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Query: UMLS:C0036690 (
sepsis
)
59,461
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Bacteremia is a hallmark of invasive
Streptococcus suis
infections of pigs, often leading to
septicemia
, meningitis, or arthritis. An important defense mechanism of neutrophils is the generation of reactive oxygen species (ROS). In this study, we report high levels of ROS production by blood granulocytes after intravenous infection of a pig with high levels of
S. suis
-specific antibodies and comparatively low levels of bacteremia. This prompted us to investigate the working hypothesis that the immunoglobulin-mediated oxidative burst contributes to the killing of
S. suis
in porcine blood. Several
S. suis
strains representing serotypes 2, 7, and 9 proved to be highly susceptible to the oxidative burst intermediate hydrogen peroxide, already at concentrations of 0.001%. The induction of ROS in granulocytes in
ex vivo
-infected reconstituted blood showed an association with pathogen-specific antibody levels. Importantly, inhibition of ROS production by the
NADPH oxidase
inhibitor apocynin led to significantly increased bacterial survival in the presence of high specific antibody levels. The oxidative burst rate of granulocytes partially depended on complement activation, as shown by specific inhibition. Furthermore, treatment of IgG-depleted serum with a specific IgM protease or heat to inactivate complement resulted in >3-fold decreased oxidative burst activity and increased bacterial survival in reconstituted porcine blood in accordance with an IgM-complement-oxidative burst axis. In conclusion, this study highlights an important control mechanism of
S. suis
bacteremia in the natural host: the induction of ROS in blood granulocytes via specific immunoglobulins such as IgM.
...
PMID:Survival of Streptococcus suis in Porcine Blood Is Limited by the Antibody- and Complement-Dependent Oxidative Burst Response of Granulocytes. 3184 67
Staphylococcus aureus
is a major human pathogen causing multiple pathologies, from cutaneous lesions to life-threatening
sepsis
. Although neutrophils contribute to immunity against
S. aureus
, multiple lines of evidence suggest that these phagocytes can provide an intracellular niche for staphylococcal dissemination. However, the mechanism of neutrophil subversion by intracellular
S. aureus
remains unknown. Targeting of intracellular pathogens by macroautophagy/autophagy is recognized as an important component of host innate immunity, but whether autophagy is beneficial or detrimental to
S. aureus
-infected hosts remains controversial. Here, using larval zebrafish, we showed that the autophagy marker Lc3 rapidly decorates
S. aureus
following engulfment by macrophages and neutrophils. Upon phagocytosis by neutrophils, Lc3-positive, non-acidified spacious phagosomes are formed. This response is dependent on phagocyte
NADPH oxidase
as both
cyba/p22phox
knockdown and diphenyleneiodonium (DPI) treatment inhibited Lc3 decoration of phagosomes. Importantly,
NADPH oxidase
inhibition diverted neutrophil
S. aureus
processing into tight acidified vesicles, which resulted in increased host resistance to the infection. Some intracellular bacteria within neutrophils were also tagged by Sqstm1/p62-GFP fusion protein and loss of Sqstm1 impaired host defense. Together, we have shown that intracellular handling of
S. aureus
by neutrophils is best explained by Lc3-associated phagocytosis (LAP), which appears to provide an intracellular niche for bacterial pathogenesis, while the selective autophagy receptor Sqstm1 is host-protective. The antagonistic roles of LAP and Sqstm1-mediated pathways in
S. aureus
-infected neutrophils may explain the conflicting reports relating to anti-staphylococcal autophagy and provide new insights for therapeutic strategies against antimicrobial-resistant
Staphylococci
.
Abbreviations:
ATG: autophagy related; CFU: colony-forming units; CMV: cytomegalovirus; Cyba/P22phox: cytochrome b-245, alpha polypeptide; DMSO: dimethyl sulfoxide; DPI: diphenyleneiodonium; EGFP: enhanced green fluorescent protein; GFP: green fluorescent protein; hpf: hours post-fertilization; hpi: hours post-infection; Irf8: interferon regulatory factor 8; LAP: LC3-associated phagocytosis; lyz: lysozyme; LWT: london wild type; Map1lc3/Lc3: microtubule-associated protein 1 light chain 3;
NADPH oxidase
: nicotinamide adenine dinucleotide phosphate oxidase; RFP: red fluorescent protein; ROS: reactive oxygen species; RT-PCR: reverse transcriptase polymerase chain reaction; Sqstm1/p62: sequestosome 1; Tg: transgenic; TSA: tyramide signal amplification.
...
PMID:The autophagic response to
Staphylococcus aureus
provides an intracellular niche in neutrophils. 3217 46
Chronic granulomatous disease (CGD) is an inherited primary immunodeficiency disorder characterised by recurrent and often life-threatening infections and hyperinflammation. It is caused by defects of the phagocytic
NADPH oxidase
, a multicomponent enzyme system responsible for effective pathogen killing. A phase I/II clinical trial of lentiviral gene therapy is underway for the most common form of CGD, X-linked, caused by mutations in the gp91
phox
subunit of the
NADPH oxidase
. We propose to use a similar strategy to tackle p47
phox
-deficient CGD, caused by mutations in NCF1, which encodes the p47
phox
cytosolic component of the enzymatic complex. We generated a pCCLCHIM-p47
phox
lentiviral vector, containing the chimeric Cathepsin G/FES myeloid promoter and a codon-optimised version of the human NCF1 cDNA. Here we show that transduction with the pCCLCHIM-p47
phox
vector efficiently restores p47
phox
expression and biochemical
NADPH oxidase
function in p47
phox
-deficient human and murine cells. We also tested the ability of our gene therapy approach to control infection by challenging p47
phox
-null mice with Salmonella Typhimurium, a leading cause of
sepsis
in CGD patients, and found that mice reconstituted with lentivirus-transduced hematopoietic stem cells had a reduced bacterial load compared with untreated mice. Overall, our results potentially support the clinical development of a gene therapy approach using the pCCLCHIM-p47
phox
vector.
...
PMID:Lentiviral gene therapy rescues p47
phox
chronic granulomatous disease and the ability to fight Salmonella infection in mice. 3253 4
Sepsis
is a life-threatening condition which affects multiple organs including the kidney.
Sepsis
-induced acute kidney injury (AKI) is a major health burden throughout the globe. Pathogenesis of
sepsis
-induced AKI is complex; however, it involves both innate and adaptive immune cells such as B cells, T cells, dendritic cells (DCs), macrophages, and neutrophils. Bruton's tyrosine kinase (BTK) is reportedly involved in inflammatory and oxidative signaling in different immune cells, however its contribution with respect to
sepsis
-induced AKI has not been delineated. This study attempted to investigate the role of BTK and its inhibition on oxidizing enzymes
NADPH oxidase
(NOX-2) and inducible nitric oxide synthase (iNOS) in DCs, neutrophils, and B cells during AKI. Our data reveal that BTK is activated in DCs, neutrophils, and B cells which causes an increase in AKI associated biochemical markers such as serum creatinine/blood urea nitrogen, renal myeloperoxidase activity, and histopathological disturbances in renal tubular structures. Activation of BTK causes upregulation of NOX-2/iNOS/nitrotyrosine in these immune cells and kidney. Treatment with BTK inhibitor, Ibrutinib causes attenuation in AKI associated dysfunction in biochemical parameters (serum creatinine/blood urea nitrogen, renal myeloperoxidase activity) and oxidative stress in immune cells and kidney (iNOS/NOX2/lipid peroxides/nitrotyrosine/protein carbonyls). In summary, the current investigation reveals a compelling role of BTK signaling in
sepsis
-induced AKI which is evident from amelioration of AKI associated renal dysfunction after its inhibition.
...
PMID:Bruton's tyrosine kinase inhibition attenuates oxidative stress in systemic immune cells and renal compartment during sepsis-induced acute kidney injury in mice. 3316 11
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