scholarly journals Avoidance of the Host Immune System through Phase Variation in Mycoplasma pulmonis

2005 ◽  
Vol 73 (4) ◽  
pp. 2033-2039 ◽  
Author(s):  
Amy M. Denison ◽  
Brenda Clapper ◽  
Kevin Dybvig
Keyword(s):  
Immune System ◽  
Phase Variation ◽  
Surface Proteins ◽  
Tissue Tropism ◽  
Host Immune System ◽  
Phase Variable ◽  
Wild Type ◽  
Mycoplasma Pulmonis ◽  
Rag 1

ABSTRACT Phase-variable lipoproteins are commonly found in Mycoplasma species. Mycoplasma pulmonis contains a family of extensively studied phase- and size-variable lipoproteins encoded by the vsa locus. The Vsa surface proteins vary at a high frequency, the in vivo significance of which has yet to be determined. We investigated the role of Vsa phase variation in respect to tissue tropism and avoidance of the immune system in the mouse host. Mycoplasmas were cultured 3, 14, and 21 days postinoculation from the nose, lung, trachea, liver, and spleen of experimentally infected C57BL/6 (wild-type), C57BL/6-RAG-1−/− (RAG−/−), and C57BL/6-inducible nitric oxide synthase (iNOS)−/− (iNOS−/−) mice. In wild-type and iNOS−/− mice, a large number of Vsa variants were seen by 21 days postinoculation. In contrast, little Vsa variation occurred in all tissues of RAG−/− mice. Analysis of isolates from 14 days postinoculation revealed less variation of the Vsa proteins in iNOS−/− mice than in the wild type. Western blot analysis of isolates from each strain of mouse demonstrated that Vsa phase variation occurred independently of size variation, indicating no obvious selection pressure for size variants. Additionally, these experiments provided no evidence that mycoplasmas producing particular Vsa proteins adhered only to specific tissues. The data strongly indicate that Vsa phase variation is a mechanism for avoidance of the immune system with no obvious contribution to tissue tropism.

scholarly journals The QseG Lipoprotein Impacts the Virulence of EnterohemorrhagicEscherichia coliandCitrobacter rodentiumand Regulates Flagellar Phase Variation inSalmonella entericaSerovar Typhimurium

2018 ◽  
Vol 86 (4) ◽  
Author(s):  
Elizabeth A. Cameron ◽  
Charley C. Gruber ◽  
Jennifer M. Ritchie ◽  
Matthew K. Waldor ◽  
Vanessa Sperandio
Keyword(s):  
Regulatory Networks ◽  
Cultured Cells ◽  
Rabbit Model ◽  
Phase Variation ◽  
Enteric Pathogens ◽  
Infection Model ◽  
Phase Variable ◽  
Wild Type ◽  
Content Type

ABSTRACTThe QseEF histidine kinase/response regulator system modulates expression of enterohemorrhagicEscherichia coli(EHEC) andSalmonella entericaserovar Typhimurium virulence genes in response to the host neurotransmitters epinephrine and norepinephrine.qseG, which encodes an outer membrane lipoprotein, is cotranscribed withqseEFin these enteric pathogens, but there is little knowledge of its role in virulence. Here, we found that in EHEC QseG interacts with the type III secretion system (T3SS) gate protein SepL and modulates the kinetics of attaching and effacing (AE) lesion formation on tissue-cultured cells. Moreover, an EHEC ΔqseGmutant had reduced intestinal colonization in an infant rabbit model. Additionally, inCitrobacter rodentium, an AE lesion-forming pathogen like EHEC, QseG is required for full virulence in a mouse model. InS. Typhimurium, we found that QseG regulates the phase switch between the two flagellin types, FliC and FljB. In anS. Typhimurium ΔqseGmutant, the phase-variable promoter forfljBis preferentially switched into the “on” position, leading to overproduction of this phase two flagellin. In infection of tissue-cultured cells, theS. Typhimurium ΔqseGmutant provokes increased inflammatory cytokine production versus the wild type;in vivo, in a murine infection model, the ΔqseGstrain caused a more severe inflammatory response and was attenuated versus the wild-type strain. Collectively, our findings demonstrate that QseG is important for full virulence in several enteric pathogens and controls flagellar phase variation inS. Typhimurium, and they highlight both the complexity and conservation of the regulatory networks that control the virulence of enteric pathogens.

scholarly journals Biofilm formation in the lung contributes to virulence and drug tolerance of Mycobacterium tuberculosis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Poushali Chakraborty ◽  
Sapna Bajeli ◽  
Deepak Kaushal ◽  
Bishan Dass Radotra ◽  
Ashwani Kumar
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Immune System ◽  
Biofilm Formation ◽  
Antimycobacterial Activity ◽  
Drug Tolerance ◽  
Host Immune System ◽  
Tissue Sections ◽  
Slow Growing

AbstractTuberculosis is a chronic disease that displays several features commonly associated with biofilm-associated infections: immune system evasion, antibiotic treatment failures, and recurrence of infection. However, although Mycobacterium tuberculosis (Mtb) can form cellulose-containing biofilms in vitro, it remains unclear whether biofilms are formed during infection in vivo. Here, we demonstrate the formation of Mtb biofilms in animal models of infection and in patients, and that biofilm formation can contribute to drug tolerance. First, we show that cellulose is also a structural component of the extracellular matrix of in vitro biofilms of fast and slow-growing nontuberculous mycobacteria. Then, we use cellulose as a biomarker to detect Mtb biofilms in the lungs of experimentally infected mice and non-human primates, as well as in lung tissue sections obtained from patients with tuberculosis. Mtb strains defective in biofilm formation are attenuated for survival in mice, suggesting that biofilms protect bacilli from the host immune system. Furthermore, the administration of nebulized cellulase enhances the antimycobacterial activity of isoniazid and rifampicin in infected mice, supporting a role for biofilms in phenotypic drug tolerance. Our findings thus indicate that Mtb biofilms are relevant to human tuberculosis.

scholarly journals Identification and Functional Mapping of the Mycoplasma fermentans P29 Adhesin

2002 ◽  
Vol 70 (9) ◽  
pp. 4925-4935 ◽  
Author(s):  
Spencer A. Leigh ◽  
Kim S. Wise
Keyword(s):  
Disulfide Bond ◽  
Hela Cells ◽  
Mammalian Cells ◽  
Flow Cytometric Analysis ◽  
Phase Variation ◽  
Surface Proteins ◽  
Mycoplasma Species ◽  
Phase Variable ◽  
Binding Region ◽  
Mycoplasma Fermentans

ABSTRACT Initial adherence interactions between mycoplasmas and mammalian cells are important for host colonization and may contribute to subsequent pathogenic processes. Despite significant progress toward understanding the role of specialized, complex tip structures in the adherence of some mycoplasmas, particularly those that infect humans, less is known about adhesins through which other mycoplasmas of this host bind to diverse cell types, even though simpler surface components are likely to be involved. We show by flow cytometric analysis that a soluble recombinant fusion protein (FP29), representing the abundant P29 surface lipoprotein of Mycoplasma fermentans, binds human HeLa cells and inhibits M. fermentans binding to these cells, in both a quantitative and a saturable manner, whereas analogous fusion proteins representing other mycoplasma surface proteins did not. Constructs representing nested N- or C-terminal truncations of FP29 allowed initial mapping of this specific adherence function to a central region of the P29 sequence containing a 36-amino-acid disulfide loop. A derivative of FP29 containing a mutation converting one participating Cys to Ser, precluding intrachain disulfide bond formation, retained full activity. Together these results suggest that the direct interaction of M. fermentans with a ligand on the HeLa cell surface involves a limited segment of the P29 surface lipoprotein and requires neither the disulfide bond nor the contribution of adjacent portions of the protein. Earlier results indicating phase-variable display of monoclonal antibody surface epitopes on P29, now recognized to be outside this ligand binding region, raise the possibility that variation of mycoplasma surface architecture might alter the presentation of the binding region and the adherence phenotype. Preliminary results further indicated that FP29 could inhibit binding to HeLa cells by Mycoplasma hominis, a distinct human mycoplasma species displaying the phase-variable adhesin Vaa, but not that by Mycoplasma capricolum, an organism infecting caprine species. This result raises the additional, testable possibility that a common host cell ligand for two human mycoplasma species may be recognized through structurally dissimilar adhesins that undergo phase variation by two distinct mechanisms, governing protein expression (Vaa) or surface masking (P29).

scholarly journals Enhancement of immune response against Bordetella spp. by disrupting immunomodulation

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Monica C. Gestal ◽  
Laura K. Howard ◽  
Kalyan Dewan ◽  
Hannah M. Johnson ◽  
Mariette Barbier ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Immune Cells ◽  
Lymphoid Tissue ◽  
Protective Immunity ◽  
Inflammatory Cells ◽  
Host Immune System ◽  
Initial Growth ◽  
Wild Type ◽  
Sterilizing Immunity

AbstractWell-adapted pathogens must evade clearance by the host immune system and the study of how they do this has revealed myriad complex strategies and mechanisms. Classical bordetellae are very closely related subspecies that are known to modulate adaptive immunity in a variety of ways, permitting them to either persist for life or repeatedly infect the same host. Exploring the hypothesis that exposure to immune cells would cause bordetellae to induce expression of important immunomodulatory mechanisms, we identified a putative regulator of an immunomodulatory pathway. The deletion of btrS in B. bronchiseptica did not affect colonization or initial growth in the respiratory tract of mice, its natural host, but did increase activation of the inflammasome pathway, and recruitment of inflammatory cells. The mutant lacking btrS recruited many more B and T cells into the lungs, where they rapidly formed highly organized and distinctive Bronchial Associated Lymphoid Tissue (BALT) not induced by any wild type Bordetella species, and a much more rapid and strong antibody response than observed with any of these species. Immunity induced by the mutant was measurably more robust in all respiratory organs, providing completely sterilizing immunity that protected against challenge infections for many months. Moreover, the mutant induced sterilizing immunity against infection with other classical bordetellae, including B. pertussis and B. parapertussis, something the current vaccines do not provide. These findings reveal profound immunomodulation by bordetellae and demonstrate that by disrupting it much more robust protective immunity can be generated, providing a pathway to greatly improve vaccines and preventive treatments against these important pathogens.

Use of immunological manipulations in studying genetically controlled responses to Leishmania donovani infection in mice

Parasitology ◽  
1984 ◽  
Vol 88 (4) ◽  
pp. 677-679 ◽  
Author(s):  
Jenefer M. Blackwell
Keyword(s):  
Immune System ◽  
Leishmania Donovani ◽  
Inbred Mouse ◽  
Parasitic Infection ◽  
Preceding Paper ◽  
Mouse Strains ◽  
Host Immune System ◽  
Inbred Mouse Strains

In the preceding paper Howard (p. 665) has given a very elegant presentation on ways in which the host immune system may be manipulated to provide valuable information about immunoregulation of parasitic infection in vivo. In our laboratory we have used some of the same manoeuvres to study immunoregulation of genetically controlled responses to Leishmania donovani infection in inbred mouse strains (Ulczak & Blackwell, 1983; Crocker, Blackwell & Bradley, 1984). As has been Howard's experience, the results obtained have not always been as one might have predicted at the outset.

Effect of Adenoviral Early Genes and the Host Immune System on In Vivo Pancreatic Gene Transfer in the Mouse

Pancreas ◽  
1997 ◽  
Vol 15 (3) ◽  
pp. 236-245 ◽  
Author(s):  
Steven J. McClane ◽  
Thomas E. Hamilton ◽  
Ronald P. DeMatteo ◽  
Charlotte Burke ◽  
Steven E. Raper
Keyword(s):  
Immune System ◽  
Gene Transfer ◽  
Host Immune System ◽  
Early Genes

scholarly journals Antitumor and immunomodulatory activity of Inonotus obliquus

2017 ◽  
Vol 63 (2) ◽  
pp. 48-58 ◽  
Author(s):  
Justyna Staniszewska ◽  
Marcin Szymański ◽  
Ewa Ignatowicz
Keyword(s):  
Immune System ◽  
Tumor Cells ◽  
Good Alternative ◽  
Immunomodulatory Activity ◽  
Host Immune System ◽  
Protein Synthesis Inhibition ◽  
Inonotus Obliquus ◽  
Different Types

SummaryThe article presents the antitumor and immunomodulatory activity of compounds and extracts fromInonotus obliquus.Polysaccharides isolated from sclerotium have a direct antitumor effect due to protein synthesis inhibition in tumor cells. Polysaccharides derived from the mycelium function by activating the immune system. Due to the limited toxicity of these substances, both extracts as well as isolated and purified chemicals may be a good alternative to current chemotherapy and play a role in cancer prevention.In vitroexperiments have shown the inhibition of inflammation with the influence of action ofI. obliquusextracts; however,in vivoexperiments on animals implanted with tumor cells of different types have shown the activation of the host immune system. This led to decrease in tumor mass and prolonged survival. The immunomodulatory mechanism of action is complex and it seems that stimulation of macrophages and induction of apoptosis in cancer cells is of great importance.

scholarly journals Rescuing the Host Immune System by Targeting the Immune Evasion Complex ORF8-IRF3 in SARS-CoV-2 Infection with Natural Products Using Molecular Modeling Approaches

2021 ◽  
Vol 19 (1) ◽  
pp. 112
Author(s):  
Aqel Albutti
Keyword(s):  
Immune System ◽  
Immune Evasion ◽  
Simulation Analysis ◽  
Dynamic Properties ◽  
Natural Compounds ◽  
Host Immune System ◽  
Structural Dynamic ◽  
Novel Drugs

The perennial emergence of SARS-CoV-2 and its new variants causing upper respiratory complexities since December 2019 has aggravated the pandemic situation around the world. SARS-CoV-2 encodes several proteins among which ORF8 is a novel factor that is unique to SARS-CoV-2 only and is reported to help the virus in disease severity and immune evasion. ORF8-IRF3 complex induces endoplasmic reticulum stress, thus helps in the evasion of immune response. Consequently, targeting the ORF8-IRF3 complex is considered as a prime target for the discovery of novel drugs against SARS-CoV-2. In this regard, computational methods are of great interest to fast track the identification and development of novel drugs. Virtual screening of South African Natural Compounds Database (SANCDB), followed by docking and molecular dynamics (MD) simulation analysis, were performed to determine novel natural compounds. Computational molecular search and rescoring of the SANCDB database followed by induced-fit docking (IFD) protocol identified Quercetin 3-O-(6″-galloyl)-beta-D-galactopyranoside (SANC00850), Tribuloside (SANC01050), and Rutin (SANC00867) are the best scoring compounds. Structural-dynamic properties assessment revealed that these three compounds have stable dynamics, compactness, and a higher number of hydrogen bonds. For validation, we used MM/GBSA, in silico bioactivity estimation and dissociation constant (KD) approaches, which revealed that these compounds are the more potent inhibitors of the ORF8-IRF3 complex and would rescue the host immune system potentially. These compounds need further in vitro and in vivo validations to be used as therapeutics against SARS-CoV-2 to rescue the host immune system during COVID-19 infection.

scholarly journals A large panel of chicken cells are invaded in vivo by Salmonella Typhimurium even when depleted of all known invasion factors

2020 ◽  
Author(s):  
S. M. Roche ◽  
S. Holbert ◽  
Y. Le Vern ◽  
C. Rossignol ◽  
A. Rossignol ◽  
...  
Keyword(s):  
Gall Bladder ◽  
Wild Type Strain ◽  
Host Cells ◽  
Poultry Meat ◽  
Tissue Tropism ◽  
Wild Type ◽  
Phagocytic Cells ◽  
Mutant Strains ◽  
Meat And Eggs

AbstractSalmonella are among the most important foodborne pathogens and contaminated poultry meat and eggs are the main source of human infection. Infected poultry are a major problem as they are asymptomatic, thus rendering the identification of infected poultry farms difficult. In this context, controlling animal infections is of primary importance. It is known that cell and tissue tropism govern disease in many infectious models, our aim was therefore to identify the infected host-cell types in chicks and the role of the three known bacterial invasion factors in this process (T3SS-1, Rck and PagN). Chicks were inoculated with wild-type or isogenic fluorescent Salmonella Typhimurium mutant strains via the intraperitoneal route. Then infected cells in the liver, spleen, gall bladder and aortic vessels were identified using flow-cytometric analyses and invasion confirmed by confocal microscopy. Our results show that all these organs could be foci of infection and that a wide array of phagocytic and non-phagocytic cells is invaded in vivo in each organ. These cells include immune cells and also epithelial and endothelial cells. Moreover, we demonstrated that, despite the invalidation of the three known invasion factors (T3SS-1, Rck and PagN), S. Typhimurium remained able to colonize internal organs and invade non-phagocytic cells in each organ studied. In line with this result, the mutant strains colonized these organs more efficiently than the wild-type strain. S. Typhimurium invasion of gall bladder cells was confirmed by immunohistochemistry and infection was shown to last several weeks after inoculation of chicks and at a level similar to that observed in the spleen. All together, these findings provide new insights into the dynamics of Salmonella spread in vivo in chicks at the organ and cellular levels.Author summaryIn many infectious models, cell and tissue tropism govern disease. Moreover, depending on the entry process, both bacterial behavior and host response are different. It is therefore important to identify the host cells targeted in vivo by a pathogen and the entry routes used by this pathogen to invade the different host cells. This is all the more important with a pathogen that enters cells in several ways like Salmonella, which is responsible for human and animal salmonellosis. As poultry meat and eggs are the main sources of human contamination, controlling animal infections is of primary importance. In this paper, we identified a large array of phagocytic and non-phagocytic cells targeted in vivo using fluorescent Salmonella Typhimurium strains inoculated by the intraperitoneal route. Surprisingly, the same host cells were infected by the wild-type strain or its isogenic mutants deleted of either the T3SS-1 or of the three known invasion factors (T3SS-1, Rck and PagN). These cells were immune cells but also epithelial and endothelial cells. Moreover, we demonstrated for the first time that the gall bladder and the aortic vessels could be foci of infection in chicks in addition to the liver and spleen.

scholarly journals Bypassing Phase Variation of Lipooligosaccharide (LOS): Using Heptose 1 Glycan Mutants To Establish Widespread Efficacy of Gonococcal Anti-LOS Monoclonal Antibody 2C7

2019 ◽  
Vol 88 (2) ◽  
Author(s):  
Srinjoy Chakraborti ◽  
Sunita Gulati ◽  
Bo Zheng ◽  
Frank J. Beurskens ◽  
Janine Schuurman ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Polymorphonuclear Leukocytes ◽  
Phase Variation ◽  
Human Infection ◽  
Phase Variable ◽  
Content Type ◽  
Human Igg1 ◽  
And Function

ABSTRACT The sialylatable lacto-N-neotetraose (LNnT; Gal-GlcNAc-Gal-Glc) moiety from heptose I (HepI) of the lipooligosaccharide (LOS) of Neisseria gonorrhoeae undergoes positive selection during human infection. Lactose (Gal-Glc) from HepII, although phase variable, is commonly expressed in humans; loss of HepII lactose compromises gonococcal fitness in mice. Anti-LOS monoclonal antibody (MAb) 2C7, a promising antigonococcal immunotherapeutic that elicits complement-dependent bactericidal activity and attenuates gonococcal colonization in mice, recognizes an epitope comprised of lactoses expressed simultaneously from HepI and HepII. Glycan extensions beyond lactose on HepI modulate binding and function of MAb 2C7 in vitro. Here, four gonococcal LOS mutants, each with lactose from HepII but fixed (unable to phase-vary) LOS HepI glycans extended beyond the lactose substitution of HepI (lactose alone, Gal-lactose, LNnT, or GalNAc-LNnT), were used to define how HepI glycan extensions affect (i) mouse vaginal colonization and (ii) efficacy in vitro and in vivo of a human IgG1 chimeric derivative of MAb 2C7 (2C7-Ximab) with a complement-enhancing E-to-G Fc mutation at position 430 (2C7-Ximab-E430G). About 10-fold lower 2C7-Ximab-E430G concentrations achieved similar complement-dependent killing of three gonococcal mutants with glycan extensions beyond lactose-substituted HepI (lactose alone, LNnT, or GalNAc-LNnT) as 2C7-Ximab (unmodified Fc). The fourth mutant (Gal-lactose) resisted direct complement-dependent killing but was killed approximately 70% by 2C7-Ximab-E430G in the presence of polymorphonuclear leukocytes and complement. Only mutants with (sialylatable) LNnT from HepI colonized mice for >3 days, reiterating the importance of LNnT sialylation for infection. 2C7-Ximab-E430G significantly attenuated colonization caused by the virulent mutants.

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