The commensal microbiota is a major regulator of the immune system. The majority of commensal bacteria inhabit the gastrointestinal tract and are known to regulate local mucosal defenses against ...intestinal pathogens. There is growing appreciation that the commensal microbiota also regulates immune responses at extraintestinal sites. Currently, however, it is unclear how this influences host defenses against bacterial infection outside the intestine. Microbiota depletion caused significant defects in the early innate response to lung infection by the major human pathogen Klebsiella pneumoniae. After microbiota depletion, early clearance of K. pneumoniae was impaired, and this could be rescued by administration of bacterial Nod-like receptor (NLR) ligands (the NOD1 ligand MurNAcTri(DAP) and NOD2 ligand muramyl dipeptide MDP) but not bacterial Toll-like receptor (TLR) ligands. Importantly, NLR ligands from the gastrointestinal, but not upper respiratory, tract rescued host defenses in the lung. Defects in early innate immunity were found to be due to reduced reactive oxygen species-mediated killing of bacteria by alveolar macrophages. These data show that bacterial signals from the intestine have a profound influence on establishing the levels of antibacterial defenses in distal tissues.
The microbiota promotes resistance to respiratory infection, but the mechanistic basis for this is poorly defined. Here, we identify members of the microbiota that protect against respiratory ...infection by the major human pathogens Streptococcus pneumoniae and Klebsiella pneumoniae. We show that the microbiota enhances respiratory defenses via granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, which stimulates pathogen killing and clearance by alveolar macrophages through extracellular signal-regulated kinase signaling. Increased pulmonary GM-CSF production in response to infection is primed by the microbiota through interleukin-17A. By combining models of commensal colonization in antibiotic-treated and germ-free mice, using cultured commensals from the Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria phyla, we found that potent Nod-like receptor-stimulating bacteria in the upper airway (Staphylococcus aureus and Staphylococcus epidermidis) and intestinal microbiota (Lactobacillus reuteri, Enterococcus faecalis, Lactobacillus crispatus and Clostridium orbiscindens) promote resistance to lung infection through Nod2 and GM-CSF. Our data reveal the identity, location, and properties of bacteria within the microbiota that regulate lung immunity, and delineate the host signaling axis they activate to protect against respiratory infection.
Functionally, circulating neutrophils in germ-free mice have defects in extravasation from the bloodstream into target tissues in response to microbial signals 7 and also in killing of bacterial ...pathogens 8. ...signals from the microbiota have a systemic effect on neutrophils promoting their production and antimicrobial capacity. Additionally, it is known that patients with concurrent intestinal helminth and TB infection have reduced natural killer cell numbers in comparison to those with TB alone 25. ...more information is required to understand the beneficial and detrimental effects different microbial groups can have on innate immunity.
The immunological impact of individual commensal species within the microbiota is poorly understood limiting the use of commensals to treat disease. Here, we systematically profile the immunological ...fingerprint of commensals from the major phyla in the human intestine (Actinobacteria, Bacteroidetes, Firmicutes and Proteobacteria) to reveal taxonomic patterns in immune activation and use this information to rationally design commensal communities to enhance antibacterial defenses and combat intestinal inflammation. We reveal that Bacteroidetes and Firmicutes have distinct effects on intestinal immunity by differentially inducing primary and secondary response genes. Within these phyla, the immunostimulatory capacity of commensals from the Bacteroidia class (Bacteroidetes phyla) reflects their robustness of TLR4 activation and Bacteroidia communities rely solely on this receptor for their effects on intestinal immunity. By contrast, within the Clostridia class (Firmicutes phyla) it reflects the degree of TLR2 and TLR4 activation, and communities of Clostridia signal via both of these receptors to exert their effects on intestinal immunity. By analyzing the receptors, intracellular signaling components and transcription factors that are engaged by different commensal species, we identify canonical NF-κB signaling as a critical rheostat which grades the degree of immune stimulation commensals elicit. Guided by this immunological analysis, we constructed a cross-phylum consortium of commensals (Bacteroides uniformis, Bacteroides ovatus, Peptostreptococcus anaerobius and Clostridium histolyticum) which enhances innate TLR, IL6 and macrophages-dependent defenses against intestinal colonization by vancomycin resistant Enterococci, and fortifies mucosal barrier function during pathological intestinal inflammation through the same pathway. Critically, the setpoint of intestinal immunity established by this consortium is calibrated by canonical NF-κB signaling. Thus, by profiling the immunological impact of major human commensal species our work paves the way for rational microbiota reengineering to protect against antibiotic resistant infections and to treat intestinal inflammation.
Rare codons cluster Clarke, 4th, Thomas F; Clark, Patricia L
PloS one,
10/2008, Letnik:
3, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Most amino acids are encoded by more than one codon. These synonymous codons are not used with equal frequency: in every organism, some codons are used more commonly, while others are more rare. ...Though the encoded protein sequence is identical, selective pressures favor more common codons for enhanced translation speed and fidelity. However, rare codons persist, presumably due to neutral drift. Here, we determine whether other, unknown factors, beyond neutral drift, affect the selection and/or distribution of rare codons. We have developed a novel algorithm that evaluates the relative rareness of a nucleotide sequence used to produce a given protein sequence. We show that rare codons, rather than being randomly scattered across genes, often occur in large clusters. These clusters occur in numerous eukaryotic and prokaryotic genomes, and are not confined to unusual or rarely expressed genes: many highly expressed genes, including genes for ribosomal proteins, contain rare codon clusters. A rare codon cluster can impede ribosome translation of the rare codon sequence. These results indicate additional selective pressures govern the use of synonymous codons, and specifically that local pauses in translation can be beneficial for protein biogenesis.
A growing number of bacteria are recognized to conduct electrons across their cell envelope, and yet molecular details of the mechanisms supporting this process remain unknown. Here, we report the ...atomic structure of an outer membrane spanning protein complex, MtrAB, that is representative of a protein family known to transport electrons between the interior and exterior environments of phylogenetically and metabolically diverse microorganisms. The structure is revealed as a naturally insulated biomolecular wire possessing a 10-heme cytochrome, MtrA, insulated from the membrane lipidic environment by embedding within a 26 strand β-barrel formed by MtrB. MtrAB forms an intimate connection with an extracellular 10-heme cytochrome, MtrC, which presents its hemes across a large surface area for electrical contact with extracellular redox partners, including transition metals and electrodes.
Display omitted
•The 20 hemes of a 3-component complex are arranged to move electrons across 185 Å•A β-barrel and 10-heme cytochrome form an insulated transmembrane nanowire•An extracellular 10-heme cytochrome has a large surface area for electron exchange•The hemes of both cytochromes are packed with a maximum inter-heme distance of 8 Å
Structural analysis shows how a naturally insulated molecular “wire” conducts electrons across lipid membranes in bacteria while protecting the membrane from redox damage and facilitating extracellular electron exchange
Increasing evidence demonstrates that DNA damage and genome instability play a crucial role in ageing. Mammalian cells have developed a wide range of complex and well‐orchestrated DNA repair pathways ...to respond to and resolve many different types of DNA lesions that occur from exogenous and endogenous sources. Defects in these repair pathways lead to accelerated or premature ageing syndromes and increase the likelihood of cancer development. Understanding the fundamental mechanisms of DNA repair will help develop novel strategies to treat ageing‐related diseases. Here, we revisit the processes involved in DNA damage repair and how these can contribute to diseases, including ageing and cancer. We also review recent mechanistic insights into DNA repair and discuss how these insights are being used to develop novel therapeutic strategies for treating human disease. We discuss the use of PARP inhibitors in the clinic for the treatment of breast and ovarian cancer and the challenges associated with acquired drug resistance. Finally, we discuss how DNA repair pathway‐targeted therapeutics are moving beyond PARP inhibition in the search for ever more innovative and efficacious cancer therapies.
In this review, we revisit the processes involved in DNA damage repair and how these can contribute to diseases, including ageing and cancer. We also review recent mechanistic insights into DNA repair and discuss how these insights are being used to develop novel therapeutic strategies for treating human disease.
Summary
Shewanella oneidensis is the best understood model organism for the study of dissimilatory iron reduction. This review focuses on the current state of our knowledge regarding this ...extracellular respiratory process and highlights its physiologic, regulatory and biochemical requirements. It seems that we have widely understood how respiratory electrons can reach the cell surface and what the minimal set of electron transport proteins to the cell surface is. Nevertheless, even after decades of work in different research groups around the globe there are still several important questions that were not answered yet. In particular, the physiology of this organism, the possible evolutionary benefit of some responses to anoxic conditions, as well as the exact mechanism of electron transfer onto solid electron acceptors are yet to be addressed. The elucidation of these questions will be a great challenge for future work and important for the application of extracellular respiration in biotechnological processes.
Extracellular respiration is a key factor for the geobiochemical cycling of elements in soil and sediments and enables a variety of microbe–electrode interaction based applications. Shewanella oneidensis is the best understood model organism for extracellular respiration. This review provides an overview of the molecular details of this process and gives insight into the physiological framework of the organism.
Microbial colonization of mucosal surfaces may be an initial event in the progression to disease, and it is often a transient process. For the extracellular pathogen Streptococcus pneumoniae studied ...in a mouse model, nasopharyngeal carriage is eliminated over a period of weeks and requires cellular rather than humoral immunity. Here, we demonstrate that primary infection led to TLR2-dependent recruitment of monocyte/macrophages into the upper airway lumen, where they engulfed pneumococci. Pharmacologic depletion of luminal monocyte/macrophages by intranasal instillation of liposomal clodronate diminished pneumococcal clearance. Efficient clearance of colonization required TLR2 signaling to generate a population of pneumococcal-specific IL-17-expressing CD4+ T cells. Depletion of either IL-17A or CD4+ T cells was sufficient to block the recruitment of monocyte/macrophages that allowed for effective late pneumococcal clearance. In contrast with naive mice, previously colonized mice showed enhanced early clearance that correlated with a more robust influx of luminal neutrophils. As for primary colonization, these cellular responses required Th17 immunity. Our findings demonstrate that monocyte/macrophages and neutrophils recruited to the mucosal surface are key effectors in clearing primary and secondary bacterial colonization, respectively.
PDF
