21 research outputs found
A Disintegrin and Metalloproteinase : Control Elements in Infectious Diseases
Despite recent advances in treatment strategies, infectious diseases are still under
the leading causes of death worldwide. Although the activation of the inflammatory
cascade is one prerequisite of defense, persistent and exuberant immune response,
however, may lead to chronicity of inflammation predisposing to a temporal or permanent
tissue damage not only of the site of infection but also among different body organs.
The initial response to invading pathogens is mediated by the recognition through
various pattern-recognition receptors along with cellular engulfment resulting in a
coordinated release of soluble effector molecules and cytokines aiming to terminate
the external stimuli. Members of the âa disintegrin and metalloproteinaseâ (ADAM)
family have the capability to proteolytically cleave transmembrane molecules close to
the plasma membrane, a process called ectodomain shedding. In fact, in infectious
diseases dysregulation of numerous ADAM substrates such as junction molecules
(e.g., E-cadherin, VE-cadherin, JAM-A), adhesion molecules (e.g., ICAM-1, VCAM-1,
L-selectin), and chemokines and cytokines (e.g., CXCL16, TNF-α) has been observed.
The alpha-cleavage by ADAM proteases represents a rate limiting step for downstream
regulated intramembrane proteolysis (RIPing) of several substrates, which influence
cellular differentiation, cell signaling pathways and immune modulation. Both the
substrates mentioned above and RIPing crucially contribute to a systematic damage in
cardiovascular, endocrine, and/or gastrointestinal systems. This review will summarize
the current knowledge of ADAM function and the subsequent RIPing in infectious
diseases (e.g., pathogen recognition and clearance) and discuss the potential long-term
effect on pathophysiological changes such as cardiovascular diseases
Pseudomonas aeruginosa Alters Critical Lung Epithelial Cell Functions through Activation of ADAM17
Severe epithelial dysfunction is one major hallmark throughout the pathophysiological
progress of bacterial pneumonia. Junctional and cellular adhesion molecules (e.g., JAMA-A, ICAM-1),
cytokines (e.g., TNFα), and growth factors (e.g., TGFα), controlling proper lung barrier function
and leukocyte recruitment, are proteolytically cleaved and released into the extracellular space
through a disintegrin and metalloproteinase (ADAM) 17. In cell-based assays, we could show that
the protein expression, maturation, and activation of ADAM17 is upregulated upon infection of lung
epithelial cells with Pseudomonas aeruginosa and Exotoxin A (ExoA), without any impact of infection
by Streptococcus pneumoniae. The characterization of released extracellular vesicles/exosomes and the
comparison to heat-inactivated bacteria revealed that this increase occurred in a cell-associated and
toxin-dependent manner. Pharmacological targeting and gene silencing of ADAM17 showed that
its activation during infection with Pseudomonas aeruginosa was critical for the cleavage of junctional
adhesion molecule A (JAM-A) and epithelial cell survival, both modulating barrier integrity, epithelial
regeneration, leukocyte adhesion and transepithelial migration. Thus, site-specific targeting of
ADAM17 or blockage of the activating toxins may constitute a novel anti-infective therapeutic option
in Pseudomonas aeruginosa lung infection preventing severe epithelial and organ dysfunctions and
stimulating future translational studies
Pseudomonas aeruginosa Triggered Exosomal Release of ADAM10 Mediates Proteolytic Cleavage in Trans
Pneumonia is a life-threatening disease often caused by infection with Streptococcus pneumo niae and Pseudomonas aeruginosa. Many of the mediators (e.g., TNF, IL-6R) and junction molecules
(e.g., E-cadherin) orchestrating inflammatory cell recruitment and loss of barrier integrity are prote olytically cleaved through a disintegrin and metalloproteinases (ADAMs). We could show by Western
blot, surface expression analysis and measurement of proteolytic activity in cell-based assays, that
ADAM10 in epithelial cells is upregulated and activated upon infection with Pseudomonas aeruginosa
and Exotoxin A (ExoA), but not upon infection with Streptococcus pneumoniae. Targeting ADAM10
by pharmacological inhibition or gene silencing, we demonstrated that this activation was critical
for cleavage of E-cadherin and modulated permeability and epithelial integrity. Stimulation with
heat-inactivated bacteria revealed that the activation was based on the toxin repertoire rather than
the interaction with the bacterial particle itself. Furthermore, calcium imaging experiments showed
that the ExoA action was based on the induction of calcium influx. Investigating the extracellular
vesicles and their proteolytic activity, we could show that Pseudomonas aeruginosa triggered exosomal
release of ADAM10 and proteolytic cleavage in trans. This newly described mechanism could consti tute an essential mechanism causing systemic inflammation in patients suffering from Pseudomonas
aeruginosa-induced pneumonia stimulating future translational studies
Characterization of the Secreted Acid Phosphatase SapS Reveals a Novel Virulence Factor of Staphylococcus aureus That Contributes to Survival and Virulence in Mice
Staphylococcus aureus possesses a large arsenal of immune-modulating factors, enabling it
to bypass the immune systemâs response. Here, we demonstrate that the acid phosphatase SapS is
secreted during macrophage infection and promotes its intracellular survival in this type of immune
cell. In animal models, the SA564 sapS mutant demonstrated a significantly lower bacterial burden
in liver and renal tissues of mice at four days post infection in comparison to the wild type, along
with lower pathogenicity in a zebrafish infection model. The SA564 sapS mutant elicits a lower
inflammatory response in mice than the wild-type strain, while S. aureus cells harbouring a functional
sapS induce a chemokine response that favours the recruitment of neutrophils to the infection site.
Our in vitro and quantitative transcript analysis show that SapS has an effect on S. aureus capacity to
adapt to oxidative stress during growth. SapS is also involved in S. aureus biofilm formation. Thus,
this study shows for the first time that SapS plays a significant role during infection, most likely
through inhibiting a variety of the hostâs defence mechanisms
ADAM8 signaling drives neutrophil migration and ARDS severity
Acute respiratory distress syndrome (ARDS) results in catastrophic lung failure and has an urgent,
unmet need for improved early recognition and therapeutic development. Neutrophil influx is a
hallmark of ARDS and is associated with the release of tissue-destructive immune effectors, such
as matrix metalloproteinases (MMPs) and membrane-anchored metalloproteinase disintegrins
(ADAMs). Here, we observed using intravital microscopy that Adam8â/â mice had impaired
neutrophil transmigration. In mouse pneumonia models, both genetic deletion and pharmacologic
inhibition of ADAM8 attenuated neutrophil infiltration and lung injury while improving bacterial
containment. Unexpectedly, the alterations of neutrophil function were not attributable to impaired
proteolysis but resulted from reduced intracellular interactions of ADAM8 with the actin-based
motor molecule Myosin1f that suppressed neutrophil motility. In 2 ARDS cohorts, we analyzed
lung fluid proteolytic signatures and identified that ADAM8 activity was positively correlated with
disease severity. We propose that in acute inflammatory lung diseases such as pneumonia and
ARDS, ADAM8 inhibition might allow fine-tuning of neutrophil responses for therapeutic gain
Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study
Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised
Pseudomonas aeruginosa Triggered Exosomal Release of ADAM10 Mediates Proteolytic Cleavage in Trans
Pneumonia is a life-threatening disease often caused by infection with Streptococcus pneumoniae and Pseudomonas aeruginosa. Many of the mediators (e.g., TNF, IL-6R) and junction molecules (e.g., E-cadherin) orchestrating inflammatory cell recruitment and loss of barrier integrity are proteolytically cleaved through a disintegrin and metalloproteinases (ADAMs). We could show by Western blot, surface expression analysis and measurement of proteolytic activity in cell-based assays, that ADAM10 in epithelial cells is upregulated and activated upon infection with Pseudomonas aeruginosa and Exotoxin A (ExoA), but not upon infection with Streptococcus pneumoniae. Targeting ADAM10 by pharmacological inhibition or gene silencing, we demonstrated that this activation was critical for cleavage of E-cadherin and modulated permeability and epithelial integrity. Stimulation with heat-inactivated bacteria revealed that the activation was based on the toxin repertoire rather than the interaction with the bacterial particle itself. Furthermore, calcium imaging experiments showed that the ExoA action was based on the induction of calcium influx. Investigating the extracellular vesicles and their proteolytic activity, we could show that Pseudomonas aeruginosa triggered exosomal release of ADAM10 and proteolytic cleavage in trans. This newly described mechanism could constitute an essential mechanism causing systemic inflammation in patients suffering from Pseudomonas aeruginosa-induced pneumonia stimulating future translational studies
Pseudomonas aeruginosa Alters Critical Lung Epithelial Cell Functions through Activation of ADAM17
Severe epithelial dysfunction is one major hallmark throughout the pathophysiological progress of bacterial pneumonia. Junctional and cellular adhesion molecules (e.g., JAMA-A, ICAM-1), cytokines (e.g., TNFα), and growth factors (e.g., TGFα), controlling proper lung barrier function and leukocyte recruitment, are proteolytically cleaved and released into the extracellular space through a disintegrin and metalloproteinase (ADAM) 17. In cell-based assays, we could show that the protein expression, maturation, and activation of ADAM17 is upregulated upon infection of lung epithelial cells with Pseudomonas aeruginosa and Exotoxin A (ExoA), without any impact of infection by Streptococcus pneumoniae. The characterization of released extracellular vesicles/exosomes and the comparison to heat-inactivated bacteria revealed that this increase occurred in a cell-associated and toxin-dependent manner. Pharmacological targeting and gene silencing of ADAM17 showed that its activation during infection with Pseudomonas aeruginosa was critical for the cleavage of junctional adhesion molecule A (JAM-A) and epithelial cell survival, both modulating barrier integrity, epithelial regeneration, leukocyte adhesion and transepithelial migration. Thus, site-specific targeting of ADAM17 or blockage of the activating toxins may constitute a novel anti-infective therapeutic option in Pseudomonas aeruginosa lung infection preventing severe epithelial and organ dysfunctions and stimulating future translational studies
Global variation in postoperative mortality and complications after cancer surgery: a multicentre, prospective cohort study in 82 countries
Background: 80% of individuals with cancer will require a surgical procedure, yet little comparative data exist on early outcomes in low-income and middle-income countries (LMICs). We compared postoperative outcomes in breast, colorectal, and gastric cancer surgery in hospitals worldwide, focusing on the effect of disease stage and complications on postoperative mortality. Methods: This was a multicentre, international prospective cohort study of consecutive adult patients undergoing surgery for primary breast, colorectal, or gastric cancer requiring a skin incision done under general or neuraxial anaesthesia. The primary outcome was death or major complication within 30 days of surgery. Multilevel logistic regression determined relationships within three-level nested models of patients within hospitals and countries. Hospital-level infrastructure effects were explored with three-way mediation analyses. This study was registered with ClinicalTrials.gov, NCT03471494. Findings: Between April 1, 2018, and Jan 31, 2019, we enrolled 15 958 patients from 428 hospitals in 82 countries (high income 9106 patients, 31 countries; upper-middle income 2721 patients, 23 countries; or lower-middle income 4131 patients, 28 countries). Patients in LMICs presented with more advanced disease compared with patients in high-income countries. 30-day mortality was higher for gastric cancer in low-income or lower-middle-income countries (adjusted odds ratio 3·72, 95% CI 1·70â8·16) and for colorectal cancer in low-income or lower-middle-income countries (4·59, 2·39â8·80) and upper-middle-income countries (2·06, 1·11â3·83). No difference in 30-day mortality was seen in breast cancer. The proportion of patients who died after a major complication was greatest in low-income or lower-middle-income countries (6·15, 3·26â11·59) and upper-middle-income countries (3·89, 2·08â7·29). Postoperative death after complications was partly explained by patient factors (60%) and partly by hospital or country (40%). The absence of consistently available postoperative care facilities was associated with seven to 10 more deaths per 100 major complications in LMICs. Cancer stage alone explained little of the early variation in mortality or postoperative complications. Interpretation: Higher levels of mortality after cancer surgery in LMICs was not fully explained by later presentation of disease. The capacity to rescue patients from surgical complications is a tangible opportunity for meaningful intervention. Early death after cancer surgery might be reduced by policies focusing on strengthening perioperative care systems to detect and intervene in common complications. Funding: National Institute for Health Research Global Health Research Unit
SARS-CoV-2 vaccination modelling for safe surgery to save lives: data from an international prospective cohort study
Background: Preoperative SARS-CoV-2 vaccination could support safer elective surgery. Vaccine numbers are limited so this study aimed to inform their prioritization by modelling.
Methods: The primary outcome was the number needed to vaccinate (NNV) to prevent one COVID-19-related death in 1 year. NNVs were based on postoperative SARS-CoV-2 rates and mortality in an international cohort study (surgical patients), and community SARS-CoV-2 incidence and case fatality data (general population). NNV estimates were stratified by age (18-49, 50-69, 70 or more years) and type of surgery. Best- and worst-case scenarios were used to describe uncertainty.
Results: NNVs were more favourable in surgical patients than the general population. The most favourable NNVs were in patients aged 70 years or more needing cancer surgery (351; best case 196, worst case 816) or non-cancer surgery (733; best case 407, worst case 1664). Both exceeded the NNV in the general population (1840; best case 1196, worst case 3066). NNVs for surgical patients remained favourable at a range of SARS-CoV-2 incidence rates in sensitivity analysis modelling. Globally, prioritizing preoperative vaccination of patients needing elective surgery ahead of the general population could prevent an additional 58 687 (best case 115 007, worst case 20 177) COVID-19-related deaths in 1 year.
Conclusion: As global roll out of SARS-CoV-2 vaccination proceeds, patients needing elective surgery should be prioritized ahead of the general population