ORCID Profile
0000-0002-4666-1846
Current Organisation
Osaka University
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Publisher: MyJove Corporation
Date: 05-04-2015
DOI: 10.3791/52736
Publisher: American Society of Hematology
Date: 12-12-2017
DOI: 10.1182/BLOODADVANCES.2017009274
Abstract: Mutations in β spectrin cause microcytosis, resulting in increased clearance of erythrocytes and enhanced resistance to malaria in mice. A homozygous CRISPR/Cas9-induced mutation in the binding site between β spectrin and ankyrin-1 increases mouse survival during malaria.
Publisher: Springer Science and Business Media LLC
Date: 17-03-2014
Publisher: Springer Science and Business Media LLC
Date: 16-11-2016
DOI: 10.1038/SREP37197
Abstract: Genetic defects in various red blood cell (RBC) cytoskeletal proteins have been long associated with changes in susceptibility towards malaria infection. In particular, while ankyrin (Ank-1) mutations account for approximately 50% of hereditary spherocytosis (HS) cases, an association with malaria is not well-established, and conflicting evidence has been reported. We describe a novel N-ethyl-N-nitrosourea (ENU)-induced ankyrin mutation MRI61689 that gives rise to two different ankyrin transcripts: one with an introduced splice acceptor site resulting a frameshift, the other with a skipped exon. Ank-1 (MRI61689/ +) mice exhibit an HS-like phenotype including reduction in mean corpuscular volume (MCV), increased osmotic fragility and reduced RBC deformability. They were also found to be resistant to rodent malaria Plasmodium chabaudi infection. Parasites in Ank-1 (MRI61689/ +) erythrocytes grew normally, but red cells showed resistance to merozoite invasion. Uninfected Ank-1 (MRI61689/ +) erythrocytes were also more likely to be cleared from circulation during infection the “bystander effect”. This increased clearance is a novel resistance mechanism which was not observed in previous ankyrin mouse models. We propose that this bystander effect is due to reduced deformability of Ank-1 (MRI61689/ +) erythrocytes. This paper highlights the complex roles ankyrin plays in mediating malaria resistance.
Publisher: Springer Science and Business Media LLC
Date: 29-07-2015
Publisher: Cold Spring Harbor Laboratory
Date: 20-10-2021
DOI: 10.1101/2021.10.19.465054
Abstract: Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) is a life-threatening condition characterized by improper activation of neutrophils and release of neutrophil extracellular traps (NETs) in small vessels. This study aimed to explain the role of NETs in AAV pathogenesis by investigating a link between neutrophil adhesion and NET release. We leveraged an imaging flow cytometry-based assay and three-dimensional culture to demonstrate that neutrophil adhesion is essential for ANCA induced NET formation. We confirmed this requirement for cell adhesion using standard microscopy on ultra-low attachment hydrogel surfaces and demonstrate that this depends on the focal adhesion kinase pathway as determined using inhibitors for multiple targets in this process. ANCA increased expression of β2 integrins on neutrophils, and we confirmed that these integrins were required for NET formation using blocking antibodies. Finally, inhibitors for oxidative burst prevented NET formation, and this oxidative burst was mediated by the focal adhesion pathway. Overall, our findings reveal a central role for neutrophil attachment in NET formation in response to ANCA, helping to explain the restricted localization pattern of vessel damage, and suggesting that targeting neutrophil adhesion factors may be beneficial in preventing pathological damage from NETs during AAV.
Publisher: Springer Science and Business Media LLC
Date: 18-11-2015
DOI: 10.1186/S12862-015-0502-2
Abstract: Major, long-term environmental changes are projected in the Southern Ocean and these are likely to have impacts for marine predators such as the Adélie penguin ( Pygoscelis adeliae ). Decadal monitoring studies have provided insight into the short-term environmental sensitivities of Adélie penguin populations, particularly to sea ice changes. However, given the long-term nature of projected climate change, it is also prudent to consider the responses of populations to environmental change over longer time scales. We investigated the population trajectory of Adélie penguins during the last glacial-interglacial transition to determine how the species was affected by climate warming over millennia. We focussed our study on East Antarctica, which is home to 30 % of the global population of Adélie penguins. Using mitochondrial DNA from extant colonies, we reconstructed the population trend of Adélie penguins in East Antarctica over the past 22,000 years using an extended Bayesian skyline plot method. To determine the relationship of East Antarctic Adélie penguins with populations elsewhere in Antarctica we constructed a phylogeny using mitochondrial DNA sequences. We found that the Adélie penguin population expanded 135-fold from approximately 14,000 years ago. The population growth was coincident with deglaciation in East Antarctica and, therefore, an increase in ice-free ground suitable for Adélie penguin nesting. Our phylogenetic analysis indicated that East Antarctic Adélie penguins share a common ancestor with Adélie penguins from the Antarctic Peninsula and Scotia Arc, with an estimated age of 29,000 years ago, in the midst of the last glacial period. This finding suggests that extant colonies in East Antarctica, the Scotia Arc and the Antarctic Peninsula were founded from a single glacial refuge. While changes in sea ice conditions are a critical driver of Adélie penguin population success over decadal and yearly timescales, deglaciation appears to have been the key driver of population change over millennia. This suggests that environmental drivers of population trends over thousands of years may differ to drivers over years or decades, highlighting the need to consider millennial-scale trends alongside contemporary data for the forecasting of species’ abundance and distribution changes under future climate change scenarios.
Publisher: Wiley
Date: 22-11-2018
DOI: 10.1111/MEC.14896
Abstract: The mechanisms that determine patterns of species dispersal are important factors in the production and maintenance of bio ersity. Understanding these mechanisms helps to forecast the responses of species to environmental change. Here, we used a comparative framework and genomewide data obtained through RAD-Seq to compare the patterns of connectivity among breeding colonies for five penguin species with shared ancestry, overlapping distributions and differing ecological niches, allowing an examination of the intrinsic and extrinsic barriers governing dispersal patterns. Our findings show that at-sea range and oceanography underlie patterns of dispersal in these penguins. The pelagic niche of emperor (Aptenodytes forsteri), king (A. patagonicus), Adélie (Pygoscelis adeliae) and chinstrap (P. antarctica) penguins facilitates gene flow over thousands of kilometres. In contrast, the coastal niche of gentoo penguins (P. papua) limits dispersal, resulting in population ergences. Oceanographic fronts also act as dispersal barriers to some extent. We recommend that forecasts of extinction risk incorporate dispersal and that management units are defined by at-sea range and oceanography in species lacking genetic data.
Publisher: Cold Spring Harbor Laboratory
Date: 08-03-2017
DOI: 10.1101/114959
Abstract: Allelic heterogeneity is a common phenomenon where a gene exhibit different phenotype depending on the nature of its genetic mutations. In the context of genes affecting malaria susceptibility, it allowed us to explore and understand the intricate host-parasite interactions during malaria infections. In this study, we described a gene encoding erythrocytic ankyrin-1 ( Ank-1 ) which exhibits allelic-dependent heterogeneous phenotypes during malaria infections. We conducted an ENU mutagenesis screen on mice and identified two Ank-1 mutations, one resulted in an amino acid substitution (MRI95845), and the other a truncated Ank-1 protein (MRI96570). Both mutations caused hereditary spherocytosis-like phenotypes and confer differing protection against Plasmodium chabaudi infections. Upon further examination, the Ank-1 (MRI96570) mutation was found to inhibit intra-erythrocytic parasite maturation, whereas Ank-1 (MW95845) caused increased bystander erythrocyte clearance during infection. This is the first description of allelic heterogeneity in ankyrin-1 from the direct comparison between two Ank-1 mutations. Despite the lack of direct evidence from population studies, this data further supported the protective roles of ankyrin-1 mutations in conferring malaria protection. This study also emphasized the importance of such phenomenon to achieve a better understanding of host-parasite interactions, which could be the basis of future studies.
Publisher: Oxford University Press (OUP)
Date: 27-12-2019
Abstract: Heparin is used extensively as an anticoagulant in a broad range of diseases and procedures however, its biological effects are not limited to coagulation and remain incompletely understood. Heparin usage can lead to the life-threatening complication known as heparin-induced thrombocytopenia (HIT), caused by the development of antibodies against heparin/PF4 complexes. Here, we demonstrate the ability of heparin to induce neutrophil extracellular traps (NETs). NETs occurred with cell lysis and death, but live neutrophils releasing extracellular DNA strands, known as vital NETs, also occurred abundantly. Formation of NETs was time and dose dependent, and required reactive oxygen species and neutrophil elastase. Other compounds related to heparin such as low molecular weight heparin, fondaparinux and heparan sulfate either failed to induce NETs, or did so to a much lesser extent. Our findings suggest the ability of heparin to directly induce NET formation should be considered in the context of heparin treatment and HIT pathogenesis.
Publisher: Wiley
Date: 15-04-2019
DOI: 10.1002/CYTO.A.23767
Abstract: Neutrophil extracellular trap (NET) formation involves the release of DNA outside the cell to neutralize pathogens. Techniques such as live microscopy, flow cytometry, and intravital imaging allow the characterization of NETs, but these either cannot be applied in vivo, lack specificity or require invasive procedures. We developed an automated analysis method to rapidly acquire and characterize cells as NETs or NET precursors, as opposed to cells undergoing other forms of cell death, using imaging flow cytometry. NETs were maintained in solution using a novel three-dimensional cell culture system in which cells are suspended at the interface of two liquids of different density. Critically, we identify NETs using an image analysis algorithm based on morphological data showing the extrusion of DNA beyond the cell boundaries. In vitro, we used this technique to demonstrate different requirements for NET formation in human and mouse neutrophils. We also measured NETs in whole blood during infection of mice with the malaria parasite Plasmodium yoelii. We expect this technique will provide a valuable approach to better understand the process of NET formation and its importance in disease. © 2019 International Society for Advancement of Cytometry.
Publisher: Oxford University Press (OUP)
Date: 20-10-2019
Abstract: Influenza A virus (IAV) triggers the infected lung to produce IL-1 and recruit neutrophil. Unlike IL-1β, however, little is known about IL-1α in terms of its mechanism of induction, action and physiological relevance to the host immunity against IAV infection. In particular, whether Z-DNA binding protein 1 (ZBP1), a key molecule for IAV-induced cell death, is involved in the IL-1α induction, neutrophil infiltration, and the physiological outcome have not been elucidated. Here we show in murine model that the IAV-induced IL-1α is mediated solely by ZBP1, in an NLRP3-inflammasome-independent manner, and is required for the optimal IL-1β production followed by the formation of neutrophil extracellular traps. During IAV infection, ZBP1 displays a dual role in anti-IAV immune responses mediated by neutrophil, resulting in either protective or pathological outcome in vivo. Thus, ZBP1-mediated IL-1α production is the key initial step of IAV-infected NETs, owing the duality of the consequent lung inflammation.
Publisher: Oxford University Press (OUP)
Date: 09-0001
Abstract: Allelic heterogeneity is a common phenomenon where a gene exhibits a different phenotype depending on the nature of its genetic mutations. In the context of genes affecting malaria susceptibility, it allowed us to explore and understand the intricate host–parasite interactions during malaria infections. In this study, we described a gene encoding erythrocytic ankyrin-1 (Ank-1) which exhibits allelic-dependent heterogeneous phenotypes during malaria infections. We conducted an ENU mutagenesis screen on mice and identified two Ank-1 mutations, one resulting in an amino acid substitution (MRI95845), and the other a truncated Ank-1 protein (MRI96570). Both mutations caused hereditary spherocytosis-like phenotypes and confer differing protection against Plasmodium chabaudi infections. Upon further examination, the Ank-1(MRI96570) mutation was found to inhibit intraerythrocytic parasite maturation, whereas Ank-1(MRI95845) caused increased bystander erythrocyte clearance during infection. This is the first description of allelic heterogeneity in ankyrin-1 from the direct comparison between two Ank-1 mutations. Despite the lack of direct evidence from population studies, this data further supported the protective roles of ankyrin-1 mutations in conferring malaria protection. This study also emphasized the importance of such phenomena in achieving a better understanding of host–parasite interactions, which could be the basis of future studies.
Publisher: Cold Spring Harbor Laboratory
Date: 31-08-2016
DOI: 10.1101/072587
Abstract: Genetic defects in various red blood cell (RBC) cytoskeletal proteins have been long associated with changes in susceptibility towards malaria infection. In particular, while ankyrin (Ank-1) mutations account for approximately 50% of hereditary spherocytosis (HS) cases, an association with malaria is not well-established, and conflicting evidence has been reported. We describe a novel N-ethyl-N-nitrosourea (ENU)-induced ankyrin mutation MRI61689 that gives rise to two different ankyrin transcripts: one with an introduced splice acceptor site resulting a frameshift, the other with a skipped exon. Ank-1 (MRI61689/+) mice exhibit an HS-like phenotype including reduction in mean corpuscular volume (MCV), increased osmotic fragility and reduced RBC deformability. They were also found to be resistant to rodent malaria Plasmodium chabaudi infection. Parasites in Ank-1 (MRI61689/+) erythrocytes grew normally, but red cells showed resistance to merozoite invasion. Uninfected Ank-1 (MRI61689/+) erythrocytes were also more likely to be cleared from circulation during infection the “bystander effect”. This increased clearance is a novel resistance mechanism which was not observed in previous ankyrin mouse models. We propose that this bystander effect is due to reduced deformability of Ank-1 (MRI61689/+) erythrocytes. This paper highlights the complex roles ankyrin plays in mediating malaria resistance.
Publisher: American Society for Microbiology
Date: 11-2015
DOI: 10.1128/IAI.00926-15
Abstract: The treatment of iron deficiency in areas of high malaria transmission is complicated by evidence which suggests that iron deficiency anemia protects against malaria, while iron supplementation increases malaria risk. Iron deficiency anemia results in an array of pathologies, including reduced systemic iron bioavailability and abnormal erythrocyte physiology however, the mechanisms by which these pathologies influence malaria infection are not well defined. In the present study, the response to malaria infection was examined in a mutant mouse line, Tfrc MRI24910 , identified during an N -ethyl- N -nitrosourea (ENU) screen. This line carries a missense mutation in the gene for transferrin receptor 1 (TFR1). Heterozygous mice exhibited reduced erythrocyte volume and density, a phenotype consistent with dietary iron deficiency anemia. However, unlike the case in dietary deficiency, the erythrocyte half-life, mean corpuscular hemoglobin concentration, and intraerythrocytic ferritin content were unchanged. Systemic iron bioavailability was also unchanged, indicating that this mutation results in erythrocytic iron deficiency without significantly altering overall iron homeostasis. When infected with the rodent malaria parasite Plasmodium chabaudi adami , mice displayed increased parasitemia and succumbed to infection more quickly than their wild-type littermates. Transfusion of fluorescently labeled erythrocytes into malaria parasite-infected mice demonstrated an erythrocyte-autonomous enhanced survival of parasites within mutant erythrocytes. Together, these results indicate that TFR1 deficiency alters erythrocyte physiology in a way that is similar to dietary iron deficiency anemia, albeit to a lesser degree, and that this promotes intraerythrocytic parasite survival and an increased susceptibility to malaria in mice. These findings may have implications for the management of iron deficiency in the context of malaria.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 09-06-2017
DOI: 10.1126/SCIIMMUNOL.AAM8093
Abstract: Plasmodium infection causes chronic inflammation and bone loss through Plasmodium product accumulation in the bone marrow.
Publisher: Proceedings of the National Academy of Sciences
Date: 10-06-2016
Publisher: American Society of Hematology
Date: 28-12-2017
DOI: 10.1182/BLOOD-2017-06-790519
Abstract: Histones promote in vitro erythrocyte aggregation, sedimentation, fragility, and spleen retention in a concentration-dependent manner. Histones induce in vivo anemia, an increase in splenic hemoglobin content, as well as thrombocytopenia and leukopenia within a few minutes.
Location: No location found
No related grants have been discovered for Patrick Lelliott.