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Denis O’meally - One of the best experts on this subject based on the ideXlab platform.
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Characterization of the antimicrobial peptide family Defensins in the Tasmanian devil (Sarcophilus harrisii), koala (Phascolarctos cinereus), and tammar wallaby (Macropus eugenii)
Immunogenetics, 2017Co-Authors: Elizabeth A. Jones, Yuanyuan Cheng, Denis O’meallyAbstract:Defensins comprise a family of cysteine-rich antimicrobial peptides with important roles in innate and adaptive immune defense in vertebrates. We characterized alpha and beta Defensin genes in three Australian marsupials: the Tasmanian devil ( Sarcophilus harrisii ), koala ( Phascolarctos cinereus ), and tammar wallaby ( Macropus eugenii ) and identified 48, 34, and 39 Defensins, respectively. One hundred and twelve have the classical antimicrobial peptides characteristics required for pathogen membrane targeting, including cationic charge (between 1+ and 15+) and a high proportion of hydrophobic residues (>30%). Phylogenetic analysis shows that gene duplication has driven unique and species-specific expansions of devil, koala, and tammar wallaby beta Defensins and devil alpha Defensins. Defensin genes are arranged in three genomic clusters in marsupials, whereas further duplications and translocations have occurred in eutherians resulting in four and five gene clusters in mice and humans, respectively. Marsupial Defensins are generally under purifying selection, particularly residues essential for Defensin structural stability. Certain hydrophobic or positively charged sites, predominantly found in the Defensin loop, are positively selected, which may have functional significance in Defensin-target interaction and membrane insertion.
Jason G. Smith - One of the best experts on this subject based on the ideXlab platform.
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Defensin driven viral evolution
PLOS Pathogens, 2020Co-Authors: Karina Diaz, Beth A Bromme, Anshu P Gounder, Youngmee Sul, Nicolle D Myers, Ksenia V Skorohodova, Jason G. SmithAbstract:Enteric alpha-Defensins are potent effectors of innate immunity that are abundantly expressed in the small intestine. Certain enteric bacteria and viruses are resistant to Defensins and even appropriate them to enhance infection despite neutralization of closely related microbes. We therefore hypothesized that Defensins impose selective pressure during fecal-oral transmission. Upon passaging a Defensin-sensitive serotype of adenovirus in the presence of a human Defensin, mutations in the major capsid protein hexon accumulated. In contrast, prior studies identified the vertex proteins as important determinants of Defensin antiviral activity. Infection and biochemical assays suggest that a balance between increased cell binding and a downstream block in intracellular trafficking mediated by Defensin interactions with all of the major capsid proteins dictates the outcome of infection. These results extensively revise our understanding of the interplay between Defensins and non-enveloped viruses. Furthermore, they provide a feasible rationale for Defensins shaping viral evolution, resulting in differences in infection phenotypes of closely related viruses.
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Defensin driven viral evolution
bioRxiv, 2020Co-Authors: Karina Diaz, Beth A Bromme, Anshu P Gounder, Youngmee Sul, Nicolle D Myers, Ksenia V Skorohodova, Jason G. SmithAbstract:Enteric alpha-Defensins are potent effectors of innate immunity that are abundantly expressed in the small intestine. Certain enteric bacteria and viruses are resistant to Defensins and even appropriate them to enhance infection, despite neutralization of closely related microbes. We therefore hypothesized that Defensins impose selective pressure during fecal-oral transmission. Upon passaging a Defensin-sensitive serotype of adenovirus in the presence of a human Defensin, mutations in the major capsid protein hexon accumulated. In contrast, prior studies identified the vertex proteins as important determinants of Defensin antiviral activity. Through infection and biochemical assays, we found that although all major capsid proteins serve a critical role in Defensin-mediated neutralization, hexon is the sole determinant of enhancement. These results extensively revise our understanding of the interplay between Defensins and non-enveloped viruses. Furthermore, they provide a feasible rationale for Defensins shaping viral evolution, resulting in differences in infection phenotypes of closely related viruses.
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Defensins in viral infection and pathogenesis
Annual Review of Virology, 2017Co-Authors: Mayumi K Holly, Karina Diaz, Jason G. SmithAbstract:α, β, and θ Defensins are effectors of the innate immune system with potent antibacterial, antiviral, and antifungal activity. Defensins have direct antiviral activity in cell culture, with varied mechanisms for individual viruses, although some common themes have emerged. In addition, Defensins have potent immunomodulatory activity that can alter innate and adaptive immune responses to viral infection. In some cases, there is evidence for paradoxical escape from Defensin neutralization or enhancement of viral infection. The direct and indirect activities of Defensins have led to their development as therapeutics and vaccine components. The major area of investigation that continues to lag is the connection between the effects of Defensins in cell culture models and viral pathogenesis in vivo. Model systems to study Defensin biology, including more physiologic models designed to bridge this gap, are also discussed.
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alpha Defensin dependent enhancement of enteric viral infection
PLOS Pathogens, 2017Co-Authors: Sarah S Wilson, Mayim E Wiens, Mayumi K Holly, Beth A Bromme, Anshu P Gounder, Youngmee Sul, Jason G. SmithAbstract:The small intestinal epithelium produces numerous antimicrobial peptides and proteins, including abundant enteric α-Defensins. Although they most commonly function as potent antivirals in cell culture, enteric α-Defensins have also been shown to enhance some viral infections in vitro. Efforts to determine the physiologic relevance of enhanced infection have been limited by the absence of a suitable cell culture system. To address this issue, here we use primary stem cell-derived small intestinal enteroids to examine the impact of naturally secreted α-Defensins on infection by the enteric mouse pathogen, mouse adenovirus 2 (MAdV-2). MAdV-2 infection was increased when enteroids were inoculated across an α-Defensin gradient in a manner that mimics oral infection but not when α-Defensin levels were absent or bypassed through other routes of inoculation. This increased infection was a result of receptor-independent binding of virus to the cell surface. The enteroid experiments accurately predicted increased MAdV-2 shedding in the feces of wild type mice compared to mice lacking functional α-Defensins. Thus, our studies have shown that viral infection enhanced by enteric α-Defensins may reflect the evolution of some viruses to utilize these host proteins to promote their own infection.
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Defensins at the mucosal surface latest insights into Defensin virus interactions
Journal of Virology, 2016Co-Authors: Sarah S Wilson, Mayim E Wiens, Mayumi K Holly, Jason G. SmithAbstract:: Defensins are innate immune effector peptides expressed at mucosal surfaces throughout the human body and are potently antiviral in vitro The role of Defensins in viral pathogenesis in vivo is poorly understood; however, recent studies have revealed that Defensin-virus interactions in vivo are complicated and distinct from their proposed antiviral mechanisms in vitro These findings highlight the need for additional research that connects Defensin neutralization of viruses in cell culture to in vivo antiviral mechanisms.
Elizabeth A. Jones - One of the best experts on this subject based on the ideXlab platform.
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Characterization of the antimicrobial peptide family Defensins in the Tasmanian devil (Sarcophilus harrisii), koala (Phascolarctos cinereus), and tammar wallaby (Macropus eugenii)
Immunogenetics, 2017Co-Authors: Elizabeth A. Jones, Yuanyuan Cheng, Denis O’meallyAbstract:Defensins comprise a family of cysteine-rich antimicrobial peptides with important roles in innate and adaptive immune defense in vertebrates. We characterized alpha and beta Defensin genes in three Australian marsupials: the Tasmanian devil ( Sarcophilus harrisii ), koala ( Phascolarctos cinereus ), and tammar wallaby ( Macropus eugenii ) and identified 48, 34, and 39 Defensins, respectively. One hundred and twelve have the classical antimicrobial peptides characteristics required for pathogen membrane targeting, including cationic charge (between 1+ and 15+) and a high proportion of hydrophobic residues (>30%). Phylogenetic analysis shows that gene duplication has driven unique and species-specific expansions of devil, koala, and tammar wallaby beta Defensins and devil alpha Defensins. Defensin genes are arranged in three genomic clusters in marsupials, whereas further duplications and translocations have occurred in eutherians resulting in four and five gene clusters in mice and humans, respectively. Marsupial Defensins are generally under purifying selection, particularly residues essential for Defensin structural stability. Certain hydrophobic or positively charged sites, predominantly found in the Defensin loop, are positively selected, which may have functional significance in Defensin-target interaction and membrane insertion.
Yuanyuan Cheng - One of the best experts on this subject based on the ideXlab platform.
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Characterization of the antimicrobial peptide family Defensins in the Tasmanian devil (Sarcophilus harrisii), koala (Phascolarctos cinereus), and tammar wallaby (Macropus eugenii)
Immunogenetics, 2017Co-Authors: Elizabeth A. Jones, Yuanyuan Cheng, Denis O’meallyAbstract:Defensins comprise a family of cysteine-rich antimicrobial peptides with important roles in innate and adaptive immune defense in vertebrates. We characterized alpha and beta Defensin genes in three Australian marsupials: the Tasmanian devil ( Sarcophilus harrisii ), koala ( Phascolarctos cinereus ), and tammar wallaby ( Macropus eugenii ) and identified 48, 34, and 39 Defensins, respectively. One hundred and twelve have the classical antimicrobial peptides characteristics required for pathogen membrane targeting, including cationic charge (between 1+ and 15+) and a high proportion of hydrophobic residues (>30%). Phylogenetic analysis shows that gene duplication has driven unique and species-specific expansions of devil, koala, and tammar wallaby beta Defensins and devil alpha Defensins. Defensin genes are arranged in three genomic clusters in marsupials, whereas further duplications and translocations have occurred in eutherians resulting in four and five gene clusters in mice and humans, respectively. Marsupial Defensins are generally under purifying selection, particularly residues essential for Defensin structural stability. Certain hydrophobic or positively charged sites, predominantly found in the Defensin loop, are positively selected, which may have functional significance in Defensin-target interaction and membrane insertion.
Andre J Ouellette - One of the best experts on this subject based on the ideXlab platform.
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strain specific polymorphisms in paneth cell α Defensins of c57bl 6 mice and evidence of vestigial myeloid α Defensin pseudogenes
Infection and Immunity, 2011Co-Authors: Michael T. Shanahan, Hiroki Tanabe, Andre J OuelletteAbstract:ABSTRACT Paneth cells at the base of small intestinal crypts secrete microbicidal α-Defensins, termed cryptdins (Crps) in mice, as mediators of innate immunity. Proteomic studies show that five abundant Paneth cell α-Defensins in C57BL/6 mice are strain specific in that they have not been identified in other inbred strains of mice. Two C57BL/6-specific peptides are coded for by the Defcr20 and -21 genes evident in the NIH C57BL/6 genome but absent from the Celera mixed-strain assembly, which excludes C57BL/6 data and differs from the NIH build with respect to the organization of the α-Defensin gene locus. Conversely, C57BL/6 mice lack the Crp1, -2, -4, and -6 peptides and their corresponding Defcr1, -2, -4, and -6 genes, which are common to several mouse strains, including those of the Celera assembly. In C57BL/6 mice, α-Defensin gene diversification appears to have occurred by tandem duplication of a multigene cassette that was not found in the mixed-strain assembly. Both mouse genome assemblies contain conserved α-Defensin pseudogenes that are closely related to functional myeloid α-Defensin genes in the rat, suggesting that the neutrophil α-Defensin defect in mice resulted from progressive gene loss. Given the role of α-Defensins in shaping the composition of the enteric microflora, such polymorphisms may influence outcomes in mouse models of disease or infection.
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a novel role for Defensins in intestinal homeostasis regulation of il 1β secretion
Journal of Immunology, 2007Co-Authors: Shelly Aono, Wuyuan Lu, Andre J Ouellette, Xueyou Hu, Yingbiao Ji, Lei Wang, Stephen D Lenz, Frederik W Van Ginkel, Mark R Liles, Christine C DykstraAbstract:Impaired expression of α-Defensin antimicrobial peptides and overproduction of the proinflammatory cytokine IL-1β have been associated with inflammatory bowel disease. In this study, we examine the interactions between α-Defensins and IL-1β and the role of Defensin deficiency in the pathogenesis of inflammatory bowel disease. It was found that matrix metalloproteinase-7-deficient ( MMP-7 −/− ) mice, which produce procryptdins but not mature cryptdins (α-Defensins) in the intestine, were more susceptible to dextran sulfate sodium-induced colitis. Furthermore, both baseline and dextran sulfate sodium-induced IL-1β production in the intestine were significantly up-regulated in MMP-7 −/− mice compared with that in control C57BL/6 mice. To elucidate the molecular mechanism for the increased IL-1β production in Defensin deficiency in vivo, we evaluated the effect of Defensins on IL-1β posttranslational processing and release. It was found that α-Defensins, including mouse Paneth cell Defensins cryptdin-3 and cryptdin-4, human neutrophil Defensin HNP-1, and human Paneth cell Defensin HD-5, blocked the release of IL-1β from LPS-activated monocytes, whereas TNF-α expression and release were not affected. Unlike α-Defensins, human β-Defensins and mouse procryptdins do not have any effect on IL-1β processing and release. Thus, α-Defensins may play an important role in intestinal homeostasis by controlling the production of IL-1β.
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paneth cell α Defensins from rhesus macaque small intestine
Infection and Immunity, 2004Co-Authors: Hiroki Tanabe, Michael E. Selsted, Jun Yuan, Melinda M Zaragoza, Satya Dandekar, Agnes H Henschenedman, Andre J OuelletteAbstract:Antimicrobial peptides are secreted by small intestinal Paneth cells as components of innate immunity. To investigate the role of α-Defensins in enteric host defenses in nonhuman primates, α-Defensin cDNAs were isolated, α-Defensin peptides were purified from rhesus macaque small bowel, and the bactericidal activities of the peptides were measured. Six rhesus enteric α-Defensin (RED) cDNAs, RED-1 to RED-6, were identified in a jejunum cDNA library; the deduced RED peptides exhibited extensive diversity relative to the primary structures of rhesus myeloid α-Defensins. RED-4 was purified from monkey jejunum, and N-terminal peptide sequencing of putative RED-4 peptides identified two N termini, RTCYCRTGR… and TCYCRTGRC…; these corresponded to alternative N termini for the RED-4 molecules, as deduced from their molecular masses and RED cDNAs. In situ hybridization experiments localized RED mRNAs exclusively to small intestinal Paneth cells. Recombinant RED-1 to RED-4 were purified to homogeneity and shown to be microbicidal in the low micromolar range (≤10 μg/ml) against gram-positive and gram-negative bacteria, with individual peptides exhibiting variable target cell specificities. Thus, compared to myeloid α-Defensins from rhesus macaques, enteric α-Defensin peptides are highly variable in both primary structure and activity. These studies should facilitate further analyses of the role of α-Defensins in primate enteric immunity.
