The Experts below are selected from a list of 5403 Experts worldwide ranked by ideXlab platform

G.k. Owens - One of the best experts on this subject based on the ideXlab platform.

  • smooth muscle cell Phenotypic Switching in atherosclerosis
    Cardiovascular Research, 2012
    Co-Authors: Delphine Gomez, G.k. Owens
    Abstract:

    Smooth muscle cells (SMCs) possess remarkable Phenotypic plasticity that allows rapid adaptation to fluctuating environmental cues, including during development and progression of vascular diseases such as atherosclerosis. Although much is known regarding factors and mechanisms that control SMC Phenotypic plasticity in cultured cells, our knowledge of the mechanisms controlling SMC Phenotypic Switching in vivo is far from complete. Indeed, the lack of definitive SMC lineage-tracing studies in the context of atherosclerosis, and difficulties in identifying Phenotypically modulated SMCs within lesions that have down-regulated typical SMC marker genes, and/or activated expression of markers of alternative cell types including macrophages, raise major questions regarding the contributions of SMCs at all stages of atherogenesis. The goal of this review is to rigorously evaluate the current state of our knowledge regarding possible phenotypes exhibited by SMCs within atherosclerotic lesions and the factors and mechanisms that may control these Phenotypic transitions.

  • epigenetic control of smooth muscle cell differentiation and Phenotypic Switching in vascular development and disease
    Annual Review of Physiology, 2012
    Co-Authors: Matthew R Alexander, G.k. Owens
    Abstract:

    The vascular smooth muscle cell (SMC) in adult animals is a highly specialized cell whose principal function is contraction. However, this cell displays remarkable plasticity and can undergo profound changes in phenotype during repair of vascular injury, during remodeling in response to altered blood flow, or in various disease states. There has been extensive progress in recent years in our understanding of the complex mechanisms that control SMC differentiation and Phenotypic plasticity, including the demonstration that epigenetic mechanisms play a critical role. In addition, recent evidence indicates that SMC Phenotypic Switching in adult animals involves the reactivation of embryonic stem cell pluripotency genes and that mesenchymal stem cells may be derived from SMC and/or pericytes. This review summarizes the current state of our knowledge in this field and identifies some of the key unresolved challenges and questions that we feel require further study.

  • Multiple repressor pathways contribute to Phenotypic Switching of vascular smooth muscle cells
    American journal of physiology. Cell physiology, 2006
    Co-Authors: Keiko Kawai-kowase, G.k. Owens
    Abstract:

    Smooth muscle cell (SMC) differentiation is an essential component of vascular development and these cells perform biosynthetic, proliferative, and contractile roles in the vessel wall. SMCs are not terminally differentiated and possess the ability to modulate their phenotype in response to changing local environmental cues. The focus of this review is to provide an overview of the current state of knowledge of molecular mechanisms involved in controlling Phenotypic Switching of SMC with particular focus on examination of processes that contribute to the repression of SMC marker genes. We discuss the environmental cues which actively regulate SMC Phenotypic Switching, such as platelet-derived growth factor-BB, as well as several important regulatory mechanisms required for suppressing expression of SMC-specific/selective marker genes in vivo, including those dependent on conserved G/C-repressive elements, and/or highly conserved degenerate CArG elements found in the promoters of many of these marker genes. Finally, we present evidence indicating that SMC Phenotypic Switching involves multiple active repressor pathways, including Kruppel-like zinc finger type 4, HERP, and ERK-dependent phosphorylation of Elk-1 that act in a complementary fashion.

Jin-kun Wen - One of the best experts on this subject based on the ideXlab platform.

Arturo Casadevall - One of the best experts on this subject based on the ideXlab platform.

  • Characterization of Phenotypic Switching in Cryptococcus neoformans Biofilms
    Mycopathologia, 2008
    Co-Authors: Luis R. Martinez, Arturo Casadevall, David C. Ibom, Bettina C. Fries
    Abstract:

    Cryptococcus neoformans is an encapsulated yeast-like fungus that is a relatively frequent cause of meningoencephalitis in immunocompromised patients and also occasionally causes disease in apparently healthy individuals. This fungus collectively forms biofilms on polystyrene plates and medical devices, whereas individually can undergo Phenotypic Switching. Both events have profound consequences in the establishment of fungal infection and are associated with persistent infection due to increase resistance to antimicrobial therapy. In this study, we characterized switch phenotypes in C. neoformans biofilms. Smooth, mucoid, and wrinkled switch phenotypes of various Switching C. neoformans strains were examined for their adhering and biofilm-forming ability on 96-well plates using cell counts and 2,3-bis (2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino) carbonyl]-2H-tetrazolium hydroxide (XTT) reduction assay, respectively. Both assays showed that C. neoformans strains with the parent smooth phenotype adhered and formed stronger biofilms than their mucoid and wrinkled counterparts. Furthermore, the Phenotypic Switching frequencies of the individual colony types grown in biofilms or as planktonic cells were investigated. For the parent smooth variant of most strains, we found enhanced Phenotypic Switching in cryptococcal biofilms when compared to Switching rates of planktonic cells. In contrast, the back-Switching rate of mucoid to smooth variant was significantly higher in planktonic cells of seven strains of C. neoformans strains. These results suggested that Phenotypic Switching can occur in cryptococcal biofilms and extend our understanding of the relationship of both phenomena.

  • Characterization of Phenotypic Switching in Cryptococcus neoformans biofilms.
    Mycopathologia, 2008
    Co-Authors: Luis R. Martinez, Arturo Casadevall, David C. Ibom, Bettina C. Fries
    Abstract:

    Cryptococcus neoformans is an encapsulated yeast-like fungus that is a relatively frequent cause of meningoencephalitis in immunocompromised patients and also occasionally causes disease in apparently healthy individuals. This fungus collectively forms biofilms on polystyrene plates and medical devices, whereas individually can undergo Phenotypic Switching. Both events have profound consequences in the establishment of fungal infection and are associated with persistent infection due to increase resistance to antimicrobial therapy. In this study, we characterized switch phenotypes in C. neoformans biofilms. Smooth, mucoid, and wrinkled switch phenotypes of various Switching C. neoformans strains were examined for their adhering and biofilm-forming ability on 96-well plates using cell counts and 2,3-bis (2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino) carbonyl]-2H-tetrazolium hydroxide (XTT) reduction assay, respectively. Both assays showed that C. neoformans strains with the parent smooth phenotype adhered and formed stronger biofilms than their mucoid and wrinkled counterparts. Furthermore, the Phenotypic Switching frequencies of the individual colony types grown in biofilms or as planktonic cells were investigated. For the parent smooth variant of most strains, we found enhanced Phenotypic Switching in cryptococcal biofilms when compared to Switching rates of planktonic cells. In contrast, the back-Switching rate of mucoid to smooth variant was significantly higher in planktonic cells of seven strains of C. neoformans strains. These results suggested that Phenotypic Switching can occur in cryptococcal biofilms and extend our understanding of the relationship of both phenomena.

  • Phenotypic Switching in Cryptococcus neoformans.
    Microbes and infection, 2002
    Co-Authors: Bettina C. Fries, David L. Goldman, Arturo Casadevall
    Abstract:

    Cryptococcus neoformans strains exhibit considerable phenotype variability with regards to the capsular polysaccharide, sterol composition of the cell wall, and cell and colony morphology. Phenotypic changes can occur spontaneously during in vitro passage of strains or during chronic infection in vivo and may be associated with differences in virulence. Studies from our laboratory have demonstrated that phenotype variability can be the result of Phenotypic Switching. Phenotypic Switching is defined as a reversible change of an observable colony phenotype that occurs at a frequency above the expected frequency for somatic mutations. This implies that Phenotypic Switching represents controlled and programmed changes in this pathogenic yeast rather than random mutations. We have shown that a Phenotypic switch from a smooth colony phenotype to a mucoid colony phenotype occurs in vitro and in vivo during chronic infection of mice. More importantly we have now demonstrated that the switch is associated with an increase in virulence and a change in the host immune response. Implications of these findings for the pathogenesis of cryptococcosis are discussed.

  • Phenotypic Switching of Cryptococcus neoformans occurs in vivo and influences the outcome of infection.
    The Journal of clinical investigation, 2001
    Co-Authors: Bettina C. Fries, Carlos Pelleschi Taborda, Evan R. Serfass, Arturo Casadevall
    Abstract:

    Phenotypic Switching has been linked to the virulence of many pathogens, including fungi. However, it has not been conclusively shown to occur in vivo or to influence the outcome of infection. Cryptococcus neoformans undergoes Phenotypic Switching in vitro to colony types that differ in their virulence in mice. In this study, we asked whether C. neoformans undergoes Phenotypic Switching in vivo and whether this phenomenon contributes to virulence. By using a small inoculum to preclude the introduction of variants that had already switched during in vitro propagation, we demonstrated that in vivo Switching to a mucoid phenotype occurred in two mice strains and was associated with a lethal outcome. Phenotypic Switching resulted in changes of the capsular polysaccharide that inhibited phagocytosis by alveolar macrophages. This promoted a more vigorous inflammatory response and rapid demise. These data document in vivo Switching in a fungus and associate this phenomenon with enhanced virulence and a lethal outcome. The importance of this finding is underscored by the increased likelihood of Phenotypic Switching in chronic cryptococcosis; thus this mechanism may account for the inability to eradicate the organism in immunocompromised hosts.

  • Phenotypic Switching in cryptococcus neoformans results in changes in cellular morphology and glucuronoxylomannan structure
    Infection and Immunity, 1999
    Co-Authors: Bettina C. Fries, David L. Goldman, Robert Cherniak, Arturo Casadevall
    Abstract:

    Cryptococcus neoformans is an encapsulated pathogenic fungus that is notorious for causing chronic infections, in particular chronic meningitis. Cryptococcosis is usually associated with impaired immune function but can also occur in apparently normal hosts (9, 25). In patients with AIDS, C. neoformans infections are often incurable, despite effective antifungal therapy. Studies of serial C. neoformans isolates from chronically infected patients have documented changes in virulence, capsular polysaccharide structure, and karyotype, suggesting that C. neoformans can undergo changes during chronic infection that may facilitate persistence in tissue (2, 5, 8, 13, 14). The propensity of C. neoformans to undergo Phenotypic changes has also been demonstrated during in vitro passage for strain 24067, a common laboratory strain, which was noted to produce different variants ranging from avirulent to highly virulent (11). This process is referred to as microevolution. Recently, Phenotypic Switching was described in three C. neoformans strains (SB4, J32, and 24067A), which resulted in various colony morphologies (17). Phenotypic Switching has been described for many other pathogens and is often associated with changes in virulence (21, 22, 24, 26, 37, 39, 40). Phenotypic Switching resulting in changes of the polysaccharide capsule and virulence has also been reported in the encapsulated bacterial pathogens Neisseria meningitidis and Haemophilus influenzae (22, 44). Although the molecular mechanisms mediating the switch are different among the various microorganisms, Phenotypic Switching is emerging as a fundamental mechanism of virulence that may allow persistence of infection in tissue by promoting the generation of new variants that successfully escape the immune response. For C. neoformans SB4, Phenotypic Switching is characterized by changes in colony morphology that range from smooth (SM) to wrinkled (WR). The switch between colony types is reversible and occurs at rates much higher than eukaryotic mutation rates. SB4 colony types differed in virulence for mice and rats, linking Phenotypic Switching and virulence in this fungus (17). C. neoformans is unique among pathogenic fungi in having a polysaccharide capsule, which is an important virulence factor. The predominant capsular polysaccharide glucuronoxylomannan (GXM) confers the antigenic characteristics of the capsule and exhibits remarkable heterogeneity in GXM structure among serial isolates from patients and even among isolates assigned to a particular serotype (5, 6). Similarly, capsule size varies in vivo and is different in brain and lung tissue during murine infection (34). Although some of the factors involved in capsule regulation have been previously described (20, 41, 45), the relationship between capsule size, polysaccharide structure, and virulence remains a central unresolved problem in the field of C. neoformans pathogenesis. In a previous study, 24067A was reported to produce at least two colony phenotypes, SM and WR (17). In this study, we carried out a detailed analysis of strain 24067A to better understand this Phenotypic Switching system and its relationship to strain microevolution. Our studies indicate that strain 24067A can switch to at least two different WR colony types, composed of cells with either a large capsule or pseudohyphal (PH) morphology. Phenotypic Switching was associated with a change in GXM structure and with differences in virulence and inflammatory response. Karyotype variability was observed but could not be directly linked to the colony type switch. Hence, our results suggest that Phenotypic Switching can provide an explanation for several unusual characteristics of C. neoformans, including its propensity toward strain microevolution, yeast-pseudohyphal transition, polysaccharide structure, and capsule size variability.

Bettina C. Fries - One of the best experts on this subject based on the ideXlab platform.

  • cryptococcus neoformans variants generated by Phenotypic Switching differ in virulence through effects on macrophage activation
    Infection and Immunity, 2010
    Co-Authors: A. Guerrero, Neena Jain, Xiabo Wang, Bettina C. Fries
    Abstract:

    Macrophages have a central role in the pathogenesis of cryptococcosis since they are an important line of defense, serve as a site for fungal replication, and also can contribute to tissue damage. The objective of this study was to investigate the interaction of macrophages with cells from smooth-colony variants (SM) and mucoid-colony variants (MC) arising from Phenotypic Switching of Cryptococcus neoformans. Alveolar macrophages (AMs) isolated from SM- and MC-infected mice exhibited differences in gene and surface expression of PD-L1, PD-L2, and major histocompatibility class II (MHC-II). PD-L1 and PD-L2 are the ligands for PD1 and are differentially regulated in Th1- and Th2-type cells. In addition, macrophage activation in SM- and MC-infected mice was characterized as alternatively activated. Flow cytometric and cytokine analysis demonstrated that MC infection was associated with the emergence of Th17 cells and higher levels of interleukin-17 (IL-17) in lung tissue, which were reduced by AM depletion. In conclusion, our results indicate that macrophages play a significant role in maintaining damage-promoting inflammation in the lung during MC infection, which ultimately results in death.

  • Phenotypic Switching in fungi
    Current Fungal Infection Reports, 2008
    Co-Authors: Neena Jain, Fahmi Hasan, Bettina C. Fries
    Abstract:

    Over the past three decades new fungal diseases have emerged that now constitute a major threat, especially for patients with chronic diseases and/or underlying immune deficiencies. Despite the epidemiologic data, the emergence of stable drug-resistant or hypervirulent fungal strains in human disease has not been demonstrated as seen in emerging viral and bacterial infections. Fungi are eukaryotic microbes that capitalize on a sophisticated built-in ability to generate Phenotypic variability. This successful strategy allows them to undergo rapid adaptation in response to environmental challenges, such as individual body locations that may exhibit drastic differences in temperature and pH. Rapid microevolution can also confer drug resistance and protect them from the host’s immune response. This review explores Phenotypic Switching in pathogenic fungi, including Candida spp and Cryptococcus spp, and how Phenotypic Switching contributes to the pathogenesis of fungal diseases.

  • Characterization of Phenotypic Switching in Cryptococcus neoformans Biofilms
    Mycopathologia, 2008
    Co-Authors: Luis R. Martinez, Arturo Casadevall, David C. Ibom, Bettina C. Fries
    Abstract:

    Cryptococcus neoformans is an encapsulated yeast-like fungus that is a relatively frequent cause of meningoencephalitis in immunocompromised patients and also occasionally causes disease in apparently healthy individuals. This fungus collectively forms biofilms on polystyrene plates and medical devices, whereas individually can undergo Phenotypic Switching. Both events have profound consequences in the establishment of fungal infection and are associated with persistent infection due to increase resistance to antimicrobial therapy. In this study, we characterized switch phenotypes in C. neoformans biofilms. Smooth, mucoid, and wrinkled switch phenotypes of various Switching C. neoformans strains were examined for their adhering and biofilm-forming ability on 96-well plates using cell counts and 2,3-bis (2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino) carbonyl]-2H-tetrazolium hydroxide (XTT) reduction assay, respectively. Both assays showed that C. neoformans strains with the parent smooth phenotype adhered and formed stronger biofilms than their mucoid and wrinkled counterparts. Furthermore, the Phenotypic Switching frequencies of the individual colony types grown in biofilms or as planktonic cells were investigated. For the parent smooth variant of most strains, we found enhanced Phenotypic Switching in cryptococcal biofilms when compared to Switching rates of planktonic cells. In contrast, the back-Switching rate of mucoid to smooth variant was significantly higher in planktonic cells of seven strains of C. neoformans strains. These results suggested that Phenotypic Switching can occur in cryptococcal biofilms and extend our understanding of the relationship of both phenomena.

  • Phenotypic Switching of Cryptococcus neoformans and Cryptococcus gattii
    Mycopathologia, 2008
    Co-Authors: Neena Jain, Bettina C. Fries
    Abstract:

    Microorganisms that live in fluctuating environments must constantly adapt their behavior to survive. The host constitutes an important microenvironment in opportunistic and primary fungal pathogens like Cryptococcus neoformans ( C. neoformans ) and Cryptococcus gattii ( C. gattii ). In clonal populations, adaptation may be achieved through the generation of diversity. For fungi phenotype Switching constitutes a mechanism that allows them to change rapidly. Both C. neoformans and C. gattii undergo Phenotypic Switching, which allows them to be successful pathogens and cause persistent disease. Similar to other encapsulated microbes that exhibit Phenotypic variation, Phenotypic Switching in Cryptococcus changes the polysaccharide capsule. Most importantly, in animal models Phenotypic Switching affects virulence and can change the outcome of infection. Virulence changes because C. neoformans and C. gattii switch variants elicit different inflammatory responses in the host. This altered host response can also affect the response to antifungal therapy and in some cases may even promote the selection of switch variants. This review highlights the similarity and differences between Phenotypic Switching in C. neoformans and C. gattii , the two dominant species that cause cryptococcosis in humans.

  • Characterization of Phenotypic Switching in Cryptococcus neoformans biofilms.
    Mycopathologia, 2008
    Co-Authors: Luis R. Martinez, Arturo Casadevall, David C. Ibom, Bettina C. Fries
    Abstract:

    Cryptococcus neoformans is an encapsulated yeast-like fungus that is a relatively frequent cause of meningoencephalitis in immunocompromised patients and also occasionally causes disease in apparently healthy individuals. This fungus collectively forms biofilms on polystyrene plates and medical devices, whereas individually can undergo Phenotypic Switching. Both events have profound consequences in the establishment of fungal infection and are associated with persistent infection due to increase resistance to antimicrobial therapy. In this study, we characterized switch phenotypes in C. neoformans biofilms. Smooth, mucoid, and wrinkled switch phenotypes of various Switching C. neoformans strains were examined for their adhering and biofilm-forming ability on 96-well plates using cell counts and 2,3-bis (2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino) carbonyl]-2H-tetrazolium hydroxide (XTT) reduction assay, respectively. Both assays showed that C. neoformans strains with the parent smooth phenotype adhered and formed stronger biofilms than their mucoid and wrinkled counterparts. Furthermore, the Phenotypic Switching frequencies of the individual colony types grown in biofilms or as planktonic cells were investigated. For the parent smooth variant of most strains, we found enhanced Phenotypic Switching in cryptococcal biofilms when compared to Switching rates of planktonic cells. In contrast, the back-Switching rate of mucoid to smooth variant was significantly higher in planktonic cells of seven strains of C. neoformans strains. These results suggested that Phenotypic Switching can occur in cryptococcal biofilms and extend our understanding of the relationship of both phenomena.

Bin Zheng - One of the best experts on this subject based on the ideXlab platform.