Type-3 Secretion System-induced pyroptosis protects Pseudomonas against cell-autonomous immunity

Inflammasome-induced pyroptosis comprises a key cell-autonomous immune process against intracellular bacteria, namely the generation of dying cell structures. These so-called pore-induced intracellular traps (PITs) entrap and weaken intracellular microbes. However, the immune importance of pyroptosis against extracellular pathogens remains unclear. Here, we report that Type-3 secretion system (T3SS)-expressing Pseudomonas aeruginosa ( P. aeruginosa ) escaped PIT immunity by inducing a NLRC4 inflammasome-dependent macrophage pyroptosis response in the extracellular environment. To the contrary, phagocytosis of Salmonella Typhimurium promoted NLRC4-dependent PIT formation and the subsequent bacterial caging. Remarkably, T3SS-deficient Pseudomonas were efficiently sequestered within PIT-dependent caging, which favored exposure to neutrophils. Conversely, both NLRC4 and caspase-11 deficient mice presented increased susceptibility to T3SS-deficient P. aeruginosa challenge, but not to T3SS-expressing P. aeruginosa. Overall, our results uncovered that P. aeruginosa uses its T3SS to overcome inflammasome-triggered pyroptosis, which is primarily effective against intracellular invaders. Importance Although innate immune components confer host protection against infections, the opportunistic bacterial pathogen Pseudomonas aeruginosa ( P. aeruginosa ) exploits the inflammatory reaction to thrive. Specifically the NLRC4 inflammasome, a crucial immune complex, triggers an Interleukin (IL)-1β and -18 deleterious host response to P. aeruginosa . Here, we provide evidence that, in addition to IL-1 cytokines, P. aeruginosa also exploits the NLRC4 inflammasome-induced pro-inflammatory cell death, namely pyroptosis, to avoid efficient uptake and killing by macrophages. Therefore, our study reveals that pyroptosis-driven immune effectiveness mainly depends on P. aeruginosa localization. This paves the way toward our comprehension of the mechanistic requirements for pyroptosis effectiveness upon microbial infections and may initiate targeted approaches in order to ameliorate the innate immune functions to infections. Graphical abstract Macrophages infected with T3SS-expressing P. aeruginosa die in a NLRC4-dependent manner, which allows bacterial escape from PIT-mediated cell-autonomous immunity and neutrophil efferocytosis. However, T3SS-deficient P. aeruginosa is detected by both NLRC4 and caspase-11 inflammasomes, which promotes bacterial trapping and subsequent efferocytosis of P. aeruginosa -containing-PITs by neutrophils

Severe toxic rhabdomyolysis under combined palbociclib and simvastatin treatment: A case report

We report the fourth described case of severe toxic rhabdomyolysis occurring in an 81-year-old woman caused by the concomitant administration of palbociclib taken at the usual dosage (125 mg per day) and simvastatin. To the best of our knowledge, this is the first reported case successfully treated by plasma exchanges, with complete functional recovery within two months. The severity of this case justifies further consideration of pharmacokinetic interactions between palbociclib or other CDK-4-6 inhibitors and statins, which potentially increase the risk of an adverse event

Cabbage and fermented vegetables : From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT(1)R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT(1)R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.Peer reviewe

Nrf2-interacting nutrients and COVID-19 : time for research to develop adaptation strategies

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPAR gamma:Peroxisome proliferator-activated receptor, NF kappa B: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2 alpha:Elongation initiation factor 2 alpha). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT(1)R axis (AT(1)R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity

Avoiding disruptions during maintenance operations on BGP sessions

This paper presents a solution aimed at avoiding losses of connectivity when an eBGP peering link is shut down by an operator for a maintenance. Currently, shutting down an eBGP session can lead to transient losses of connectivity even though alternate path are available at the borders of the network. This is very unfortunate as ISPs face more and more stringent service level agreements, and maintenance operations are predictable operations, so that there is time to adapt to the change and preserve the respect of the service level agreement.Anglai

Transfusion sanguine : un modèle de questionnement en recherche et développement

International audienc

<p>Assessing pulmonary hypertension in COPD. Is there a role for computed tomography?</p>

International audiencePulmonary hypertension (PH) is a common complication of chronic obstructive pulmonary disease (COPD) and is associated with increased morbidity and mortality. Reference standard method to diagnose PH is right heart catheterization. Several non-invasive imaging techniques have been employed in the detection of PH. Among them, computed tomography (CT) is the most commonly used for phenotyping and detecting complications of COPD. Several CT findings have also been described in patients with severe PH. Nevertheless, CT analysis is currently based on visual findings which can lead to reproducibility failure. Therefore, there is a need for quantification in order to assess objective criteria. In this review, progresses in automated analyses of CT parameters and their values in predicting PH and COPD outcomes are presented

Impact of Kupffer cells on high fat induced insulin resistance and liver fetuin-A expression.

Backgroun and aims: Hepatokines (liver secreted proteins with possible distant action) are emerging potential players in insulin resistance in type 2 diabetic patients. Here, we explore the effect of a high fat diet on the expression of fetuin-A, one of those candidate liver proteins, and its relation with liver macrophage (Kupffer cell) activation. Methods: Male mice of 5 weeks of age were fed a normal diet (ND) or a high fat diet (HFD) for 3 days, known to initiate steatosis and insulin resistance. A preventive Kupffer cell (KC) depletion was obtained by intravenous injection of clodronate loaded liposomes and compared with PBS liposomes. The mRNA and protein expression of fetuin-A was evaluated by RT-PCR, Western-blot and immunofluorescence (IF) on different insulin-sensitive tissues (liver, adipose tissue and muscle). Results: Short term HFD induced steatosis, KC activation and insulin resistance together with a significant increased expression of liver fetuin-A mRNA (1.5 fold, p<0.01). However, liver fetuin-A protein expression remained unchanged under short term HFD. This increase in fetuin-A under high fat diet was not evidenced in the peripheral insulin sensitive tissues (skeletal muscle and adipose tissue) whether at the mRNA or at the protein level. Kupffer cell depletion in this setting did not reduce hepatic steatosis but significantly ameliorated insulin sensitivity proved by clamp studies. This amelioration in insulin sensitivity in KC-depleted mice was associated with a significant decrease in fetuin-A mRNA expression (0.7 fold, p<0.01) compared to animals with KC. On immunofluorescence, fetuin-A was mostly expressed in centrilobular hepatocytes. Interestingly, while selectively depleting liver macrophages without affecting adipose tissue macrophage infiltration, intravenous clodronate injection was associated with a significant reduction in epididymal adipose tissue expansion compared to PBS injection (1.1% of body weight versus 1.6% of body weight, p<0.001). Conclusion: This study demonstrates liver fetuin-A overexpression at the initiation of HFD feeding, concurrent with hepatic steatosis and insulin resistance. Targeting KC in this setting improved insulin sensitivity and was associated with a decreased adiposity and a reduced liver fetuin-A expression suggesting that fetuin-A acts as an hepatokine with pro-adiposity and pro-insulin resistance effects

A new midshelf record in the northern Bay of Biscay (NE Atlantic, CBT-CS11 core): Sedimentological, geochemical and palynological data over the last 7 kyrs

International audienc