uwe Völker ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Bloodstream Infection ◽  
Acute Phase ◽  
Acute Phase Proteins ◽  
High Density Lipoproteins ◽  
Protective Function ◽  
Content Type ◽  
Early Stages ◽  
Serum Igg ◽  
Igg Binding

ABSTRACT Systemic and quantitative investigations of human plasma proteins (proteomics) and Staphylococcus aureus-specific antibodies (immunoproteomics) provide complementary information and hold promise for the discovery of biomarkers in Staphylococcus aureus bloodstream infection (SABSI). Usually, data-dependent acquisition (DDA) is used for proteome analysis of serum or plasma, but data-independent acquisition (DIA) is more comprehensive and reproducible. In this prospective cohort study, we aimed to identify biomarkers associated with the early stages of SABSI using a serum DIA proteomic and immunoproteomic approach. Sera from 49 SABSI patients and 43 noninfected controls were analyzed. In total, 608 human serum proteins were identified with DIA. A total of 386 proteins could be quantified, of which 9 proteins, mainly belonging to acute-phase proteins, were significantly increased, while 7 high-density lipoproteins were lower in SABSI. In SABSI, total anti-S. aureus serum IgG was reduced compared with controls as shown by immunoproteomic quantification of IgG binding to 143 S. aureus antigens. IgG binding to 48 of these anti-S. aureus proteins was significantly lower in SABSI, while anti-Ecb IgG was the only one increased in SABSI. Serum IgG binding to autoinducing peptide MsrB, FadB, EsxA, Pbp2, FadB, SspB, or SodA was very low in SABSI. This marker panel discriminated early SABSI from controls with 95% sensitivity and 100% specificity according to random forest prediction. This holds promise for patient stratification according to their risk of S. aureus infection, underlines the protective function of the adaptive immune system, and encourages further efforts in the development of a vaccine against S. aureus. IMPORTANCE S. aureus sepsis has a high complication and mortality rate. Given the limited therapeutic possibilities, effective prevention strategies, e.g., a vaccine, or the early identification of high-risk patients would be important but are not available. Our study showed an acute-phase response in patients with S. aureus bloodstream infection and evidence that lipoproteins are downregulated in plasma. Using immunoproteomics, stratification of patients appears to be achievable, since at the early stages of systemic S. aureus infection patients had low preexisting anti-S. aureus antibody levels. This strengthens the notion that a robust immune memory for S. aureus protects against infections with the pathogen.

scholarly journals Immunization with Pneumococcal Polysaccharide Serotype 3 and Lipopolysaccharide Modulates Lung and Liver Inflammation during a Virulent Streptococcus pneumoniae Infection in Mice

2013 ◽  
Vol 20 (5) ◽  
pp. 639-650 ◽  
Author(s):  
Katherine H. Restori ◽  
Mary J. Kennett ◽  
A. Catharine Ross
Keyword(s):  
Gene Expression ◽  
Streptococcus Pneumoniae ◽  
Acute Phase ◽  
Acute Phase Proteins ◽  
Expression Profiles ◽  
Cytokine Gene Expression ◽  
Dependent Manner ◽  
Pneumonia Severity ◽  
Content Type ◽  
Amyloid A

ABSTRACTVaccination reduces morbidity and mortality from pneumonia, but its effect on the tissue-level response to infection is still poorly understood. We evaluated pneumonia disease progression, acute-phase response, and lung gene expression profiles in mice inoculated intranasally with virulent Gram-positiveStreptococcus pneumoniaeserotype 3 (ST 3) with and without prior immunization with pneumococcal polysaccharide ST 3 (PPS3) or after coimmunization with PPS3 and a low dose of lipopolysaccharide (PPS3+LPS). Pneumonia severity was assessed in the acute phase at 5, 12, 24 and 48 h postinoculation (p.i.) and in the resolution phase at 7 days p.i. Primary PPS3-specific antibody production was upregulated, and IgM binding to pneumococci increased in PPS3-immunized mice. Immunizations with PPS3 or PPS3+LPS decreased bacterial recovery in the lung and blood at 24 and 48 h and increased survival. Microarray analysis of whole-lung RNA revealed significant changes in the acute-phase protein serum amyloid A (SAA) levels between noninfected and infected mice, and these changes were attenuated by immunization. SAA transcripts were higher in the liver and lungs of infected controls, and SAA protein was elevated in serum but decreased in PPS3-immunized mice. Thus, during a virulent pneumonia infection, prior immunization with PPS3 in an IgM-dependent manner as well as immunization with PPS3+LPS attenuated pneumonia severity and promoted resolution of infection, concomitant with significant regulation of cytokine gene expression levels in the lungs and acute-phase proteins in the lungs, liver, and serum.

scholarly journals Important Late-Stage Symbiotic Role of theSinorhizobium melilotiExopolysaccharide Succinoglycan

2018 ◽  
Vol 200 (13) ◽  
pp. e00665-17 ◽  
Author(s):  
Markus F. F. Arnold ◽  
Jon Penterman ◽  
Mohammed Shabab ◽  
Esther J. Chen ◽  
Graham C. Walker
Keyword(s):  
Molecular Weight ◽  
High Molecular Weight ◽  
Late Stage ◽  
Sinorhizobium Meliloti ◽  
Antimicrobial Action ◽  
Protective Function ◽  
Content Type ◽  
Early Stages ◽  
Symbiotic Interactions ◽  
Legume Symbiosis

ABSTRACTSinorhizobium melilotienters into beneficial symbiotic interactions withMedicagospecies of legumes. Bacterial exopolysaccharides play critical signaling roles in infection thread initiation and growth during the early stages of root nodule formation. After endocytosis ofS. melilotiby plant cells in the developing nodule, plant-derived nodule-specific cysteine-rich (NCR) peptides mediate terminal differentiation of the bacteria into nitrogen-fixing bacteroids. Previous transcriptional studies showed that the intensively studied cationic peptide NCR247 induces expression of theexogenes that encode the proteins required for succinoglycan biosynthesis. In addition, genetic studies have shown that someexomutants exhibit increased sensitivity to the antimicrobial action of NCR247. Therefore, we investigated whether the symbiotically activeS. melilotiexopolysaccharide succinoglycan can protectS. melilotiagainst the antimicrobial activity of NCR247. We discovered that high-molecular-weight forms of succinoglycan have the ability to protectS. melilotifrom the antimicrobial action of the NCR247 peptide but low-molecular-weight forms of wild-type succinoglycan do not. The protective function of high-molecular-weight succinoglycan occurs via direct molecular interactions between anionic succinoglycan and the cationic NCR247 peptide, but this interaction is not chiral. Taken together, our observations suggest thatS. melilotiexopolysaccharides not only may be critical during early stages of nodule invasion but also are upregulated at a late stage of symbiosis to protect bacteria against the bactericidal action of cationic NCR peptides. Our findings represent an important step forward in fully understanding the complete set of exopolysaccharide functions during legume symbiosis.IMPORTANCESymbiotic interactions between rhizobia and legumes are economically important for global food production. The legume symbiosis also is a major part of the global nitrogen cycle and is an ideal model system to study host-microbe interactions. Signaling between legumes and rhizobia is essential to establish symbiosis, and understanding these signals is a major goal in the field. Exopolysaccharides are important in the symbiotic context because they are essential signaling molecules during early-stage symbiosis. In this study, we provide evidence suggesting that theSinorhizobium melilotiexopolysaccharide succinoglycan also protects the bacteria against the antimicrobial action of essential late-stage symbiosis plant peptides.

Mechanisms and implications of hypoalbuminemia in head-injured patients

1988 ◽  
Vol 69 (3) ◽  
pp. 386-392 ◽  
Author(s):  
Craig J. McClain ◽  
Bernhard Hennig ◽  
Linda G. Ott ◽  
Simeon Goldblum ◽  
A. Byron Young
Keyword(s):  
Endothelial Cell ◽  
Acute Phase ◽  
Nutritional Support ◽  
Cell Injury ◽  
Acute Phase Proteins ◽  
Interleukin 1 ◽  
Endothelial Permeability ◽  
Content Type ◽  
Head Injured ◽  
Injured Patients

✓ Severely head-injured patients are hypermetabolic/hypercatabolic and exhibit many aspects of the postinjury acute-phase response. These patients have hypoalbuminemia, hypozincemia, hypoferremia, hypercupria, fever, and increased synthesis of acute-phase proteins such as ceruloplasmin and higher C-reactive protein levels. It has been suggested that increased interleukin-1 (IL-1) in the ventricular fluid may be responsible, at least in part, for these metabolic abnormalities. In the present study, serum albumin levels were evaluated throughout an 18-day study period in 62 head-injured patients receiving aggressive nutritional support. Hypoalbuminemia (mean ± standard error of the mean 3.10 ± 0.2 gm/dl; normal value 3.5 to 5 gm/dl) was observed upon hospital admission; these albumin levels continued to decrease until 2 weeks postinjury, despite aggressive nutritional support. This hypoalbuminemia may be mediated via altered endothelial permeability properties due to endothelial cell dysfunction caused by cytokines such as IL-1. Transendothelial movement of albumin was assayed using a pulmonary artery endothelial cell culture system. Both a crude macrophage supernatant derived from a murine P388D cell line having IL-1 activity (mIL-1) and human recombinant IL-1 (rIL-1) were tested. The amount of albumin transferred was time- and concentration-dependent, with maximal transfer at 24 hours and 20 U of mIL-1 per 0.5 ml of culture medium. Endothelial permeability changes observed after incubation with mIL-1 were confirmed using rIL-1. Compared to control cultures, 20 U of rIL-1 and 20 U of mIL-1 increased albumin transfer across endothelial monolayers 205% and 459%, respectively. These findings suggest that the mechanism of hypoalbuminemia seen after severe head trauma can be explained in part by IL-1-induced endothelial cell injury, resulting in enhanced endothelial permeability to albumin.

Haptoglobin and serum amyloid A in milk and serum during acute and chronic experimentally induced Staphylococcus aureus mastitis

2003 ◽  
Vol 70 (4) ◽  
pp. 379-386 ◽  
Author(s):  
Ulrika Grönlund ◽  
Cecilia Hultén ◽  
Peter D. Eckersall ◽  
Caroline Hogarth ◽  
Karin Persson Waller
Keyword(s):  
Staphylococcus Aureus ◽  
Acute Phase ◽  
Serum Amyloid A ◽  
Acute Phase Proteins ◽  
Chronic Phase ◽  
Subclinical Mastitis ◽  
Serum Amyloid ◽  
Amyloid A ◽  
Healthy Control ◽  
Experimentally Induced

Local and systemic changes in the acute phase proteins, haptoglobin and serum amyloid A (SAA), were studied in six dairy cows during the acute and chronic phases of experimentally induced Staphylococcus aureus mastitis. Haptoglobin and SAA were measured in serum, and in milk from infected and healthy control udder quarters within each cow. Concentrations of haptoglobin and SAA increased rapidly in both serum and milk during the acute phase of mastitis and followed a similar pattern. Significantly raised milk concentrations of SAA were also found during chronic subclinical mastitis. Serum concentrations of SAA also tended to be higher during the chronic phase than pre-infection. Increases in milk haptoglobin and SAA were specific for the infected udder quarters. In conclusion, measurement of SAA in milk samples could be a useful tool in diagnosing mastitis.

scholarly journals Identification of a Novel LysR-Type Transcriptional Regulator in Staphylococcus aureus That Is Crucial for Secondary Tissue Colonization during Metastatic Bloodstream Infection

mBio ◽  
2020 ◽  
Vol 11 (4) ◽  
Author(s):  
Michaela Groma ◽  
Sarah A. Horst ◽  
Sudip Das ◽  
Bruno Huettel ◽  
Maximilian Klepsch ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Bloodstream Infection ◽  
Murine Model ◽  
Bacterial Colonization ◽  
Critical Role ◽  
Transcriptional Regulator ◽  
Metabolic Adaptation ◽  
Mutant Library ◽  
Copper Transporter ◽  
Content Type

ABSTRACT Staphylococcus aureus is a common cause of bacteremia that can lead to severe complications once the bacteria exit the bloodstream and establish infection in secondary organs. Despite its clinical relevance, little is known about the bacterial factors facilitating the development of these metastatic infections. Here, we used an S. aureus transposon mutant library coupled to transposon insertion sequencing (Tn-Seq) to identify genes that are critical for efficient bacterial colonization of secondary organs in a murine model of metastatic bloodstream infection. Our transposon screen identified a LysR-type transcriptional regulator (LTTR), which was required for efficient colonization of secondary organs such as the kidneys in infected mice. The critical role of LTTR in secondary organ colonization was confirmed using an isogenic mutant deficient in the expression of LTTR. To identify the set of genes controlled by LTTR, we used an S. aureus strain carrying the LTTR gene in an inducible expression plasmid. Gene expression analysis upon induction of LTTR showed increased transcription of genes involved in branched-chain amino acid biosynthesis, a methionine sulfoxide reductase, and a copper transporter as well as decreased transcription of genes coding for urease and components of pyrimidine nucleotides. Furthermore, we show that transcription of LTTR is repressed by glucose, is induced under microaerobic conditions, and required trace amounts of copper ions. Our data thus pinpoints LTTR as an important element that enables a rapid adaptation of S. aureus to the changing host microenvironment. IMPORTANCE Staphylococcus aureus is an important pathogen that can disseminate via the bloodstream and establish metastatic infections in distant organs. To achieve a better understanding of the bacterial factors facilitating the development of these metastatic infections, we used in this study a Staphylococcus aureus transposon mutant library in a murine model of intravenous infection, where bacteria first colonize the liver as the primary infection site and subsequently progress to secondary sites such as the kidney and bones. We identified a novel LysR-type transcriptional regulator (LTTR), which was specifically required by S. aureus for efficient colonization of secondary organs. We also determined the transcriptional activation as well as the regulon of LTTR, which suggests that this regulator is involved in the metabolic adaptation of S. aureus to the host microenvironment found in secondary infection sites.

scholarly journals Impact ofsarAand Phenol-Soluble Modulins on the Pathogenesis of Osteomyelitis in Diverse Clinical Isolates of Staphylococcus aureus

2016 ◽  
Vol 84 (9) ◽  
pp. 2586-2594 ◽  
Author(s):  
Allister J. Loughran ◽  
Dana Gaddy ◽  
Karen E. Beenken ◽  
Daniel G. Meeker ◽  
Roy Morello ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Bone Formation ◽  
Virulence Factors ◽  
Acute Phase ◽  
Bone Destruction ◽  
Extracellular Proteins ◽  
Clinical Isolates ◽  
Raw 264.7 Cells ◽  
Content Type ◽  
Posttraumatic Osteomyelitis

We used a murine model of acute, posttraumatic osteomyelitis to evaluate the virulence of two divergentStaphylococcus aureusclinical isolates (the USA300 strain LAC and the USA200 strain UAMS-1) and their isogenicsarAmutants. The results confirmed that both strains caused comparable degrees of osteolysis and reactive new bone formation in the acute phase of osteomyelitis. Conditioned medium (CM) from stationary-phase cultures of both strains was cytotoxic to cells of established cell lines (MC3TC-E1 and RAW 264.7 cells), primary murine calvarial osteoblasts, and bone marrow-derived osteoclasts. Both the cytotoxicity of CM and the reactive changes in bone were significantly reduced in the isogenicsarAmutants. These results confirm thatsarAis required for the production and/or accumulation of extracellular virulence factors that limit osteoblast and osteoclast viability and that thereby promote bone destruction and reactive bone formation during the acute phase ofS. aureusosteomyelitis. Proteomic analysis confirmed the reduced accumulation of multiple extracellular proteins in the LAC and UAMS-1sarAmutants. Included among these were the alpha class of phenol-soluble modulins (PSMs), which were previously implicated as important determinants of osteoblast cytotoxicity and bone destruction and repair processes in osteomyelitis. Mutation of the corresponding operon reduced the cytotoxicity of CM from both UAMS-1 and LAC cultures for osteoblasts and osteoclasts. It also significantly reduced both reactive bone formation and cortical bone destruction by CM from LAC cultures. However, this was not true for CM from cultures of a UAMS-1psmαmutant, thereby suggesting the involvement of additional virulence factors in such strains that remain to be identified.

scholarly journals Vaccine Protection of Leukopenic Mice against Staphylococcus aureus Bloodstream Infection

2014 ◽  
Vol 82 (11) ◽  
pp. 4889-4898 ◽  
Author(s):  
Sabine Rauch ◽  
Portia Gough ◽  
Hwan Keun Kim ◽  
Olaf Schneewind ◽  
Dominique Missiakas
Keyword(s):  
Staphylococcus Aureus ◽  
Bloodstream Infection ◽  
Immune Cell ◽  
Hematologic Malignancy ◽  
Surface Proteins ◽  
Sortase A ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Time To Death ◽  
Von Willebrand

ABSTRACTThe risk forStaphylococcus aureusbloodstream infection (BSI) is increased in immunocompromised individuals, including patients with hematologic malignancy and/or chemotherapy. Due to the emergence of antibiotic-resistant strains, designated methicillin-resistantS. aureus(MRSA), staphylococcal BSI in cancer patients is associated with high mortality; however, neither a protective vaccine nor pathogen-specific immunotherapy is currently available. Here, we modeled staphylococcal BSI in leukopenic CD-1 mice that had been treated with cyclophosphamide, a drug for leukemia and lymphoma patients. Cyclophosphamide-treated mice were highly sensitive toS. aureusBSI and developed infectious lesions lacking immune cell infiltrates. Virulence factors ofS. aureusthat are key for disease establishment in immunocompetent hosts—α-hemolysin (Hla), iron-regulated surface determinants (IsdA and IsdB), coagulase (Coa), and von Willebrand factor binding protein (vWbp)—are dispensable for the pathogenesis of BSI in leukopenic mice. In contrast, sortase A mutants, which cannot assemble surface proteins, display delayed time to death and increased survival in this model. A vaccine with four surface antigens (ClfA, FnBPB, SdrD, and SpAKKAA), which was identified by genetic vaccinology using sortase A mutants, raised antigen-specific immune responses that protected leukopenic mice against staphylococcal BSI.

scholarly journals Protein A Suppresses Immune Responses during Staphylococcus aureus Bloodstream Infection in Guinea Pigs

mBio ◽  
2015 ◽  
Vol 6 (1) ◽  
Author(s):  
Hwan Keun Kim ◽  
Fabiana Falugi ◽  
Lena Thomer ◽  
Dominique M. Missiakas ◽  
Olaf Schneewind
Keyword(s):  
Staphylococcus Aureus ◽  
Guinea Pig ◽  
B Cell ◽  
Bloodstream Infection ◽  
Guinea Pigs ◽  
Protective Immunity ◽  
Protein A ◽  
Pig Model ◽  
Content Type ◽  
Guinea Pig Model

ABSTRACT  Staphylococcus aureusinfection is not associated with the development of protective immunity, and disease relapses occur frequently. We hypothesize that protein A, a factor that binds immunoglobulin Fcγ and cross-links VH3 clan B cell receptors (IgM), is the staphylococcal determinant for host immune suppression. To test this, vertebrate IgM was examined for protein A cross-linking. High VH3 binding activity occurred with human and guinea immunoglobulin, whereas mouse and rabbit immunoglobulins displayed little and no binding, respectively. Establishing a guinea pig model of S. aureus bloodstream infection, we show that protein A functions as a virulence determinant and suppresses host B cell responses. Immunization with SpAKKAA, which cannot bind immunoglobulin, elicits neutralizing antibodies that enable guinea pigs to develop protective immunity.IMPORTANCE Staphylococcus aureusis the leading cause of soft tissue and bloodstream infections; however, a vaccine with clinical efficacy is not available. Using mice to model staphylococcal infection, earlier work identified protective antigens; however, corresponding human clinical trials did not reach their endpoints. We show that B cell receptor (IgM) cross-linking by protein A is an important immune evasion strategy of S. aureus that can be monitored in a guinea pig model of bloodstream infection. Further, immunization with nontoxigenic protein A enables infected guinea pigs to elicit antibody responses that are protective against S. aureus. Thus, the guinea pig model may support preclinical development of staphylococcal vaccines.

scholarly journals Acute Phase Proteins in Bovine Milk in an Experimental Model of Staphylococcus aureus Subclinical Mastitis

2006 ◽  
Vol 89 (5) ◽  
pp. 1488-1501 ◽  
Author(s):  
P.D. Eckersall ◽  
F.J. Young ◽  
A.M. Nolan ◽  
C.H. Knight ◽  
C. McComb ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Experimental Model ◽  
Acute Phase ◽  
Acute Phase Proteins ◽  
Bovine Milk ◽  
Subclinical Mastitis

scholarly journals Activation of Hepatic STAT3 Maintains Pulmonary Defense during Endotoxemia

2015 ◽  
Vol 83 (10) ◽  
pp. 4015-4027 ◽  
Author(s):  
Kristie L. Hilliard ◽  
Eri Allen ◽  
Katrina E. Traber ◽  
Yuri Kim ◽  
Gregory A. Wasserman ◽  
...  
Keyword(s):  
Acute Phase ◽  
Host Defense ◽  
Bronchoalveolar Lavage Fluid ◽  
Acute Phase Proteins ◽  
Ex Vivo ◽  
Reactive Oxygen Species Generation ◽  
Lavage Fluid ◽  
Phase Changes ◽  
Content Type

Pneumonia and infection-induced sepsis are worldwide public health concerns. Both pathologies elicit systemic inflammation and induce a robust acute-phase response (APR). Although APR activation is well regarded as a hallmark of infection, the direct contributions of liver activation to pulmonary defense during sepsis remain unclear. By targeting STAT3-dependent acute-phase changes in the liver, we evaluated the role of liver STAT3 activity in promoting host defense in the context of sepsis and pneumonia. We employed a two-hit endotoxemia/pneumonia model, whereby administration of 18 h of intraperitoneal lipopolysaccharide (LPS; 5 mg/kg of body weight) was followed by intratrachealEscherichia coli(106CFU) in wild-type mice or those lacking hepatocyte STAT3 (hepSTAT3−/−). Pneumonia alone (without endotoxemia) was effectively controlled in the absence of liver STAT3. Following endotoxemia and pneumonia, however, hepSTAT3−/−mice, with significantly reduced levels of circulating and airspace acute-phase proteins, exhibited significantly elevated lung and blood bacterial burdens and mortality. These data suggested that STAT3-dependent liver responses are necessary to promote host defense. While neither recruited airspace neutrophils nor lung injury was altered in endotoxemic hepSTAT3−/−mice, alveolar macrophage reactive oxygen species generation was significantly decreased. Additionally, bronchoalveolar lavage fluid from this group of hepSTAT3−/−mice allowed greater bacterial growthex vivo. These results suggest that hepatic STAT3 activation promotes both cellular and humoral lung defenses. Taken together, induction of liver STAT3-dependent gene expression programs is essential to countering the deleterious consequences of sepsis on pneumonia susceptibility.

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