scholarly journals Yersinia pestis lipopolysaccharide remodeling confers resistance to a Xenopsylla cheopis cecropin

2021 ◽  
Author(s):  
Basil Mathew ◽  
Kari L. Aoyagi ◽  
Mark A. Fisher
Keyword(s):  
Immune Responses ◽  
Yersinia Pestis ◽  
Bacterial Infections ◽  
Antimicrobial Activities ◽  
Innate Immune Responses ◽  
Binding Assays ◽  
Bacterial Killing ◽  
Bacterial Membranes ◽  
Xenopsylla Cheopis ◽  
In The Wild

Fleas are major vectors of Yersinia pestis, the causative agent of plague. It has been proposed that Y. pestis has developed the ability to overcome the innate immune responses of fleas. Despite the fact that they transmit a number of bacterial infections, very little is known about the immune responses in fleas. In this study, we describe the antimicrobial activities of cecropin from Xenopsylla cheopis (cheopin), a major vector for Y. pestis in the wild. This is the first cecropin-class antimicrobial peptide described from Siphonaptera insects. Cheopin showed potent activity against Gram-negative bacteria, but little activity against wild-type Y. pestis KIM6+. Deletion of the aminoarabinose operon, which is responsible for the 4-amino-4-deoxy-L-arabinose (Ara4N) modification of LPS, rendered Y. pestis highly susceptible to cheopin. Confocal microscopy and whole cell binding assays indicated that Ara4N modification reduces the affinity of cheopin for Y. pestis. Further, cheopin only permeabilized bacterial membranes in the absence of Ara4N-modified LPS, which was correlated with bacterial killing. This study provides insights into innate immunity of the flea and evidence for the crucial role of Ara4N modification of Y. pestis LPS in conferring resistance against flea antimicrobial peptides.

scholarly journals Infection triggers tumor regression through activation of innate immunity in Drosophila

2019 ◽  
Author(s):  
Camille Jacqueline ◽  
Jean-Philippe Parvy ◽  
Dominique Faugère ◽  
François Renaud ◽  
Dorothée Missé ◽  
...  
Keyword(s):  
Immune Responses ◽  
Tumor Size ◽  
Bacterial Infections ◽  
Tumor Regression ◽  
Acute Infection ◽  
Innate Immune ◽  
Immune Gene ◽  
Infectious Agents ◽  
Innate Immune Responses

AbstractThe pioneering work of Dr. William Coley has shown that infections can stimulate the immune system and improve tumor growth control. However, the immune mechanisms responsible for the protective role of infectious agents have still not been identified. Here, we investigated the role of innate immune pathways in tumor regression by performing experimental infections in genetically modified Drosophila that develop invasive neoplastic tumors. After quantifying tumor size, through image processing, and immune gene expression with transcriptomic analyses, we analyzed the link between tumor size and pathogen-induced immune responses thanks to a combination of statistical and mathematical modeling. Drosophila larvae infected with a naturally-occurring bacterium showed a smaller tumor size compared to controls and fungus-infected larvae, thanks to an increase expression of Imd and Toll pathways. Our mathematical model reinforces this idea by showing that repeated acute infection could results in an even higher decrease in tumor size. Thus, our study suggests that infectious agents can induce tumor regression through the alteration of innate immune responses. This phenomenon, currently neglected in oncology, could have major implications for the elaboration of new preventive and immunotherapeutic strategies.One Sentence SummaryBacterial infections can decrease cancer cell accumulation through stimulation of innate immune responses.

scholarly journals Interaction of the Gelsolin-Derived Antibacterial PBP 10 Peptide with Lipid Bilayers and Cell Membranes

2006 ◽  
Vol 50 (9) ◽  
pp. 2932-2940 ◽  
Author(s):  
Robert Bucki ◽  
Paul A. Janmey
Keyword(s):  
Antimicrobial Peptides ◽  
Lipid Bilayers ◽  
Cell Membranes ◽  
Plasma Membranes ◽  
Antimicrobial Activities ◽  
Eukaryotic Cells ◽  
Hypotonic Solution ◽  
Antibacterial Peptides ◽  
Bacterial Killing ◽  
Bacterial Membranes

ABSTRACTPBP 10, an antibacterial, cell membrane-permeant rhodamine B-conjugated peptide derived from the polyphosphoinositide binding site of gelsolin, interacts selectively with both lipopolysaccharides (LPS) and lipoteichoic acid (LTA), the distinct components of gram-negative and gram-positive bacteria, respectively. Isolated LPS and LTA decrease the antimicrobial activities of PBP 10, as well as other antimicrobial peptides, such as cathelicidin-LL37 (LL37) and mellitin. In an effort to elucidate the mechanism of bacterial killing by PBP 10, we compared its effects on artificial lipid bilayers and eukaryotic cell membranes with the actions of the mellitin, magainin II, and LL37 peptides. This study reveals that pore formation is unlikely to be involved in PBP 10-mediated membrane destabilization. We also investigated the effects of these peptides on platelets and red blood cells (RBCs). Comparison of these antimicrobial peptides shows that only mellitin has a toxic effect on platelets and RBCs in a concentration range concomitant with its bactericidal activity. The hemolytic activities of the PBP 10 and LL37 peptides significantly increase when RBCs are osmotically swollen in hypotonic solution, indicating that these antibacterial peptides may take advantage of the more extended form of bacterial membranes in exerting their killing activities. Additionally, we found that LL37 hemolytic activity was much higher when RBCs were induced to expose phosphatidylserine to the external leaflet of their plasma membranes. This finding suggests that asymmetrical distribution of phospholipids in the external membranes of eukaryotic cells may represent an important factor in determining the specificity of antibacterial peptides for targeting bacteria rather than eukaryotic cells.

scholarly journals Innate Immune Effectors in Mycobacterial Infection

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Hiroyuki Saiga ◽  
Yosuke Shimada ◽  
Kiyoshi Takeda
Keyword(s):  
Immune Responses ◽  
Bacterial Infections ◽  
Mycobacterial Infection ◽  
Innate Immune ◽  
Pathogenic Microorganisms ◽  
Lipocalin 2 ◽  
Innate Immune Responses ◽  
Active Vitamin ◽  
Lectin Receptors ◽  
Adaptive Immune

Tuberculosis, which is caused by infection withMycobacterium tuberculosis(Mtb), remains one of the major bacterial infections worldwide. Host defense against Mtb is mediated by a combination of innate and adaptive immune responses. In the last 15 years, the mechanisms for activation of innate immunity have been elucidated. Toll-like receptors (TLRs) have been revealed to be critical for the recognition of pathogenic microorganisms including mycobacteria. Subsequent studies further revealed that NOD-like receptors and C-type lectin receptors are responsible for the TLR-independent recognition of mycobacteria. Several molecules, such as active vitamin D3, secretary leukocyte protease inhibitor, and lipocalin 2, all of which are induced by TLR stimulation, have been shown to direct innate immune responses to mycobacteria. In addition, Irgm1-dependent autophagy has recently been demonstrated to eliminate intracellular mycobacteria. Thus, our understanding of the mechanisms for the innate immune response to mycobacteria is developing.

scholarly journals Sex-dependent neurobiological features of prenatal immune activation via TLR7

2019 ◽  
Vol 25 (10) ◽  
pp. 2330-2341 ◽  
Author(s):  
Galen Missig ◽  
James O. Robbins ◽  
Emery L. Mokler ◽  
Kenneth M. McCullough ◽  
Staci D. Bilbo ◽  
...  
Keyword(s):  
Autoimmune Disease ◽  
Immune Responses ◽  
Immune Activation ◽  
Bacterial Infections ◽  
Developmental Trajectories ◽  
Dorsal Striatum ◽  
Gonadal Hormone ◽  
Innate Immune Responses ◽  
Wide Range ◽  
Maternal Administration

Abstract Immune activation during pregnancy via infection or autoimmune disease is a risk factor for neuropsychiatric illness. Mouse models of prenatal immune activation often involve maternal administration of agents that activate toll-like receptors (TLRs), a class of pattern recognition receptors that initiate innate immune responses. Such studies have focused primarily on activating the TLR3 or TLR4 subtypes, to mimic immune responses to viral or bacterial infections, respectively. Here, we characterize the effects of prenatal activation of TLR7, which is implicated in the pathogenesis of autoimmune disease. Prenatal TLR7 activation via administration of the selective agonist imiquimod (5.0 mg/kg) induces a phenotype in offspring characterized by reduced anxiety-like behavior, fragmented social behavior, and altered ultrasonic vocalization patterns at 6–12 weeks of age. The characteristics of this phenotype are readily distinguishable from—and in some ways opposite to—those seen following prenatal activation of TLR3 and/or TLR4. Prenatal TLR7-activated mice have normal baseline locomotor activity, but are hyperresponsive to stimuli including social partners, circadian cues, and gonadal hormone fluctuations. These alterations are accompanied by decreases in microglia density but increases in ramifications. RNA-sequencing of dorsal striatum, a region showing profound changes in microglial markers, indicates that prenatal TLR7 activation induces differential expression of hundreds of genes at 13 weeks of age, with virtually no overlap in differentially expressed genes between males and females. Our findings demonstrate that prenatal immune activation can promote a wide range of developmental trajectories, depending on the type and/or pattern of TLR activation and the sex of the offspring.

scholarly journals Quantitative Models of Phage-Antibiotic Combination Therapy

mSystems ◽  
2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Rogelio A. Rodriguez-Gonzalez ◽  
Chung Yin Leung ◽  
Benjamin K. Chan ◽  
Paul E. Turner ◽  
Joshua S. Weitz
Keyword(s):  
Combination Therapy ◽  
Immune Responses ◽  
Bacterial Infections ◽  
System Level ◽  
Innate Immune Responses ◽  
Therapeutic Success ◽  
Content Type ◽  
Therapeutic Outcomes

ABSTRACT The spread of multidrug-resistant (MDR) bacteria is a global public health crisis. Bacteriophage therapy (or “phage therapy”) constitutes a potential alternative approach to treat MDR infections. However, the effective use of phage therapy may be limited when phage-resistant bacterial mutants evolve and proliferate during treatment. Here, we develop a nonlinear population dynamics model of combination therapy that accounts for the system-level interactions between bacteria, phage, and antibiotics for in vivo application given an immune response against bacteria. We simulate the combination therapy model for two strains of Pseudomonas aeruginosa, one which is phage sensitive (and antibiotic resistant) and one which is antibiotic sensitive (and phage resistant). We find that combination therapy outperforms either phage or antibiotic alone and that therapeutic effectiveness is enhanced given interaction with innate immune responses. Notably, therapeutic success can be achieved even at subinhibitory concentrations of antibiotics, e.g., ciprofloxacin. These in silico findings provide further support to the nascent application of combination therapy to treat MDR bacterial infections, while highlighting the role of innate immunity in shaping therapeutic outcomes. IMPORTANCE This work develops and analyzes a novel model of phage-antibiotic combination therapy, specifically adapted to an in vivo context. The objective is to explore the underlying basis for clinical application of combination therapy utilizing bacteriophage that target antibiotic efflux pumps in Pseudomonas aeruginosa. In doing so, the paper addresses three key questions. How robust is combination therapy to variation in the resistance profiles of pathogens? What is the role of immune responses in shaping therapeutic outcomes? What levels of phage and antibiotics are necessary for curative success? As we show, combination therapy outperforms either phage or antibiotic alone, and therapeutic effectiveness is enhanced given interaction with innate immune responses. Notably, therapeutic success can be achieved even at subinhibitory concentrations of antibiotic. These in silico findings provide further support to the nascent application of combination therapy to treat MDR bacterial infections, while highlighting the role of system-level feedbacks in shaping therapeutic outcomes.

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