scholarly journals The antibiotic bedaquiline activates host macrophage innate immune resistance to bacterial infection

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Alexandre Giraud-Gatineau ◽  
Juan Manuel Coya ◽  
Alexandra Maure ◽  
Anne Biton ◽  
Michael Thomson ◽  
...  
Keyword(s):  
Defense Mechanisms ◽  
Bacterial Infections ◽  
Bacterial Species ◽  
Innate Immune ◽  
Immune Resistance ◽  
Genome Wide ◽  
Activation Of Transcription ◽  
Wide Range ◽  
Transcription Factor Eb ◽  
Genome Wide Gene Expression

Antibiotics are widely used in the treatment of bacterial infections. Although known for their microbicidal activity, antibiotics may also interfere with the host’s immune system. Here, we analyzed the effects of bedaquiline (BDQ), an inhibitor of the mycobacterial ATP synthase, on human macrophages. Genome-wide gene expression analysis revealed that BDQ reprogramed cells into potent bactericidal phagocytes. We found that 579 and 1,495 genes were respectively differentially expressed in naive- and M. tuberculosis-infected macrophages incubated with the drug, with an over-representation of lysosome-associated genes. BDQ treatment triggered a variety of antimicrobial defense mechanisms, including phagosome-lysosome fusion, and autophagy. These effects were associated with activation of transcription factor EB, involved in the transcription of lysosomal genes, resulting in enhanced intracellular killing of different bacterial species that were naturally insensitive to BDQ. Thus, BDQ could be used as a host-directed therapy against a wide range of bacterial infections.

scholarly journals The antibiotic bedaquiline activates host macrophage innate immune resistance to bacterial infection

2019 ◽  
Author(s):  
Alexandre Giraud-Gatineau ◽  
Juan Manuel Coya ◽  
Alexandra Maure ◽  
Anne Biton ◽  
Michael Thomson ◽  
...  
Keyword(s):  
Defense Mechanisms ◽  
Bacterial Infections ◽  
Bacterial Species ◽  
Immune Resistance ◽  
Lysosome Biogenesis ◽  
Genome Wide ◽  
Activation Of Transcription ◽  
Wide Range ◽  
Transcription Factor Eb ◽  
Genome Wide Gene Expression

AbstractAntibiotics are widely used in the treatment of bacterial infections. Although known for their microbicidal activity, antibiotics may also interfere with the host’s immune system. Here we analyzed the effects of bedaquiline (BDQ), an inhibitor of the mycobacterial ATP synthase, on human macrophages. Genome-wide gene expression analysis revealed that BDQ reprogramed macrophages into potent bactericidal phagocytes. We found that 1,495 genes were differentially expressed in M. tuberculosis-infected macrophages incubated with the drug, with an over-representation of genes involved in metabolism, lysosome biogenesis and activation. BDQ treatment triggered a variety of antimicrobial defense mechanisms, including nitric oxide production, phagosome-lysosome fusion, and autophagy. These effects were associated with activation of transcription factor EB (TFEB), involved in the transcription of lysosomal genes, resulting in enhanced intracellular killing of different bacterial species that were naturally insensitive to BDQ. Thus, BDQ could be used as a host-directed therapy against a wide range of bacterial infections.

scholarly journals Integrating genome-wide CRISPR immune screen with multi-omic clinical data reveals distinct classes of tumor intrinsic immune regulators

2021 ◽  
Vol 9 (2) ◽  
pp. e001819
Author(s):  
Jiakai Hou ◽  
Yunfei Wang ◽  
Leilei Shi ◽  
Yuan Chen ◽  
Chunyu Xu ◽  
...  
Keyword(s):  
T Cell ◽  
Cancer Immunotherapy ◽  
Clinical Data ◽  
Specific Inhibitor ◽  
Cell Tumor ◽  
Tumor Infiltration ◽  
Intrinsic Factors ◽  
Immune Resistance ◽  
Genome Wide ◽  
Wide Range

BackgroundDespite approval of immunotherapy for a wide range of cancers, the majority of patients fail to respond to immunotherapy or relapse following initial response. These failures may be attributed to immunosuppressive mechanisms co-opted by tumor cells. However, it is challenging to use conventional methods to systematically evaluate the potential of tumor intrinsic factors to act as immune regulators in patients with cancer.MethodsTo identify immunosuppressive mechanisms in non-responders to cancer immunotherapy in an unbiased manner, we performed genome-wide CRISPR immune screens and integrated our results with multi-omics clinical data to evaluate the role of tumor intrinsic factors in regulating two rate-limiting steps of cancer immunotherapy, namely, T cell tumor infiltration and T cell-mediated tumor killing.ResultsOur studies revealed two distinct types of immune resistance regulators and demonstrated their potential as therapeutic targets to improve the efficacy of immunotherapy. Among them, PRMT1 and RIPK1 were identified as a dual immune resistance regulator and a cytotoxicity resistance regulator, respectively. Although the magnitude varied between different types of immunotherapy, genetically targeting PRMT1 and RIPK1 sensitized tumors to T-cell killing and anti-PD-1/OX40 treatment. Interestingly, a RIPK1-specific inhibitor enhanced the antitumor activity of T cell-based and anti-OX40 therapy, despite limited impact on T cell tumor infiltration.ConclusionsCollectively, the data provide a rich resource of novel targets for rational immuno-oncology combinations.

scholarly journals Phage Therapy as a Focused Management Strategy in Aquaculture

2021 ◽  
Vol 22 (19) ◽  
pp. 10436
Author(s):  
José Ramos-Vivas ◽  
Joshua Superio ◽  
Jorge Galindo-Villegas ◽  
Félix Acosta
Keyword(s):  
Bacterial Infections ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Control Strategies ◽  
Bacterial Species ◽  
Lytic Enzymes ◽  
Wide Range ◽  
Cultured Fish

Therapeutic bacteriophages, commonly called as phages, are a promising potential alternative to antibiotics in the management of bacterial infections of a wide range of organisms including cultured fish. Their natural immunogenicity often induces the modulation of a variated collection of immune responses within several types of immunocytes while promoting specific mechanisms of bacterial clearance. However, to achieve standardized treatments at the practical level and avoid possible side effects in cultivated fish, several improvements in the understanding of their biology and the associated genomes are required. Interestingly, a particular feature with therapeutic potential among all phages is the production of lytic enzymes. The use of such enzymes against human and livestock pathogens has already provided in vitro and in vivo promissory results. So far, the best-understood phages utilized to fight against either Gram-negative or Gram-positive bacterial species in fish culture are mainly restricted to the Myoviridae and Podoviridae, and the Siphoviridae, respectively. However, the current functional use of phages against bacterial pathogens of cultured fish is still in its infancy. Based on the available data, in this review, we summarize the current knowledge about phage, identify gaps, and provide insights into the possible bacterial control strategies they might represent for managing aquaculture-related bacterial diseases.

scholarly journals Glycobiology of syndecan-1 in bacterial infections

2018 ◽  
Vol 46 (2) ◽  
pp. 371-377 ◽  
Author(s):  
Rafael S. Aquino ◽  
Yvonne Hui-Fang Teng ◽  
Pyong Woo Park
Keyword(s):  
Cell Surface ◽  
Defense Mechanisms ◽  
Bacterial Infections ◽  
Bacterial Pathogens ◽  
Innate Immune ◽  
Host Cells ◽  
Innate Defense ◽  
Immune Clearance ◽  
Bacterial Adhesins ◽  
A Cell

Syndecan-1 (Sdc1) is a major cell surface heparan sulfate (HS) proteoglycan of epithelial cells, a cell type targeted by many bacterial pathogens early in their pathogenesis. Loss of Sdc1 in mice is a gain-of-function mutation that significantly decreases the susceptibility to several bacterial infections, suggesting that subversion of Sdc1 is an important virulence strategy. HS glycosaminoglycan (GAG) chains of cell surface Sdc1 promote bacterial pathogenesis by facilitating the attachment of bacteria to host cells. Engagement of cell surface Sdc1 HS chains by bacterial adhesins transmits signal through the highly conserved Sdc1 cytoplasmic domain, which can lead to uptake of intracellular bacterial pathogens. On the other hand, several bacteria that do not require Sdc1 for their attachment and invasion stimulate Sdc1 shedding and exploit the capacity of Sdc1 ectodomain HS GAGs to disarm innate defense mechanisms to evade immune clearance. Recent data suggest that select HS sulfate motifs, and not the overall charge of HS, are important in the inhibition of innate immune mechanisms. Here, we discuss several examples of Sdc1 subversion in bacterial infections.

scholarly journals Innate immunity against infectious diseases, particularly in swine

2020 ◽  
Vol 76 (2) ◽  
pp. 67-70
Author(s):  
ZYGMUNT PEJSAK ◽  
MARIAN TRUSZCZYŃSKI ◽  
KAZIMIERZ TARASIUK
Keyword(s):  
Infectious Diseases ◽  
Defense Mechanisms ◽  
Bacterial Infections ◽  
Innate Immune ◽  
Mononuclear Phagocytes ◽  
Phagocytic Cells ◽  
Host Defense Peptides ◽  
Innate Defense ◽  
Etiologic Agents ◽  
Monocytes And Macrophages

The importance of innate defense mechanisms especially refering to swine, was characterized. Physical, chemical and microbial barriers were mentioned. The role of cells was underlined in controlling infection by phagocytosis without earlier immunisation by antigens and only depending on the genome of the born animal. The two main types of phagocytic cells were evaluated in antiinfectious activity: a)granular leucocytes, including neutrophils, basophils, eosynophils and mast cells, b)mononuclear phagocytes. These include blood circulating monocytes and macrophages. It was stated that natural killer cells belonging also to innate immune system can kill bacteria and viruses participating as etiologic agents in infectious diseases. Another group of innate immune factors, not cells but molecules, are creating defensins being host defense peptides. The complement mediates the inflammatory response, controlling bacterial infections. The following antiinfectious activity is exerted by Toll-like receptors. The presented cytokines are protein or glycoprotein molecules secreted by cells. They participate in intercellular and intracellular signalling.

The role of platelets in defence against pathogens

2011 ◽  
Vol 31 (04) ◽  
pp. 264-268 ◽  
Author(s):  
K. J. Clemetson
Keyword(s):  
Immune System ◽  
Immune Function ◽  
Bacterial Infections ◽  
Innate Immune ◽  
Viral Diseases ◽  
Parasitic Diseases ◽  
Defence Mechanisms ◽  
Wide Range ◽  
Storage Granules

SummaryMany more platelets are present in healthy mammals than are necessary for routine haemostasis. Thus, they could have other functions. Platelets have many of the attributes of innate immune function including Toll-like receptors. They also contain a wide range of anti-microbial peptides in storage granules. Platelets play an important role in bacterial infections, both in disease progress and in defence mechanisms depending on circumstances. Similar mechanisms are used in defence against fungi. Platelets are also involved in viral diseases, either in protecting from the immune system or in killing viruses that activate platelets. Finally, platelets have a role in defence against parasitic diseases, in particular malaria, that should not be ignored, and may aggravate some of the worst aspects. Platelets also have receptors for IgE and are implicated via parasitic disorders in development and problems of allergy.

scholarly journals The relationship between biofilm formation, genes of virulence and iron metabolism in Escherichia coli

2018 ◽  
Author(s):  
Lívia Handrová ◽  
Anna Čuvalová ◽  
Vladimír Kmeť
Keyword(s):  
Escherichia Coli ◽  
Iron Metabolism ◽  
Biofilm Formation ◽  
Bacterial Infections ◽  
Opportunistic Infections ◽  
Bacterial Species ◽  
Pcr Amplification ◽  
Bacterial Strains ◽  
E Coli ◽  
Wide Range

Escherichia coli is known as one of the bacterial species with the widest adaptability to variety of niches either within organisms or outside in environment. Most strains of E. coli are of low virulence and associated with opportunistic infections, whereas others are highly virulent. The success of E. coli in colonising such a wide range of hosts and environments is basically due to a noticeable ductility in exploiting the available resources. It is becoming increasingly clear that biofilms have an enormous impact on medicine because since 65% of animal and human bacterial infections involve biofilms. In present study, we isolated strains of E. coli from animals. 19 interesting isolates were selected and tested by PCR amplification to virulence – iutA, cvaC, iss, tsh, papC, kps, iha and iron metabolism genes – sitA, feoB, irp2, fyuA, iroN, ireA. The ability of biofilm formation was assessed in a quantitative assay using a microtiter-plate test. Bacterial strains were grown on BHI. We divided isolates of E. coli into four classes: very weak (63.0%), weak (10.5%), moderate (10.5%) and strong (16.0%) biofilm producers. Representation genes of virulence were highly in isolates from very weak biofilm producers – from 7 genes were 6 highly; only papC (P fimbrial adhesin) was low. Genes of iron metabolism were different. Genes – sitA, fyuA, ireA in strong isolates producing biofilm and feoB, irp2, iroN in weak producers were most represented. The results show possible relation between presence virulence factor and low biofilm formation.

scholarly journals Identification of Polyvalent Vaccine Candidates From Extracellular Secretory Proteins in Vibrio alginolyticus

2021 ◽  
Vol 12 ◽  
Author(s):  
Yu-ming Peng ◽  
Jian-jun Tao ◽  
Su-fang Kuang ◽  
Ming Jiang ◽  
Xuan-xian Peng ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Dna Vaccines ◽  
Vibrio Alginolyticus ◽  
Innate Immune ◽  
Secretory Proteins ◽  
Protective Effects ◽  
Vaccine Candidates ◽  
Polyvalent Vaccine ◽  
Protective Antigens ◽  
Wide Range

Bacterial infections cause huge losses in aquaculture and a wide range of health issues in humans. A vaccine is the most economical, efficient, and environment-friendly agent for protecting hosts against bacterial infections. This study aimed to identify broad, cross-protective antigens from the extracellular secretory proteome of the marine bacterium Vibrio alginolyticus. Of the 69 predicted extracellular secretory proteins in its genome, 16 were randomly selected for gene cloning to construct DNA vaccines, which were used to immunize zebrafish (Danio rerio). The innate immune response genes were also investigated. Among the 16 DNA vaccines, 3 (AT730_21605, AT730_22220, and AT730_22910) were protective against V. alginolyticus infection with 47–66.7% increased survival compared to the control, while other vaccines had lower or no protective effects. Furthermore, AT730_22220, AT730_22910, and AT730_21605 also exhibited cross-immune protective effects against Pseudomonas fluorescens and/or Aeromonas hydrophila infection. Mechanisms for cross-protective ability was explored based on conserved epitopes, innate immune responses, and antibody neutralizing ability. These results indicate that AT730_21605, AT730_22220, and AT730_22910 are potential polyvalent vaccine candidates against bacterial infections. Additionally, our results suggest that the extracellular secretory proteome is an antigen pool that can be used for the identification of cross-protective immunogens.

scholarly journals Genome-wide gene expression changes of Pseudomonas veronii 1YdBTEX2 during bioaugmentation in polluted soils

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Marian Morales ◽  
Vladimir Sentchilo ◽  
Noushin Hadadi ◽  
Jan Roelof van der Meer
Keyword(s):  
Gene Expression ◽  
Defense Mechanisms ◽  
Catalytic Performance ◽  
Bacterial Strains ◽  
Growth And Survival ◽  
Degrading Bacterium ◽  
Genome Wide ◽  
Pseudomonas Veronii ◽  
Specific Reactions ◽  
Genome Wide Gene Expression

Abstract Background Bioaugmentation aims to use the capacities of specific bacterial strains inoculated into sites to enhance pollutant biodegradation. Bioaugmentation results have been mixed, which has been attributed to poor inoculant growth and survival in the field, and, consequently, moderate catalytic performance. However, our understanding of biodegradation activity mostly comes from experiments conducted under laboratory conditions, and the processes occurring during adaptation and invasion of inoculants into complex environmental microbiomes remain poorly known. The main aim of this work was thus to study the specific and different cellular reactions of an inoculant for bioaugmentation during adaptation, growth and survival in natural clean and contaminated non-sterile soils, in order to better understand factors limiting bioaugmentation. Results As inoculant we focused on the monoaromatic compound-degrading bacterium Pseudomonas veronii 1YdBTEX2. The strain proliferated in all but one soil types in presence and in absence of exogenously added toluene. RNAseq and differential genome-wide gene expression analysis illustrated both a range of common soil responses such as increased nutrient scavenging and recycling, expression of defense mechanisms, as well as environment-specific reactions, notably osmoprotection and metal homeostasis. The core metabolism of P. veronii remained remarkably constant during exponential growth irrespective of the environment, with slight changes in cofactor regeneration pathways, possibly needed for balancing defense reactions. Conclusions P. veronii displayed a versatile global program, enabling it to adapt to a variety of soil environments in the presence and even in absence of its target pollutant toluene. Our results thus challenge the widely perceived dogma of poor survival and growth of exogenous inoculants in complex microbial ecosystems such as soil and provide a further basis to developing successful bioaugmentation strategies.

scholarly journals Biofilms: Novel Strategies Based on Antimicrobial Peptides

Pharmaceutics ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 322 ◽  
Author(s):  
Emilia Galdiero ◽  
Lucia Lombardi ◽  
Annarita Falanga ◽  
Giovanni Libralato ◽  
Marco Guida ◽  
...  
Keyword(s):  
Antimicrobial Peptides ◽  
Defense Mechanisms ◽  
Bacterial Infections ◽  
Bacterial Species ◽  
Medical Field ◽  
Self Defense ◽  
Key Features ◽  
Real Challenge ◽  
Alternative Drugs

The problem of drug resistance is very worrying and ever increasing. Resistance is due not only to the reckless use of antibiotics but also to the fact that pathogens are able to adapt to different conditions and develop self-defense mechanisms such as living in biofilms; altogether these issues make the search for alternative drugs a real challenge. Antimicrobial peptides appear as promising alternatives but they have disadvantages that do not make them easily applicable in the medical field; thus many researches look for solutions to overcome the disadvantages and ensure that the advantages can be exploited. This review describes the biofilm characteristics and identifies the key features that antimicrobial peptides should have. Recalcitrant bacterial infections caused by the most obstinate bacterial species should be treated with a strategy to combine conventional peptides functionalized with nano-tools. This approach could effectively disrupt high density infections caused by biofilms. Moreover, the importance of using in vivo non mammalian models for biofilm studies is described. In particular, here we analyze the use of amphibians as a model to substitute the rodent model.

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