Dissecting the Human Response to Staphylococcus aureus Systemic Infections

Staphylococcus aureus is a common human commensal and the leading cause of diverse infections. To identify distinctive parameters associated with infection and colonization, we compared the immune and inflammatory responses of patients with a diagnosis of invasive S. aureus disease to healthy donors. We analyzed the inflammatory responses founding a pattern of distinctive cytokines significantly higher in the patients with invasive disease. The measure of antibody levels revealed a wide antibody responsiveness from all subjects to most of the antigens, with significantly higher response for some antigens in the invasive patients compared to control. Moreover, functional antibodies against toxins distinctively associated with the invasive disease. Finally, we examined the genomic variability of isolates, showing no major differences in genetic distribution compared to a panel of representative strains. Overall, our study shows specific signatures of cytokines and functional antibodies in patients with different primary invasive diseases caused by S. aureus. These data provide insight into human responses towards invasive staphylococcal infections and are important for guiding the identification of novel preventive and therapeutic interventions against S. aureus.

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Functional Antibodies against Placental Malaria Parasites Are Variant Dependent and Differ by Geographic Region

Infection and Immunity ◽

10.1128/iai.00865-18 ◽

2019 ◽

Vol 87 (7) ◽

Cited By ~ 4

Author(s):

Justin Doritchamou ◽

Andrew Teo ◽

Robert Morrison ◽

Gunjan Arora ◽

Jennifer Kwan ◽

...

Keyword(s):

Recombinant Proteins ◽

Inflammatory Responses ◽

Placental Malaria ◽

Geographic Region ◽

Surface Reactivity ◽

Content Type ◽

Functional Activities ◽

Binding Inhibition ◽

Functional Antibodies ◽

Antibody Levels

ABSTRACTDuring pregnancy, Plasmodium falciparum-infected erythrocytes (IE) accumulate in the intervillous spaces of the placenta by binding to chondroitin sulfate A (CSA) and elicit inflammatory responses that are associated with poor pregnancy outcomes. Primigravidae lack immunity to IE that sequester in the placenta and thus are susceptible to placental malaria (PM). Women become resistant to PM over successive pregnancies as antibodies to placental IE are acquired. Here, we assayed plasma collected at delivery from Malian and Tanzanian women of different parities for total antibody levels against recombinant VAR2CSA antigens (FCR3 allele), and for surface reactivity and binding inhibition and opsonizing functional activities against IE using two CSA-binding laboratory isolates (FCR3 and NF54). Overall, antibody reactivity to VAR2CSA recombinant proteins and to CSA-binding IE was higher in multigravidae than in primigravidae. However, plasma from Malian gravid women reacted more strongly with FCR3 whereas Tanzanian plasma preferentially reacted with NF54. Further, acquisition of functional antibodies was variant dependent: binding inhibition of P. falciparum strain NF54 (P < 0.001) but not of the strain FCR3 increased significantly with parity, while only opsonizing activity against FCR3 (P < 0.001) increased significantly with parity. In addition, opsonizing and binding inhibition activities of plasma of multigravidae were significantly correlated in assays of FCR3 (r = 0.4, P = 0.01) but not of NF54 isolates; functional activities did not correlate in plasma from primigravidae. These data suggest that IE surface-expressed epitopes involved in each functional activity differ among P. falciparum strains. Consequently, geographic bias in circulating strains may impact antibody functions. Our study has implications for the development of PM vaccines aiming to achieve broad protection against various parasite strains.

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Transcriptomic Data Analysis Reveals a Down-Expression of Galectin-8 in Schizophrenia Hippocampus

Brain Sciences ◽

10.3390/brainsci11080973 ◽

2021 ◽

Vol 11 (8) ◽

pp. 973

Author(s):

Maria Cristina Petralia ◽

Rosella Ciurleo ◽

Alessia Bramanti ◽

Placido Bramanti ◽

Andrea Saraceno ◽

...

Keyword(s):

Inflammatory Responses ◽

Clinical Manifestations ◽

Antipsychotic Agents ◽

Standards Of Care ◽

Specific Gene ◽

Contributing Factors ◽

Healthy Donors ◽

Dorsolateral Prefrontal ◽

Inflammatory Processes ◽

Disease Specific

Schizophrenia (SCZ) is a severe psychiatric disorder with several clinical manifestations that include cognitive dysfunction, decline in motivation, and psychosis. Current standards of care treatment with antipsychotic agents are often ineffective in controlling the disease, as only one-third of SCZ patients respond to medications. The mechanisms underlying the pathogenesis of SCZ remain elusive. It is believed that inflammatory processes may play a role as contributing factors to the etiology of SCZ. Galectins are a family of β-galactoside-binding lectins that contribute to the regulation of immune and inflammatory responses, and previous reports have shown their role in the maintenance of central nervous system (CNS) homeostasis and neuroinflammation. In the current study, we evaluated the expression levels of the galectin gene family in post-mortem samples of the hippocampus, associative striatum, and dorsolateral prefrontal cortex from SCZ patients. We found a significant downregulation of LGALS8 (Galectin-8) in the hippocampus of SCZ patients as compared to otherwise healthy donors. Interestingly, the reduction of LGALS8 was disease-specific, as no modulation was observed in the hippocampus from bipolar nor major depressive disorder (MDD) patients. Prediction analysis identified TBL1XR1, BRF2, and TAF7 as potential transcription factors controlling LGALS8 expression. In addition, MIR3681HG and MIR4296 were negatively correlated with LGALS8 expression, suggesting a role for epigenetics in the regulation of LGALS8 levels. On the other hand, no differences in the methylation levels of LGALS8 were observed between SCZ and matched control hippocampus. Finally, ontology analysis of the genes negatively correlated with LGALS8 expression identified an enrichment of the NGF-stimulated transcription pathway and of the oligodendrocyte differentiation pathway. Our study identified LGALS8 as a disease-specific gene, characterizing SCZ patients, that may in the future be exploited as a potential therapeutic target.

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Evaluating Functional Immunity Following Encapsulated Bacterial Infection and Vaccination

Vaccines ◽

10.3390/vaccines9060677 ◽

2021 ◽

Vol 9 (6) ◽

pp. 677

Author(s):

Zheng Quan Toh ◽

Rachel A. Higgins ◽

Nadia Mazarakis ◽

Elysia Abbott ◽

Jordan Nathanielsz ◽

...

Keyword(s):

Protective Immunity ◽

Invasive Disease ◽

Haemophilus Influenzae Type ◽

Current State ◽

Primary Mechanism ◽

Antibody Assays ◽

Functional Immunity ◽

Accurate Comparison ◽

Encapsulated Bacteria ◽

Functional Antibodies

Encapsulated bacteria such as Streptococcus pneumoniae, Haemophilus influenzae type b and Neisseria meningitidis cause significant morbidity and mortality in young children despite the availability of vaccines. Highly specific antibodies are the primary mechanism of protection against invasive disease. Robust and standardised assays that measure functional antibodies are also necessary for vaccine evaluation and allow for the accurate comparison of data between clinical studies. This mini review describes the current state of functional antibody assays and their importance in measuring protective immunity.

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855. Significance of Invasive Infections due to Methicillin Sensitive Staphylococcus aureus in the neonatal population

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1044 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S468-S468

Author(s):

Mariawy Riollano ◽

Deena Altman ◽

shanna kowalsky ◽

Stephanie Pan

Keyword(s):

Staphylococcus Aureus ◽

Clinical Characteristics ◽

Invasive Disease ◽

Control Measures ◽

Invasive Infection ◽

Single Center ◽

Infection Control Measures ◽

Invasive Infections ◽

Mrsa Colonization ◽

Neonatal Population

Abstract Background Staphylococcus aureus is a well-known cause of hospital acquired infections. Methicillin resistant staphylococcus aureus (MRSA) colonization is a recognized risk factor for invasive infections. The neonatal population in the intensive care unit (NICU) is particularly vulnerable to these types of infections, resulting in high mortality and morbidity. However, only scant data is available to establish the risk for invasive disease in patients with Methicillin sensitive staphylococcus aureus (MSSA). As a result, surveillance and prevention strategies are only address for MRSA colonization. Here, we describe the clinical characteristics of S. aureus colonized patients identified in late 2018 during transmission events in a single center NICU. As a result of the targeted surveillance investigation for MRSA infection control measures, S. aureus colonization was stratified, and we were able to compare the differences in invasive disease between MRSA and MSSA. Methods This is a retrospective chart review of the 47 colonized patients identified during October 2018- January 2019 SA transmission events in single center NICU. Risk factors, clinical characteristics, and the hospital course of these cases, including the proportion of invasive illness were reviewed. Results We found that most clinical characteristic, risk factors, and hospital course were the same between MRSA and MSSA colonized infants (p values > 0.05). Additionally, there was no difference in the proportion of invasive infection between MRSA and MSSA colonized patients (p value > 0.05). The type of invasive infections identified were SSTI, bacteremia, and osteomyelitis. Conclusion The proportion of invasive infection was the same in MSSA and MRSA colonized patients. This data provides us with supportive material for future recommendations of infection control measures for MSSA colonized patients. Disclosures All Authors: No reported disclosures

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Molecular Alterations in Sporadic and SOD1-ALS Immortalized Lymphocytes: Towards a Personalized Therapy

International Journal of Molecular Sciences ◽

10.3390/ijms22063007 ◽

2021 ◽

Vol 22 (6) ◽

pp. 3007

Author(s):

Isabel Lastres-Becker ◽

Gracia Porras ◽

Marina Arribas-Blázquez ◽

Inés Maestro ◽

Daniel Borrego-Hernández ◽

...

Keyword(s):

Motor Neurons ◽

Molecular Mechanisms ◽

Cell Types ◽

Therapeutic Interventions ◽

Autophagic Flux ◽

Metabolic Disturbances ◽

Molecular Alterations ◽

Healthy Donors ◽

Inflammatory Profile ◽

Als Patients

Amyotrophic lateral sclerosis (ALS) is a fatal neurological condition where motor neurons (MNs) degenerate. Most of the ALS cases are sporadic (sALS), whereas 10% are hereditarily transmitted (fALS), among which mutations are found in the gene that codes for the enzyme superoxide dismutase 1 (SOD1). A central question in ALS field is whether causative mutations display selective alterations not found in sALS patients, or they converge on shared molecular pathways. To identify specific and common mechanisms for designing appropriate therapeutic interventions, we focused on the SOD1-mutated (SOD1-ALS) versus sALS patients. Since ALS pathology involves different cell types other than MNs, we generated lymphoblastoid cell lines (LCLs) from sALS and SOD1-ALS patients and healthy donors and investigated whether they show changes in oxidative stress, mitochondrial dysfunction, metabolic disturbances, the antioxidant NRF2 pathway, inflammatory profile, and autophagic flux. Both oxidative phosphorylation and glycolysis appear to be upregulated in lymphoblasts from sALS and SOD1-ALS. Our results indicate significant differences in NRF2/ARE pathway between sALS and SOD1-ALS lymphoblasts. Furthermore, levels of inflammatory cytokines and autophagic flux discriminate between sALS and SOD1-ALS lymphoblasts. Overall, different molecular mechanisms are involved in sALS and SOD1-ALS patients and thus, personalized medicine should be developed for each case.

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Nuclear receptor Nur77: its role in chronic inflammatory diseases

Essays in Biochemistry ◽

10.1042/ebc20210004 ◽

2021 ◽

Author(s):

Sanne C. Lith ◽

Carlie J.M. de Vries

Keyword(s):

Nuclear Receptor ◽

Inflammatory Disease ◽

Inflammatory Responses ◽

Current Knowledge ◽

Inflammatory Diseases ◽

Cell Types ◽

Experimental Models ◽

Therapeutic Interventions ◽

Alternative Mechanism ◽

Signaling Complex

Abstract Nur77 is a nuclear receptor that has been implicated as a regulator of inflammatory disease. The expression of Nur77 increases upon stimulation of immune cells and is differentially expressed in chronically inflamed organs in human and experimental models. Furthermore, in a variety of animal models dedicated to study inflammatory diseases, changes in Nur77 expression alter disease outcome. The available studies comprise a wealth of information on the function of Nur77 in diverse cell types and tissues. Negative cross-talk of Nur77 with the NFκB signaling complex is an example of Nur77 effector function. An alternative mechanism of action has been established, involving Nur77-mediated modulation of metabolism in macrophages as well as in T cells. In this review, we summarize our current knowledge on the role of Nur77 in atherosclerosis, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and sepsis. Detailed insight in the control of inflammatory responses will be essential in order to advance Nur77-targeted therapeutic interventions in inflammatory disease.

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Histologic Features of Zygomycosis

Archives of Pathology & Laboratory Medicine ◽

10.5858/2001-125-0375-hfoz ◽

2001 ◽

Vol 125 (3) ◽

pp. 375-378 ◽

Cited By ~ 11

Author(s):

John L. Frater ◽

Gerri S. Hall ◽

Gary W. Procop

Keyword(s):

Perineural Invasion ◽

Inflammatory Responses ◽

Fungal Growth ◽

Positive Culture ◽

Clinical History ◽

Invasive Disease ◽

Medical Intervention ◽

Common Finding ◽

Fungus Ball ◽

Fungal Morphology

Abstract Objective.—Invasive zygomycosis is rapidly progressive and is associated with angioinvasion and infarction. Invasive disease requires emergent surgical and medical intervention. Because it is important for surgical pathologists to recognize these fungi and their preferential sites of growth, the objective of this article is to describe the fungal morphology and histopathologic findings in biopsies from patients with zygomycotic disease, with emphasis on preferential sites of fungal growth. Design.—Medical record and histologic review identified 20 patients with zygomycosis. Inclusion criteria included the presence of typical ribbonlike hyphae and positive culture, a clinical history of invasive zygomycosis, or both. The histologic features of disease and the fungal morphology were assessed. Results.—Fungus ball (15%), rhinocerebral (55%), and pulmonary (30%) disease were the types of disease represented. The inflammatory responses were predominantly neutrophilic (50%), predominantly granulomatous (5%), pyogranulomatous (25%), or absent (20%). Invasive disease was characterized by prominent infarcts (94%), angioinvasion (100%), and, surprisingly, prominent perineural invasion (90%) in biopsies that contained nerves for evaluation. At least rare hyphal septa were always seen (100%), and most branches (95%) varied from 45° to 90°. Conclusions.—As known to mycologists, zygomycetes are pauciseptate, rather than aseptate, molds. Therefore, the presence of an occasional septum is expected. Perineural invasion is a common finding in invasive zygomycosis, as are angioinvasion and infarcts. Therefore, prior to excluding the presence of these fungi in biopsies suspected to contain zygomycetes, the perineural space should be carefully examined.

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Galleria mellonella Larvae as an Infection Model to Investigate sRNA-Mediated Pathogenesis in Staphylococcus aureus

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.631710 ◽

2021 ◽

Vol 11 ◽

Author(s):

Guillaume Ménard ◽

Astrid Rouillon ◽

Gevorg Ghukasyan ◽

Mathieu Emily ◽

Brice Felden ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Galleria Mellonella ◽

Inflammatory Responses ◽

Expression Profiles ◽

Bacterial Pathogens ◽

Infection Model ◽

Animal Testing ◽

Easy Method ◽

Larval Infection ◽

Over Time

Small regulatory RNAs (sRNAs) are key players in bacterial regulatory networks. Monitoring their expression inside living colonized or infected organisms is essential for identifying sRNA functions, but few studies have looked at sRNA expression during host infection with bacterial pathogens. Insufficient in vivo studies monitoring sRNA expression attest to the difficulties in collecting such data, we therefore developed a non-mammalian infection model using larval Galleria mellonella to analyze the roles of Staphylococcus aureus sRNAs during larval infection and to quickly determine possible sRNA involvement in staphylococcal virulence before proceeding to more complicated animal testing. We began by using the model to test infected larvae for immunohistochemical evidence of infection as well as host inflammatory responses over time. To monitor sRNA expression during infection, total RNAs were extracted from the larvae and invading bacteria at different time points. The expression profiles of the tested sRNAs were distinct and they fluctuated over time, with expression of both sprD and sprC increased during infection and associated with mortality, while rnaIII expression remained barely detectable over time. A strong correlation was observed between sprD expression and the mortality. To confirm these results, we used sRNA-knockout mutants to investigate sRNA involvement in Staphylococcus aureus pathogenesis, finding that the decrease in death rates is delayed when either sprD or sprC was lacking. These results demonstrate the relevance of this G. mellonella model for investigating the role of sRNAs as transcriptional regulators involved in staphylococcal virulence. This insect model provides a fast and easy method for monitoring sRNA (and mRNA) participation in S. aureus pathogenesis, and can also be used for other human bacterial pathogens.

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P2X7 Receptor–Mediated Inflammation in Cardiovascular Disease

Frontiers in Pharmacology ◽

10.3389/fphar.2021.654425 ◽

2021 ◽

Vol 12 ◽

Author(s):

Junteng Zhou ◽

Zhichao Zhou ◽

Xiaojing Liu ◽

Hai-Yan Yin ◽

Yong Tang ◽

...

Keyword(s):

Cardiovascular Disease ◽

Cardiovascular Diseases ◽

P2x7 Receptor ◽

Cardiac Fibrosis ◽

Inflammatory Responses ◽

Interleukin 1 ◽

Experimental Studies ◽

Therapeutic Interventions ◽

Receptor Protein ◽

Inflammasome Activation

Purinergic P2X7 receptor, a nonselective cation channel, is highly expressed in immune cells as well as cardiac smooth muscle cells and endothelial cells. Its activation exhibits to mediate nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome activation, resulting in the release of interleukin-1 beta (IL-1β) and interleukin-18 (IL-18), and pyroptosis, thus triggering inflammatory response. These pathological mechanisms lead to the deterioration of various cardiovascular diseases, including atherosclerosis, arrhythmia, myocardial infarction, pulmonary vascular remodeling, and cardiac fibrosis. All these worsening cardiac phenotypes are proven to be attenuated after the P2X7 receptor inhibition in experimental studies. The present review aimed to summarize key aspects of P2X7 receptor–mediated inflammation and pyroptosis in cardiovascular diseases. The main focus is on the evidence addressing the involvement of the P2X7 receptor in the inflammatory responses to the occurrence and development of cardiovascular disease and therapeutic interventions.

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Everybody Nose: Molecular and Clinical Characteristics of Nasal Colonization During Active Methicillin-Resistant Staphylococcus Aureus Bloodstream Infection

10.21203/rs.3.rs-1112075/v1 ◽

2021 ◽

Author(s):

Erika Reategui Schwarz ◽

Adriana van de Guchte ◽

Amy C. Dupper ◽

Ana Berbel Caban ◽

Devika Nadkarni ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Bloodstream Infection ◽

Bloodstream Infections ◽

Invasive Disease ◽

Nasal Colonization ◽

Healthcare Associated Infections ◽

Staphylococcal Protein A ◽

Record System ◽

Methicillin Resistant ◽

Healthcare Associated

Abstract Background. Healthcare-associated infections pose a potentially fatal threat to patients worldwide and Staphylococcus aureus is one of the most common causes of healthcare-associated infections. S. aureus is a common commensal pathogen and a frequent cause of bacteremia, with studies demonstrating that nasal and blood isolates from single patients match more than 80% of the time. Here we report on a contemporary collection of colonizing isolates from those with methicillin-resistant S. aureus (MRSA) bloodstream infections to evaluate the diversity within hosts, and detail the clinical features associated with concomitant nasal colonization.Methods. Swabs of the bilateral anterior nares were obtained from patients diagnosed with MRSA bacteremia. A single colony culture from the blood and an average of 6 colonies from the nares were evaluated for MRSA growth. For the nares cultures, we typed multiple isolates for staphylococcal protein A (spa) and derived the clonal complexes. Demographic and clinical data were obtained retrospectively from the electronic medical record system and analysed using univariate and multivariable regression models.Results. Over an 11-month period, 68 patients were diagnosed with MRSA bloodstream infection, 53 were swabbed, and 37 (70%) were colonized with MRSA in the anterior nares. We performed molecular typing on 210 nasal colonies. Spa types and clonal complexes found in the blood were also detected in the nares in 95% of the cases. We also found that 11% of patients carried more than one clone of MRSA in the nares. Male sex and history of prior hospitalization within the past 90 days increased odds for MRSA colonization. Conclusion. The molecular epidemiological landscape of colonization in the setting of invasive disease is diverse and defining the interplay between colonization and invasive disease is critical to combating invasive MRSA disease.

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