Lethal Bacterial Infection Research Articles

Biological analysis of phage vB_AhaP_PT2 and treatment rescued crucian carp infected with Aeromonas hydrophila

Phage therapy is an alternative approach to overcoming the problem of multidrug resistance in bacteria. In this study, we isolated and purified a virulent phage named vB_AhaP_PT2 from A. hydrophila-TPS. We examined the biological characteristics and genome sequences of vB_AhaP_PT2. After intraperitoneal injection of bacteriophage (8 × 107 PFU/mL) into crucian carp, most of the phage distributed in the liver, spleen, kidney, intestine, and peripheral blood, and disappeared within 72 h. No substantial adverse symptoms were found in major organs after receiving phage injections continuously for 14 days. Vitro and Vivo results indicated that phage can effectively eliminate A. hydrophila-TPS. The phage vB_AhaP_PT2 (8 × 107 PFU/mL, 100 μL) can effectively protect the fish that exhibited a double median lethal dose of bacteria (2 × 106 CFU/fish). Although phage vB_AhaP_PT2 triggered the generation of phage-specific antibodies in carp, when the antibody titer was maximum, 8 × 107 PFU doses of bacteriophage could still protect crucian carp with lethal bacterial infections, the survival rate could reach 80 %. We also found that members of the genus Aeromonas could enter and colonize the intestine. The phage vB_AhaP_PT2 reduced the number of colonies of the genus Aeromonas. However, no significant changes were observed in α-diversity and β-diversity parameters, which suggested that the consumed phage had little effect on the intestine microflora. All the above results suggested that vB_AhaP_PT2 was a safe and effective therapeutic that can be considered as a potential tool to treat the infection caused by A. hydrophila-TPS in aquaculture.

Designing Fast-Moving Antibacterial Microtorpedoes to Treat Lethal Bacterial Biofilm Infections.

Engineering fast-moving microrobot swarms that can physically disassemble bacterial biofilms and kill the bacteria released from the biofilms is a promising way to combat bacterial biofilm infections. Here, we report electrochemical design of Ag7O8NO3 microtorpedoes with outstanding antibacterial performance and meanwhile capable of moving at speeds of hundreds of body lengths per second in clinically used H2O2 aqueous solutions. These fast-moving antibacterial Ag7O8NO3 microtorpedoes could penetrate into and disintegrate the bacterial biofilms and, in turn, kill the bacteria released from the biofilms. Based on the understanding of the growth behavior of the microtorpedoes, we could fine-tune the morphology of the microtorpedoes to accelerate the moving speed and increase their penetration depth into the biofilms simply via controlling the potential waveforms. We further developed an automatic shaking method to selectively peel off the uniformly structured microtorpedoes from the electrode surface, realizing continuous electrochemical production of the microtorpedoes. Animal experiments proved that the microtorpedo swarms greatly increased the survival rate of the mice infected by lethal biofilms to >90%. We used the electrochemical method to design and massively produce uniformly structured fast-moving antibacterial microtorpedo swarms with application potentials in treatment of lethal bacterial biofilm infections.

Effect of acetylcholinesterase inhibition on immune cells in the murine intestinal mucosa

The gastrointestinal tract (GI) is the largest immune organ whose function is controlled by a complex network of neurons from the enteric nervous system (ENS) as well as the sympathetic and parasympathetic system. Evolving evidence indicates that cross-communication between gut-innervating neurons and immune cells regulates many essential physiological functions including protection against mucosal infections. We previously demonstrated that following paraoxon treatment, 70 % of the mice were able to survive an oral infection with S. typhimurium, a virulent strain of Salmonella enterica serovar Typhimurium. The present study aims to investigate the effect that rivastigmine, a reversible AChE inhibitor used for the treatment of neurodegenerative diseases, has on the murine immune defenses of the intestinal mucosa. Our findings show that, similar to what is observed with paraoxon, administration of rivastigmine promoted the release of secretory granules from goblet and Paneth cells, resulting in increased mucin layer. Surprisingly, however, and unlike paraoxon, rivastigmine treatment did not affect overall mortality of infected mice. In order to investigate the mechanistic basis for the differential effects observed between paraoxon and rivastigmine, we used multi-color flowcytometric analysis to characterize the immune cell landscape in the intraepithelial (IE) and lamina propria (LP) compartments of intestinal mucosa. Our data indicate that treatment with paraoxon, but not rivastigmine, led to an increase of resident CD3+CD8+ T lymphocytes in the ileal mucosa (epithelium and lamina propria) and CD11b− CD11c+ dendritic cells in the LP. Our findings indicate the requirement for persistent cholinergic pathway engagement to effect a change in the cellular landscape of the mucosal tissue that is necessary for protection against lethal bacterial infections. Moreover, optimal protection requires a collaboration between innate and adaptive mucosal immune responses in the intestine.

3-Hydroxykynurenine targets kainate receptors to promote defense against infection.

Bacterial infection involves a complex interaction between the pathogen and host where the outcome of infection is not solely determined by pathogen eradication. To identify small molecules that promote host survival by altering the host-pathogen dynamic, we conducted an in vivo chemical screen using zebrafish embryos and found that treatment with 3-hydroxykynurenine (3-HK) protects from lethal bacterial infection. 3-HK, a metabolite produced through host tryptophan metabolism, has no direct antibacterial activity but enhances host survival by restricting bacterial expansion in macrophages through a systemic mechanism that targets kainate-sensitive glutamate receptors. These findings reveal a new pathway by which tryptophan metabolism and kainate-sensitive glutamate receptors function and interact to modulate immunity, with important implications for the coordination between the immune and nervous systems in pathological conditions.

Neutrophils and galectin-3 defend mice from lethal bacterial infection and humans from acute respiratory failure

Respiratory infection by Pseudomonas aeruginosa, common in hospitalized immunocompromised and immunocompetent ventilated patients, can be life-threatening because of antibiotic resistance. This raises the question of whether the host’s immune system can be educated to combat this bacterium. Here we show that prior exposure to a single low dose of lipopolysaccharide (LPS) protects mice from a lethal infection by P. aeruginosa. LPS exposure trained the innate immune system by promoting expansion of neutrophil and interstitial macrophage populations distinguishable from other immune cells with enrichment of gene sets for phagocytosis- and cell-killing-associated genes. The cell-killing gene set in the neutrophil population uniquely expressed Lgals3, which encodes the multifunctional antibacterial protein, galectin-3. Intravital imaging for bacterial phagocytosis, assessment of bacterial killing and neutrophil-associated galectin-3 protein levels together with use of galectin-3-deficient mice collectively highlight neutrophils and galectin-3 as central players in LPS-mediated protection. Patients with acute respiratory failure revealed significantly higher galectin-3 levels in endotracheal aspirates (ETAs) of survivors compared to non-survivors, galectin-3 levels strongly correlating with a neutrophil signature in the ETAs and a prognostically favorable hypoinflammatory plasma biomarker subphenotype. Taken together, our study provides impetus for harnessing the potential of galectin-3-expressing neutrophils to protect from lethal infections and respiratory failure.

Discovery of benzopyridone cyanoacetates as new type of potential broad-spectrum antibacterial candidates

Unique benzopyridone cyanoacetates (BCs) as new type of promising broad-spectrum antibacterial candidates were discovered with large potential to combat the lethal multidrug-resistant bacterial infections. Many prepared BCs showed broad antibacterial spectrum with low MIC values against the tested strains. Some highly active BCs exhibited rapid sterilization capacity, low resistant trend and good predictive pharmacokinetic properties. Furthermore, the highly active sodium BCs (NaBCs) displayed low hemolysis and cytotoxicity, and especially octyl NaBC 5g also showed in vivo potent anti-infective potential and appreciable pharmacokinetic profiles. A series of preliminary mechanistic explorations indicated that these active BCs could effectively eliminate bacterial biofilm and destroy membrane integrity, thus resulting in the leakage of bacterial cytoplasm. Moreover, their unique structures might further bind to intracellular DNA, DNA gyrase and topoisomerase IV through various direct noncovalent interactions to hinder bacterial reproduction. Meanwhile, the active BCs also induced bacterial oxidative stress and metabolic disturbance, thereby accelerating bacterial apoptosis. These results provided a bright hope for benzopyridone cyanoacetates as potential novel multitargeting broad-spectrum antibacterial candidates to conquer drug resistance.

Resveratrol-Encapsulated Glutathione-Modified Robust Mesoporous Silica Nanoparticles as an Antibacterial and Antibiofilm Coating Agent for Medical Devices.

The emergence of various lethal bacterial infections and their adherence to medical devices are major public health concerns. The increased bacterial exposure and titer are accompanied by the inappropriate use of antibiotics that sometimes lead to antibiotic resistance, and therefore, a drug-free antibacterial approach is required. Several nanoparticles (NPs) have been developed as antibacterial and antibiofilm coating agents, which can overcome different drug resistance mechanisms by inhibiting the important processes related to bacterial virulence potential. However, developing safe and biocompatible nanomaterials (NMs) for these applications has remained a major challenge due to their poorly understood mechanism of action. In this work, biogenic silica NPs were modified with glutathione (GSH) to form GSH@SNP (∼80 ± 15 nm) for targeting the bacterial cell surface and biofilm. GSH@SNP was loaded with resveratrol to obtain Res_GSH@SNP (∼124 ± 15 nm) that enhances the antibacterial activity of the NPs against Staphylococcus aureus and Escherichia coli by ∼51 and ∼49%, respectively, compared to GSH@SNP. Res_GSH@SNP is responsible for binding to the bacterial cell surface receptors that interrupt the cell membrane potential, leading to reactive oxygen species (ROS) generation, membrane disruption, and DNA damage and eventually resulting in antibacterial activity. Moreover, the antibiofilm activity of Res_GSH@SNP has been found to result from the interaction of the NPs with the abundant carbohydrates present on the biofilm surface. To check the practical utility of Res_GSH@SNP, these were further evaluated as an antibacterial and antibiofilm coating agent for urinary catheters and were found to be effective even after multiple washes. Res_GSH@SNP has been found to exhibit ∼80 ± 1.4% cytocompatibility toward fibroblast NIH-3T3 cells. Overall, this study is expected to pave the way for the development of biocompatible NP-based coating agents for medical devices.

Case Report of Rare Necrotizing Fasciitis with Pseudomonas in a Healthy Infant

Necrotizing fasciitis is a rare and lethal bacterial infection of the subcutaneous tissue and fascia in pediatrics, particularly when Pseudomonas Aeruginosa is involved. The similarity between cellulitis and Necrotizing fasciitis can lead to misdiagnosis. A 5-month-old male is introduced, presenting with fever and ecchymoses on his left thigh, which was treated as cellulitis. However, the diagnosis was changed to necrotizing fasciitis due to rapid progression in infection and pseudomonas growth in cultures. The antibiotics were leveled up, and the surgeon debrided and grafted the skin. Finally, the patient was discharged in good condition. In the early stages of soft tissue infections, it is not possible to distinguish Necrotizing fasciitis from cellulitis, so empirical antibiotics should be started to cover poly-microbial infections, and the patient should be observed closely. When the infection does not respond to the antibiotics appropriately over 24 hours, the surgeon.

Assessment of CD200R Activation in Combination with Doxycycline in a Model of Melioidosis.

Antimicrobial resistance continues to be a global issue. Pathogens, such as Burkholderia pseudomallei, have evolved mechanisms to efflux certain antibiotics and manipulate the host response. New treatment strategies are therefore required, such as a layered defense approach. Here, we demonstrate, using biosafety level 2 (BSL-2) and BSL-3 in vivo murine models, that combining the antibiotic doxycycline with an immunomodulatory drug that targets the CD200 axis is superior to antibiotic treatment in combination with an isotype control. CD200-Fc treatment alone significantly reduces bacterial burden in lung tissue in both the BSL-2 and BSL-3 models. When CD200-Fc treatment is combined with doxycycline to treat the acute BSL-3 model of melioidosis, there is a 50% increase in survival compared with relevant controls. This benefit is not due to increasing the area under the concentration-time curve (AUC) of the antibiotic, suggesting the immunomodulatory nature of CD200-Fc treatment is playing an important role by potentially controlling the overactive immune response seen with many lethal bacterial infections. IMPORTANCE Traditional treatments for infectious disease have focused on the use of antimicrobial compounds (e.g. antibiotics) that target the infecting organism. However, timely diagnosis and administration of antibiotics remain crucial to ensure efficacy of these treatments especially for the highly virulent biothreat organisms. The need for early antibiotic treatment, combined with the increasing emergence of antibiotic resistant bacteria, means that new therapeutic strategies are required for organisms that cause rapid, acute infections. Here, we show that a layered defense approach, where an immunomodulatory compound is combined with an antibiotic, is better than an antibiotic combined with a relevant isotype control following infection with the biothreat agent Burkholderia pseudomallei. This approach has the potential to be truly broad spectrum and since the strategy includes manipulation of the host response it's application could be used in the treatment of a wide range of diseases.

Enhancer-instructed epigenetic landscape and chromatin compartmentalization dictate a primary antibody repertoire protective against specific bacterial pathogens.

Antigen receptor loci are organized into variable (V), diversity (D) and joining (J) gene segments that rearrange to generate antigen receptor repertoires. Here, we identified an enhancer (E34) in the murine immunoglobulin kappa (Igk) locus that instructed rearrangement of Vκ genes located in a sub-topologically associating domain, including a Vκ gene encoding for antibodies targeting bacterial phosphorylcholine. We show that E34 instructs the nuclear repositioning of the E34 sub-topologically associating domain from a recombination-repressive compartment to a recombination-permissive compartment that is marked by equivalent activating histone modifications. Finally, we found that E34-instructed Vκ-Jκ rearrangement was essential to combat Streptococcus pneumoniae but not methicillin-resistant Staphylococcus aureus or influenza infections. We propose that the merging of Vκ genes with Jκ elements is instructed by one-dimensional epigenetic information imposed by enhancers across Vκ and Jκ genomic regions. The data also reveal how enhancers generate distinct antibody repertoires that provide protection against lethal bacterial infection.

Роль микробной транслокации в развитии хронической иммунной активации и иммунодефицита при ВИЧ-инфекции

HIV-infection is a widespread incurable viral disease. The major pathogenetic mechanism for the development of HIV-infection is a violation of the cellular immunity functioning that is associated with progressive depletion of CD4+ T-lymphocytes. The growing immunodeficiency increases the risk for developing malignancies and lethal viral, bacterial, or fungal infections. However, contrary to the accepted belief, the virus itself is not the main cause for the immunodeficiency progression. The massive CD4+ T-lymphocytes death is due to the phenomenon of chronic immune activation. In HIV-positive individuals, a large number of various CD4+ T-cells express activation markers, secrete pro- and anti-inflammatory cytokines, and induce the active phases of the cell cycle. Meanwhile, it is uncontrolled activation that leads these cells to death. The present review briefly discusses the reasons for developing chronic immune activation in HIV-positive patients, including pathologies of the gastrointestinal tract that contribute to the translocation of bacteria and their products into areas under the immune system supervision. It also touches the reasons for death of activated cells in HIV-infection setting. Furthermore, it covers the known ways to controlling the chronic immune activation.

A case of chronic granulomatous disease and acne: is isotretinoin a safe treatment?

We report the case of a patient with chronic granulomatous disease and acne treated with isotretinoin, who developed a diffuse staphylococcal skin infection during the therapy. Chronic granulomatous disease is a rare genetic disorder characterized by an altered innate immunity with an increased risk of potentially lethal bacterial and fungal infections. Although chronic granulomatous disease is rare, acne is a common manifestation in these patients, but there are no data about the gold standard therapy.

Bacterial induced miR-144-5p modulates intestinal inflammatory response of Japanese flounder by targeting Hsp90α-dependent NLR signaling pathway

Pathogens infection could induce intestinal inflammatory processes, appropriate intestinal inflammation response had beneficial effects in fish, while excessive inflammation alters enteroendocrine signaling, leading to deregulated immune response. Recently, many researches revealed that microRNAs in teleost serve as vital regulators in innate immunity responses against pathogen infection. However, there are few studies on miRNAs mediated regulatory networks of intestinal inflammatory response in teleost. In our study, miR-144-5p was identified as negative regulators in teleost against bacterial infection. First, we found that the expression of miR-144-5p in flounder both in vivo and in vitro was significantly up-regulated, while the expression of Hsp90α, NLRP3, Caspase1 and IL-1β were significantly down-regulated upon the stimulation of Edwardsiella tarda and lipopolysaccharide (LPS). Furthermore, we confirmed that miR-144-5p modulates intestinal inflammatory responses of flounder by targeting Hsp90α-dependent NLR signaling pathway, in which the miR-144-5p-Hsp90α-NLRP3 signaling pathway was constructed. Besides, the miR-144-5p-Hsp90α-NLRP3 signaling pathway could inhibit antibacterial immune response of flounder and promote the survival of E. tarda. Moreover, the study demonstrated that the miR-144-5p-Hsp90α regulatory network was widely existed in other teleost and human. In conclusion, the expression of miR-144-5p was significantly up-regulated after challenged by E. tarda and LPS, which then down-regulated the expression of inflammation-related cytokines of NLRP3, Caspase1 and IL-1β by targeting Hsp90α, and ultimately promoted bacterial infection. Our findings constructed a novel miR-144-5p-Hsp90α-NLRP3 signaling pathway, which enriched the regulatory network of miRNA on fish intestinal mucosal immunity and would benefit the development of fish disease therapeutic strategies to prevent potentially lethal bacterial infection.

An evolutionary trade-off between host immunity and metabolism drives fatty liver in male mice.

Adaptations to infectious and dietary pressures shape mammalian physiology and disease risk. How such adaptations affect sex-biased diseases remains insufficiently studied. In this study, we show that sex-dependent hepatic gene programs confer a robust (~300%) survival advantage for male mice during lethal bacterial infection. The transcription factor B cell lymphoma 6 (BCL6), which masculinizes hepatic gene expression at puberty, is essential for this advantage. However, protection by BCL6 protein comes at a cost during conditions of dietary excess, which result in overt fatty liver and glucose intolerance in males. Deleting hepatic BCL6 reverses these phenotypes but markedly lowers male survival during infection, thus establishing a sex-dependent trade-off between host defense and metabolic systems. Our findings offer strong evidence that some current sex-biased diseases are rooted in ancient evolutionary trade-offs between immunity and metabolism.

Contribution of Lipid Mediators in Divergent Outcomes following Acute Bacterial and Viral Lung Infections in the Obese Host.

Obesity is considered an important comorbidity for a range of noninfectious and infectious disease states including those that originate in the lung, yet the mechanisms that contribute to this susceptibility are not well defined. In this study, we used the diet-induced obesity (DIO) mouse model and two models of acute pulmonary infection, Francisella tularensis subspecies tularensis strain SchuS4 and SARS-CoV-2, to uncover the contribution of obesity in bacterial and viral disease. Whereas DIO mice were more resistant to infection with SchuS4, DIO animals were more susceptible to SARS-CoV-2 infection compared with regular weight mice. In both models, neither survival nor morbidity correlated with differences in pathogen load, overall cellularity, or influx of inflammatory cells in target organs of DIO and regular weight animals. Increased susceptibility was also not associated with exacerbated production of cytokines and chemokines in either model. Rather, we observed pathogen-specific dysregulation of the host lipidome that was associated with vulnerability to infection. Inhibition of specific pathways required for generation of lipid mediators reversed resistance to both bacterial and viral infection. Taken together, our data demonstrate disparity among obese individuals for control of lethal bacterial and viral infection and suggest that dysregulation of the host lipidome contributes to increased susceptibility to viral infection in the obese host.

Pneumococcal meningitis and COVID-19: dangerous coexistence. A case report

BackgroundSARS-CoV-2 is the major cause of infections in humans since December 2019 and is top of the global health concern currently. Streptococcus pneumoniae is one of the leading pathogens of invasive bacterial diseases, including pneumonia, sepsis, and meningitis. Moreover, this bacteria is mostly responsible for secondary infections subsequent to post-viral respiratory disease. Co-infections with bacterial and viral pathogens are associated with severe course of the disease and are a major cause of mortality. In this report, we describe a rare case of COVID-19 patient with pneumococcal sepsis and meningitis of unsuccessful course.Case presentationA 89-year-old man, not vaccinated against SARS-CoV-2 infection, was diagnosed with COVID-19 pneumonia. Patient required oxygen therapy due to respiratory failure. The initial treatment of viral infection with tocilizumab and dexamethasone allowed for the stabilization of the patient’s condition and improvement of laboratory parameters. On the 9th day of hospitalization the patient’s condition deteriorated. Consciousness disorders and acute respiratory disorders requiring intubation and mechanical ventilation were observed. Brain computed tomography excluded intracranial bleeding. The Streptococcus pneumoniae sepsis with concomitant pneumoniae and meningitis was diagnosed based on microbiological culture of blood, bronchial wash, and cerebrospinal fluid examination. Despite targeted antibiotic therapy with ceftriaxone and multidisciplinary treatment, symptoms of multiple organ failure increased. On the 13th day of hospitalization, the patient died.ConclusionsCo-infections with bacterial pathogens appear to be not common among COVID-19 patients, but may cause a sudden deterioration of the general condition. Not only vascular neurological complications, but also meningitis should be always considered in patients with sudden disturbances of consciousness. Anti-inflammatory treatment with the combination of corticosteroids and tocilizumab (or tocilizumab alone) pose a severe risk for secondary lethal bacterial or fungal infections. Thus, treating a high-risk population (i.e. elderly and old patients) with these anti-inflammatory agents, require daily clinical assessment, regular monitoring of C-reactive protein and procalcitonin, as well as standard culture of blood, urine and sputum in order to detect concomitant infections, as rapidly as possible.

Cellular adaptation of Clostridioides difficile to high salinity encompasses a compatible solute-responsive change in cell morphology.

Infections by the pathogenic gut bacterium Clostridioides difficile cause severe diarrhoeas up to a toxic megacolon and are currently among the major causes of lethal bacterial infections. Successful bacterial propagation in the gut is strongly associated with the adaptation to changing nutrition-caused environmental conditions; e.g. environmental salt stresses. Concentrations of 350 mM NaCl, the prevailing salinity in the colon, led to significantly reduced growth of C. difficile. Metabolomics of salt-stressed bacteria revealed a major reduction of the central energy generation pathways, including the Stickland-fermentation reactions. No obvious synthesis of compatible solutes was observed up to 24 h of growth. The ensuing limited tolerance to high salinity and absence of compatible solute synthesis might result from an evolutionary adaptation to the exclusive life of C. difficile in the mammalian gut. Addition of the compatible solutes carnitine, glycine-betaine, γ-butyrobetaine, crotonobetaine, homobetaine, proline-betaine and dimethylsulfoniopropionate restored growth (choline and proline failed) under conditions of high salinity. A bioinformatically identified OpuF-type ABC-transporter imported most of the used compatible solutes. A long-term adaptation after 48 h included a shift of the Stickland fermentation-based energy metabolism from the utilization to the accumulation of l-proline and resulted in restored growth. Surprisingly, salt stress resulted in the formation of coccoid C. difficile cells instead of the typical rod-shaped cells, a process reverted by the addition of several compatible solutes. Hence, compatible solute import via OpuF is the major immediate adaptation strategy of C. difficile to high salinity-incurred cellular stress.

Discovery of unique thiazolidinone-conjugated coumarins as novel broad spectrum antibacterial agents

Unique coumarin conjugates with thiazolidinone as novel structural antibacterial modulators were exploited to combat the lethal multidrug-resistant bacterial infections. Bioactivity evaluation identified that indole-incorporated coumarin thiazolidinone conjugate 14a with low cytotoxicity to mammalian cells showed a broad antibacterial spectrum and exerted potent inhibition efficiencies to the tested germs at low concentrations (0.25–2 μg/mL). Moreover, the favorable performance of 14a in eradicating bacterial biofilm was beneficial to avert developing drug resistance. Mechanistic explorations revealed that molecule 14a was able to destroy cell membrane, leading to the leakage of intracellular materials and metabolism inhibition. The accumulation of excess reactive oxygen species (ROS) mediated by compound 14a could impede glutathione (GSH) activity and induce lipid peroxidation to suppress bacteria growth. Furthermore, compound 14a could not only intercalate into DNA base pair but also take part in non-covalent interaction with DNA gyrase B to hinder their biological function. Quantum chemical study indicated that molecule 14a had low HOMO-LUMO energy gap, which resulted in more stabilizing interactions and was conducive to displaying better antibacterial activity. ADMET analysis manifested that 14a possessed promising pharmacokinetic properties.

Efficient production of human neutrophils from iPSCs that prevent murine lethal infection with immune cell recruitment

AbstractNeutrophils play an essential role in innate immune responses to bacterial and fungal infections, and loss of neutrophil function can increase the risk of acquiring lethal infections in clinical settings. Here, we show that engineered neutrophil-primed progenitors derived from human induced pluripotent stem cells can produce functional neutrophil-like cells at a clinically applicable scale that can act rapidly in vivo against lethal bacterial infections. Using 5 different mouse models, we systematically demonstrated that these neutrophil-like cells migrate to sites of inflammation and infection and increase survival against bacterial infection. In addition, we found that these human neutrophil-like cells can recruit murine immune cells. This system potentially provides a straight-forward solution for patients with neutrophil deficiency: an off-the-shelf neutrophil transfusion. This platform should facilitate the administration of human neutrophils for a broad spectrum of physiological and pathological conditions.

Trained Immunity Confers Prolonged Protection From Listeriosis.

Trained immunity refers to the ability of the innate immune system exposed to a first challenge to provide an enhanced response to a secondary homologous or heterologous challenge. We reported that training induced with β-glucan one week before infection confers protection against a broad-spectrum of lethal bacterial infections. Whether this protection persists over time is unknown. To tackle this question, we analyzed the immune status and the response to Listeria monocytogenes (L. monocytogenes) of mice trained 9 weeks before analysis. The induction of trained immunity increased bone marrow myelopoiesis and blood counts of Ly6Chigh inflammatory monocytes and polymorphonuclear neutrophils (PMNs). Ex vivo, whole blood, PMNs and monocytes from trained mice produced increased levels of cytokines in response to microbial products and limited the growth of L. monocytogenes. In vivo, following challenge with L. monocytogenes, peripheral blood leukocytes were massively depleted in control mice but largely preserved in trained mice. PMNs were reduced also in the spleen from control mice, and increased in the spleen of trained mice. In transwell experiments, PMNs from trained mice showed increased spontaneous migration and CXCL2/MIP2α-induced chemotaxis, suggesting that training promotes the migration of PMNs in peripheral organs targeted by L. monocytogenes. Trained PMNs and monocytes had higher glycolytic activity and mitochondrial respiration than control cells when exposed to L. monocytogenes. Bacterial burden and dissemination in blood, spleen and liver as well as systemic cytokines and inflammation (multiplex bead assay and bioluminescence imaging) were reduced in trained mice. In full agreement with these results, mice trained 9 weeks before infection were powerfully protected from lethal listeriosis. Altogether, these data suggest that training increases the generation and the antimicrobial activity of PMNs and monocytes, which may confer prolonged protection from lethal bacterial infection.