The Experts below are selected from a list of 33036 Experts worldwide ranked by ideXlab platform
Lalita Ramakrishna - One of the best experts on this subject based on the ideXlab platform.
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immunity and immunopathology in the tuberculous Granuloma
Cold Spring Harbor Perspectives in Medicine, 2015Co-Authors: Antonio J Paga, Lalita RamakrishnaAbstract:Granulomas, organized aggregates of immune cells, are a defining feature of tuberculosis (TB). Granuloma formation is implicated in the pathogenesis of a variety of inflammatory disorders. However, the tuberculous Granuloma has been assigned the role of a host protective structure which "walls-off" mycobacteria. Work conducted over the past decade has provided a more nuanced view of its role in pathogenesis. On the one hand, pathogenic mycobacteria accelerate and exploit Granuloma formation for their expansion and dissemination by manipulating host immune responses to turn leukocyte recruitment and cell death pathways in their favor. On the other hand, Granuloma macrophages can preserve Granuloma integrity by exerting a microbicidal immune response, thus preventing an even more rampant expansion of infection in the extracellular milieu. Even this host-beneficial immune response required to maintain the bacteria intracellular must be tempered, as an overly vigorous immune response can also cause Granuloma breakdown, thereby directly supporting bacterial growth extracellularly. This review will discuss how mycobacteria manipulate inflammatory responses to drive Granuloma formation and will consider the roles of the Granuloma in pathogenesis and protective immunity, drawing from clinical studies of TB in humans and from animal models--rodents, zebrafish, and nonhuman primates. A deeper understanding of TB pathogenesis and immunity in the Granuloma could suggest therapeutic approaches to abrogate the host-detrimental aspects of Granuloma formation to convert it into the host-beneficial structure that it has been thought to be for nearly a century.
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neutrophils exert protection in the early tuberculous Granuloma by oxidative killing of mycobacteria phagocytosed from infected macrophages
Cell Host & Microbe, 2012Co-Authors: Chaotsung Yang, Muse J Davis, C J Cambie, Christophe J Hall, Philip S Crosie, Lalita RamakrishnaAbstract:Neutrophils are typically the first responders in host defense against invading pathogens, which they destroy by both oxidative and nonoxidative mechanisms. However, despite a longstanding recognition of neutrophil presence at disease sites in tuberculosis, their role in defense against mycobacteria is unclear. Here we exploit the genetic tractability and optical transparency of zebrafish to monitor neutrophil behavior and its consequences during infection with Mycobacterium marinum, a natural fish pathogen. In contrast to macrophages, neutrophils do not interact with mycobacteria at initial infection sites. Neutrophils are subsequently recruited to the nascent Granuloma in response to signals from dying infected macrophages within the Granuloma, which they phagocytose. Some neutrophils then rapidly kill the internalized mycobacteria through NADPH oxidase-dependent mechanisms. Our results provide a mechanistic link to the observed patterns of neutrophils in human tuberculous Granulomas and the susceptibility of humans with chronic Granulomatous disease to mycobacterial infection.
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tuberculous Granuloma induction via interaction of a bacterial secreted protein with host epithelium
Science, 2010Co-Authors: Hannah E Volkma, Muse J Davis, Tamara C Pozos, Joh Zheng, Joh F Rawls, Lalita RamakrishnaAbstract:Granulomas, organized aggregates of immune cells, are a hallmark of tuberculosis and have traditionally been thought to restrict mycobacterial growth. However, analysis of Mycobacterium marinum in zebrafish has shown that the early Granuloma facilitates mycobacterial growth; uninfected macrophages are recruited to the Granuloma where they are productively infected by M. marinum. Here, we identified the molecular mechanism by which mycobacteria induce Granulomas: The bacterial secreted protein 6-kD early secreted antigenic target (ESAT-6), which has long been implicated in virulence, induced matrix metalloproteinase-9 (MMP9) in epithelial cells neighboring infected macrophages. MMP9 enhanced recruitment of macrophages, which contributed to nascent Granuloma maturation and bacterial growth. Disruption of MMP9 function attenuated Granuloma formation and bacterial growth. Thus, interception of epithelial MMP9 production could hold promise as a host-targeting tuberculosis therapy.
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the role of the Granuloma in expansion and dissemination of early tuberculous infection
Cell, 2009Co-Authors: Muse J Davis, Lalita RamakrishnaAbstract:Granulomas, organized aggregates of immune cells, form in response to persistent stimuli and are hallmarks of tuberculosis. Tuberculous Granulomas have long been considered host-protective structures formed to contain infection. However, work in zebrafish infected with Mycobacterium marinum suggests that Granulomas contribute to early bacterial growth. Here we use quantitative intravital microscopy to reveal distinct steps of Granuloma formation and assess their consequence for infection. Intracellular mycobacteria use the ESX-1/RD1 virulence locus to induce recruitment of new macrophages to, and their rapid movement within, nascent Granulomas. This motility enables multiple arriving macrophages to efficiently find and phagocytose infected macrophages undergoing apoptosis, leading to rapid, iterative expansion of infected macrophages and thereby bacterial numbers. The primary Granuloma then seeds secondary Granulomas via egress of infected macrophages. Our direct observations provide insight into how pathogenic mycobacteria exploit the Granuloma during the innate immune phase for local expansion and systemic dissemination.
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tuberculous Granuloma formation is enhanced by a mycobacterium virulence determinant
PLOS Biology, 2004Co-Authors: Hannah E Volkma, Hilary Clay, Dana Eery, Jennife C Chang, David R Sherma, Lalita RamakrishnaAbstract:Granulomas are organized host immune structures composed of tightly interposed macrophages and other cells that form in response to a variety of persistent stimuli, both infectious and noninfectious. The tuberculous Granuloma is essential for host containment of mycobacterial infection, although it does not always eradicate it. Therefore, it is considered a host-beneficial, if incompletely efficacious, immune response. The Mycobacterium RD1 locus encodes a specialized secretion system that promotes mycobacterial virulence by an unknown mechanism. Using transparent zebrafish embryos to monitor the infection process in real time, we found that RD1-deficient bacteria fail to elicit efficient Granuloma formation despite their ability to grow inside of infected macrophages. We showed that macrophages infected with virulent mycobacteria produce an RD1-dependent signal that directs macrophages to aggregate into Granulomas. This Mycobacterium-induced macrophage aggregation in turn is tightly linked to intercellular bacterial dissemination and increased bacterial numbers. Thus, mycobacteria co-opt host Granulomas for their virulence.
Lalita Ramakrishnan - One of the best experts on this subject based on the ideXlab platform.
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tumor necrosis factor signaling mediates resistance to mycobacteria by inhibiting bacterial growth and macrophage death
Immunity, 2008Co-Authors: Hilary Clay, Hannah E Volkman, Lalita RamakrishnanAbstract:Tumor necrosis factor (TNF), a key effector in controlling tuberculosis, is thought to exert protection by directing formation of Granulomas, organized aggregates of macrophages and other immune cells. Loss of TNF signaling causes progression of tuberculosis in humans, and the increased mortality of Mycobacterium tuberculosis-infected mice is associated with disorganized necrotic Granulomas, although the precise roles of TNF signaling preceding this endpoint remain undefined. We monitored transparent Mycobacterium marinum-infected zebrafish live to conduct a stepwise dissection of how TNF signaling operates in mycobacterial pathogenesis. We found that loss of TNF signaling caused increased mortality even when only innate immunity was operant. In the absence of TNF, intracellular bacterial growth and Granuloma formation were accelerated and was followed by necrotic death of overladen macrophages and Granuloma breakdown. Thus, TNF is not required for tuberculous Granuloma formation, but maintains Granuloma integrity indirectly by restricting mycobacterial growth within macrophages and preventing their necrosis.
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complex pattern of mycobacterium marinum gene expression during long term Granulomatous infection
Proceedings of the National Academy of Sciences of the United States of America, 2002Co-Authors: Kaman Chan, Timothy Knaak, Laura Satkamp, Olivier Humbert, Stanley Falkow, Lalita RamakrishnanAbstract:During latent infection of humans with Mycobacterium tuberculosis, bacteria persist in the asymptomatic host within Granulomas, organized collections of differentiated macrophages, and other immune cells. The mechanisms for persistence remain poorly understood, as is the metabolic and replicative state of the microbes within Granulomas. We analyzed the gene expression profile of Mycobacterium marinum, the cause of fish and amphibian tuberculosis, during its persistence in Granulomas. We identified genes expressed specifically when M. marinum persists within Granulomas. These Granuloma-activated genes were not activated in vitro in response to various conditions postulated to be operant in tuberculous Granulomas, suggesting that their Granuloma-specific activation was caused by complex conditions that could not be mimicked in vitro. In addition to the Granuloma-activated genes, the bacteria resident in Granulomas expressed a wide range of metabolic and synthetic genes that are expressed during logarithmic growth in laboratory medium. Our results suggest a dynamic host-pathogen interaction in the Granuloma, where metabolically active bacteria are kept in check by the host immune system and where the products of Granuloma-specific bacterial genes may thwart the host's attempt to completely eradicate the bacteria.
Meenal Datta - One of the best experts on this subject based on the ideXlab platform.
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abstract b19 anti vegf treatment normalizes tuberculosis Granuloma vasculature and improves small molecule delivery
Molecular Cancer Therapeutics, 2015Co-Authors: Meenal Datta, Laura E Via, Walid S Kamou, Chong Liu, Wei Che, Giorgio Seano, Danielle M Weine, Daniel Schimel, Kathlee England, Joh D MartiAbstract:Tuberculosis (TB) causes almost 2 million deaths annually, and an increasing number of patients are resistant to existing therapies. TB patients require lengthy chemotherapy, possibly because of poor penetration of antibiotics into Granulomas where the bacilli reside. Granulomas are morphologically similar to solid cancerous tumors in that they contain hypoxic microenvironments and can be highly fibrotic. Here we show that TB-infected rabbits have impaired small molecule distribution into these disease sites due to a functionally abnormal vasculature, with a low molecular weight tracer accumulating only in peripheral regions of Granulomatous lesions. Granuloma-associated vessels are morphologically and spatially heterogeneous, with poor vessel pericyte coverage in both human and experimental rabbit TB Granulomas. Moreover, we found enhanced vascular endothelial growth factor (VEGF) expression in both species. In tumors, anti-angiogenic, specifically anti-VEGF, treatments can “normalize” their vasculature, reducing hypoxia and creating a window-of-opportunity for conjunctive chemotherapy; thus, we investigated vessel normalization in rabbit TB Granulomas. Treatment of TB-infected rabbits with the anti-VEGF antibody bevacizumab significantly decreased the total number of vessels while normalizing those that remained. As a result, hypoxic fractions of these Granulomas were reduced and small molecule tracer delivery increased. These findings demonstrate that bevacizumab treatment promotes vascular normalization, improves small molecule delivery, and decreases hypoxia in TB Granulomas, thereby providing a potential new avenue to improve delivery and efficacy of current treatment regimens. Citation Format: Meenal Datta, Laura E. Via, Walid S. Kamoun, Chong Liu, Wei Chen, Giorgio Seano, Danielle M. Weiner, Daniel Schimel, Kathleen England, John D. Martin, Xing Gao, Lei Xu, Clifton E. Barry, III, Rakesh K. Jain. Anti-VEGF treatment normalizes tuberculosis Granuloma vasculature and improves small molecule delivery. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers; Mar 5-8, 2015; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl):Abstract nr B19.
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anti vascular endothelial growth factor treatment normalizes tuberculosis Granuloma vasculature and improves small molecule delivery
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Meenal Datta, Laura E Via, Walid S Kamou, Chong Liu, Wei Che, Giorgio Seano, Danielle M Weine, Daniel Schimel, Kathlee EnglandAbstract:Tuberculosis (TB) causes almost 2 million deaths annually, and an increasing number of patients are resistant to existing therapies. Patients who have TB require lengthy chemotherapy, possibly because of poor penetration of antibiotics into Granulomas where the bacilli reside. Granulomas are morphologically similar to solid cancerous tumors in that they contain hypoxic microenvironments and can be highly fibrotic. Here, we show that TB-infected rabbits have impaired small molecule distribution into these disease sites due to a functionally abnormal vasculature, with a low-molecular-weight tracer accumulating only in peripheral regions of Granulomatous lesions. Granuloma-associated vessels are morphologically and spatially heterogeneous, with poor vessel pericyte coverage in both human and experimental rabbit TB Granulomas. Moreover, we found enhanced VEGF expression in both species. In tumors, antiangiogenic, specifically anti-VEGF, treatments can “normalize” their vasculature, reducing hypoxia and creating a window of opportunity for concurrent chemotherapy; thus, we investigated vessel normalization in rabbit TB Granulomas. Treatment of TB-infected rabbits with the anti-VEGF antibody bevacizumab significantly decreased the total number of vessels while normalizing those vessels that remained. As a result, hypoxic fractions of these Granulomas were reduced and small molecule tracer delivery was increased. These findings demonstrate that bevacizumab treatment promotes vascular normalization, improves small molecule delivery, and decreases hypoxia in TB Granulomas, thereby providing a potential avenue to improve delivery and efficacy of current treatment regimens.
Hilary Clay - One of the best experts on this subject based on the ideXlab platform.
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tumor necrosis factor signaling mediates resistance to mycobacteria by inhibiting bacterial growth and macrophage death
Immunity, 2008Co-Authors: Hilary Clay, Hannah E Volkman, Lalita RamakrishnanAbstract:Tumor necrosis factor (TNF), a key effector in controlling tuberculosis, is thought to exert protection by directing formation of Granulomas, organized aggregates of macrophages and other immune cells. Loss of TNF signaling causes progression of tuberculosis in humans, and the increased mortality of Mycobacterium tuberculosis-infected mice is associated with disorganized necrotic Granulomas, although the precise roles of TNF signaling preceding this endpoint remain undefined. We monitored transparent Mycobacterium marinum-infected zebrafish live to conduct a stepwise dissection of how TNF signaling operates in mycobacterial pathogenesis. We found that loss of TNF signaling caused increased mortality even when only innate immunity was operant. In the absence of TNF, intracellular bacterial growth and Granuloma formation were accelerated and was followed by necrotic death of overladen macrophages and Granuloma breakdown. Thus, TNF is not required for tuberculous Granuloma formation, but maintains Granuloma integrity indirectly by restricting mycobacterial growth within macrophages and preventing their necrosis.
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tuberculous Granuloma formation is enhanced by a mycobacterium virulence determinant
PLOS Biology, 2004Co-Authors: Hannah E Volkma, Hilary Clay, Dana Eery, Jennife C Chang, David R Sherma, Lalita RamakrishnaAbstract:Granulomas are organized host immune structures composed of tightly interposed macrophages and other cells that form in response to a variety of persistent stimuli, both infectious and noninfectious. The tuberculous Granuloma is essential for host containment of mycobacterial infection, although it does not always eradicate it. Therefore, it is considered a host-beneficial, if incompletely efficacious, immune response. The Mycobacterium RD1 locus encodes a specialized secretion system that promotes mycobacterial virulence by an unknown mechanism. Using transparent zebrafish embryos to monitor the infection process in real time, we found that RD1-deficient bacteria fail to elicit efficient Granuloma formation despite their ability to grow inside of infected macrophages. We showed that macrophages infected with virulent mycobacteria produce an RD1-dependent signal that directs macrophages to aggregate into Granulomas. This Mycobacterium-induced macrophage aggregation in turn is tightly linked to intercellular bacterial dissemination and increased bacterial numbers. Thus, mycobacteria co-opt host Granulomas for their virulence.
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real time visualization of mycobacterium macrophage interactions leading to initiation of Granuloma formation in zebrafish embryos
Immunity, 2002Co-Authors: Muse J Davis, Hilary Clay, Jessica L Lewis, Nafisa Ghori, Philippe Herbomel, Lalita RamakrishnaAbstract:Infection of vertebrate hosts with pathogenic Mycobacteria, the agents of tuberculosis, produces Granulomas, highly organized structures containing differentiated macrophages and lymphocytes, that sequester the pathogen. Adult zebrafish are naturally susceptible to tuberculosis caused by Mycobacterium marinum. Here, we exploit the optical transparency of zebrafish embryos to image the events of M. marinum infection in vivo. Despite the fact that the embryos do not yet have lymphocytes, infection leads to the formation of macrophage aggregates with pathological hallmarks of Granulomas and activation of previously identified Granuloma-specific Mycobacterium genes. Thus, Mycobacterium-macrophage interactions can initiate Granuloma formation solely in the context of innate immunity. Strikingly, infection can redirect normal embryonic macrophage migration, even recruiting macrophages seemingly committed to their developmentally dictated tissue sites.
Andrew N J Mckenzie - One of the best experts on this subject based on the ideXlab platform.
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t1 st2 deficient mice demonstrate the importance of t1 st2 in developing primary t helper cell type 2 responses
Journal of Experimental Medicine, 2000Co-Authors: Michael J Townsend, Padraic G Fallon, David John Matthews, Helen E. Jolin, Andrew N J MckenzieAbstract:We have generated mice with a deficiency in T1/ST2 expression to clarify the roles of T1/ST2 in T helper cell type 2 (Th2) responses. Using immunological challenges normally characterized by a Th2-like response, we have compared the responses of T1/ST2-deficient mice with those generated by wild-type mice. Using a primary pulmonary Granuloma model, induced with Schistosoma mansoni eggs, we demonstrate that Granuloma formation, characterized by eosinophil infiltration, is abrogated in T1/ST2-deficient mice. Furthermore, we clearly demonstrate that in the absence of T1/ST2 expression, the levels of Th2 cytokine production are severely impaired after immunization. Thus, in a secondary pulmonary Granuloma model, draining lymph node cells from the T1/ST2-deficient animals produced significantly reduced levels of IL-4 and IL-5, despite developing Granulomas of a magnitude similar to those of wild-type mice and comparable antigen-specific immunoglobulin isotype production. These data clearly demonstrate that T1/ST2 expression plays a role in the development of Th2-like cytokine responses and indicate that effector functions are inhibited in its absence.
