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1. Corrigendum: Dynamics of host immune response development during Schistosoma mansoni infection

Author

Costain, Alice H., primary, Phythian-Adams, Alexander T., additional, Colombo, Stefano A. P., additional, Marley, Angela K., additional, Owusu, Christian, additional, Cook, Peter C., additional, Brown, Sheila L., additional, Webb, Lauren M., additional, Lundie, Rachel J., additional, Borger, Jessica G., additional, Smits, Hermelijn H., additional, Berriman, Matthew, additional, and MacDonald, Andrew S., additional

Published
2023
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4. Dynamics of host immune response development during Schistosoma mansoni infection.

Author

Costain, Alice H., Phythian-Adams, Alexander T., Colombo, Stefano A. P., Marley, Angela K., Owusu, Christian, Cook, Peter C., Brown, Sheila L., Webb, Lauren M., Lundie, Rachel J., Borger, Jessica G., Smits, Hermelijn H., Berriman, Matthew, and MacDonald, Andrew S.

Subjects
SCHISTOSOMA mansoni, IMMUNE response, HEPATIC fibrosis, HELMINTHIASIS, SCHISTOSOMIASIS
Abstract

Schistosomiasis is a disease of global significance, with severity and pathology directly related to how the host responds to infection. The immunological narrative of schistosomiasis has been constructed through decades of study, with researchers often focussing on isolated time points, cell types and tissue sites of interest. However, the field currently lacks a comprehensive and up-to-date understanding of the immune trajectory of schistosomiasis over infection and across multiple tissue sites. We have defined schistosome-elicited immune responses at several distinct stages of the parasite lifecycle, in three tissue sites affected by infection: the liver, spleen, and mesenteric lymph nodes. Additionally, by performing RNA-seq on the livers of schistosome infected mice, we have generated novel transcriptomic insight into the development of schistosomeassociated liver pathology and fibrosis across the breadth of infection. Through depletion of CD11c+ cells during peak stages of schistosome-driven inflammation, we have revealed a critical role for CD11c+ cells in the co-ordination and regulation of Th2 inflammation during infection. Our data provide an updated and high-resolution account of how host immune responses evolve over the course of murine schistosomiasis, underscoring the significance of CD11c+ cells in dictating host immunopathology against this important helminth infection. [ABSTRACT FROM AUTHOR]

Published
2023
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6. Dynamics of host immune response development during Schistosoma mansoni infection

Author

Costain, Alice H., primary, Phythian-Adams, Alexander T., additional, Colombo, Stefano A. P., additional, Marley, Angela K., additional, Owusu, Christian, additional, Cook, Peter C., additional, Brown, Sheila L., additional, Webb, Lauren M., additional, Lundie, Rachel J., additional, Borger, Jessica G., additional, Smits, Hermelijn H., additional, Berriman, Matthew, additional, and MacDonald, Andrew S., additional

Published
2022
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13. Plasmacytoid Dendritic Cells Facilitate Th Cell Cytokine Responses throughout Schistosoma mansoni Infection

Author

Webb, Lauren M., primary, Phythian-Adams, Alexander T., additional, Costain, Alice H., additional, Brown, Sheila L., additional, Lundie, Rachel J., additional, Forde-Thomas, Josephine, additional, Cook, Peter C., additional, Jackson-Jones, Lucy H., additional, Marley, Angela K., additional, Smits, Hermelijn H., additional, Hoffmann, Karl F., additional, Tait Wojno, Elia D., additional, and MacDonald, Andrew S., additional

Published
2021
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20. Acute Plasmodium berghei Mouse Infection Elicits Perturbed Erythropoiesis With Features That Overlap With Anemia of Chronic Disease

Author

Lakkavaram, Asha, Lundie, Rachel J., Do, Hang, Ward, Alister C., De Koning-Ward, Tania F., Lakkavaram, Asha, Lundie, Rachel J., Do, Hang, Ward, Alister C., and De Koning-Ward, Tania F.

Abstract

Severe malaria anemia is one of the most common causes of morbidity and mortality arising from infection with Plasmodium falciparum. The pathogenesis of malarial anemia is complex, involving both parasite and host factors. As mouse models of malaria also develop anemia, they can provide a useful resource to study the impact of Plasmodium infections and the resulting host innate immune response on erythropoiesis. In this study, we have characterized the bone marrow and splenic responses of the erythroid as well as other hematopoietic lineages after an acute infection of Balb/c mice with Plasmodium berghei. Such characterization of the hematopoietic changes is critical to underpin future studies, using knockout mice and transgenic parasites, to tease out the interplay between host genes and parasite modulators implicated in susceptibility to malaria anemia. P. berghei infection led to a clear perturbation of steady-state erythropoiesis, with the most profound defects in polychromatic and orthochromatic erythroblasts as well as erythroid colony- and burst-forming units (CFU-E and BFU-E), resulting in an inability to compensate for anemia. The perturbation in erythropoiesis was not attributable to parasites infecting erythroblasts and affecting differentiation, nor to insufficient erythropoietin (EPO) production or impaired activation of the Signal transducer and activator of transcription 5 (STAT5) downstream of the EPO receptor, indicating EPO-signaling remained functional in anemia. Instead, the results point to acute anemia in P. berghei-infected mice arising from increased myeloid cell production in order to clear the infection, and the concomitant release of pro-inflammatory cytokines and chemokines from myeloid cells that inhibit erythroid development, in a manner that resembles the pathophysiology of anemia of chronic disease.

Published
2020

26. A dominant role for the methyl-CpG-binding protein Mbd2 in controlling Th2 induction by dendritic cells

Author

Cook, Peter C., Owen, Heather, Deaton, Aimée M., Borger, Jessica G., Brown, Sheila L., Clouaire, Thomas, Jones, Gareth-Rhys, Jones, Lucy H., Lundie, Rachel J., Marley, Angela K., Morrison, Vicky L., Phythian-Adams, Alexander T., Wachter, Elisabeth, Webb, Lauren M., Sutherland, Tara E., Thomas, Graham D., Grainger, John R., Selfridge, Jim, McKenzie, Andrew N. J., Allen, Judith E., Fagerholm, Susanna C., Maizels, Rick M., Ivens, Alasdair C., Bird, Adrian, and MacDonald, Andrew S.

Subjects
CD4-Positive T-Lymphocytes, Chromatin Immunoprecipitation, Chemistry(all), Enzyme-Linked Immunosorbent Assay, Physics and Astronomy(all), Lymphocyte Activation, Article, Epigenesis, Genetic, Mice, Th2 Cells, Hypersensitivity, Animals, RNA, Messenger, Mice, Knockout, Biochemistry, Genetics and Molecular Biology(all), Reverse Transcriptase Polymerase Chain Reaction, Pyroglyphidae, Cell Polarity, Dendritic Cells, Schistosoma mansoni, Allergens, DNA Methylation, Flow Cytometry, Schistosomiasis mansoni, DNA-Binding Proteins, Gene Expression Regulation
Abstract

Dendritic cells (DCs) direct CD4+ T-cell differentiation into diverse helper (Th) subsets that are required for protection against varied infections. However, the mechanisms used by DCs to promote Th2 responses, which are important both for immunity to helminth infection and in allergic disease, are currently poorly understood. We demonstrate a key role for the protein methyl-CpG-binding domain-2 (Mbd2), which links DNA methylation to repressive chromatin structure, in regulating expression of a range of genes that are associated with optimal DC activation and function. In the absence of Mbd2, DCs display reduced phenotypic activation and a markedly impaired capacity to initiate Th2 immunity against helminths or allergens. These data identify an epigenetic mechanism that is central to the activation of CD4+ T-cell responses by DCs, particularly in Th2 settings, and reveal methyl-CpG-binding proteins and the genes under their control as possible therapeutic targets for type-2 inflammation., How anti-helminth and allergic immune responses are initiated is poorly understood. Here the authors show that to trigger these responses, dendritic cells specifically require methyl-CpG-binding domain-2, a protein promoting repressed chromatin state.

Published
2015
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27. Daptomycin‐resistant Staphylococcus aureus clinical isolates are poorly sensed by dendritic cells.

Author

Patton, Timothy, Jiang, Jhih‐Hang, Lundie, Rachel J, Bafit, Mariam, Gao, Wei, Peleg, Anton Y, and O'Keeffe, Meredith

Subjects
STAPHYLOCOCCUS aureus, DRUG resistance in bacteria, METHICILLIN-resistant staphylococcus aureus, DENDRITIC cells, ENDEMIC diseases, DAPTOMYCIN
Abstract

Methicillin‐resistant Staphylococcus aureus (MRSA) presents an increasing threat to public health, with antimicrobial resistance on the rise and infections endemic in the hospital setting. Despite a global research effort to understand and combat antimicrobial resistance, less work has focused on understanding the nuances in the immunopathogenesis of clinical strains. In particular, there is a surprising gap of knowledge in the literature pertaining to how clinical strains are recognized by dendritic cells (DCs). Here, we show that the activation of DCs is compromised in response to MRSA strains resistant to the last‐line antibiotic daptomycin. We found a significant reduction in the secretion of proinflammatory cytokines including tumor necrosis factor‐α, interleukin‐6, regulated upon activation, normal T cell expressed, and secreted and macrophage inflammatory protein‐1β, as well as decreased expression of CD80 by DCs responding to daptomycin‐resistant MRSA. We further demonstrate that this phenotype is coincident with the acquisition of specific point mutations in the cardiolipin synthase gene cls2, and, partly, in the bifunctional lysylphosphatidylglycerol flippase/synthetase gene mprF, which are genes that are often mutated in clinical daptomycin‐resistant strains. Therefore, throughout infection and antibiotic therapy, MRSA has the capacity to not only develop further antibiotic resistance, but also develop resistance to immunological recognition by DCs, because of single amino acid point mutations occurring under the selective pressures of both host immunity and antibiotic therapy. Understanding the diversity of clinical MRSA isolates and the nuances in their immune recognition will have important implications for future therapeutics and the treatment of these infections. [ABSTRACT FROM AUTHOR]

Published
2020
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28. Type I interferon is required for T helper (Th) 2 induction by dendritic cells

Author

Webb, Lauren M., Lundie, Rachel J., Borger, Jessica G., Brown, Sheila L., Connor, Lisa M., Cartwright, Adam N.R., Dougall, Annette M., Wilbers, Ruud H.P., Cook, Peter C., Jackson-Jones, Lucy H., Phythian-Adams, Alexander T., Johansson, Cecilia, Davis, Daniel M., Dewals, Benjamin G., Ronchese, Franca, Macdonald, Andrew S., Webb, Lauren M., Lundie, Rachel J., Borger, Jessica G., Brown, Sheila L., Connor, Lisa M., Cartwright, Adam N.R., Dougall, Annette M., Wilbers, Ruud H.P., Cook, Peter C., Jackson-Jones, Lucy H., Phythian-Adams, Alexander T., Johansson, Cecilia, Davis, Daniel M., Dewals, Benjamin G., Ronchese, Franca, and Macdonald, Andrew S.

Abstract

Type 2 inflammation is a defining feature of infection with parasitic worms (helminths), as well as being responsible for widespread suffering in allergies. However, the precise mechanisms involved in T helper (Th) 2 polarization by dendritic cells (DCs) are currently unclear. We have identified a previously unrecognized role for type I IFN (IFN-I) in enabling this process. An IFN-I signature was evident in DCs responding to the helminth Schistosoma mansoni or the allergen house dust mite (HDM). Further, IFN-I signaling was required for optimal DC phenotypic activation in response to helminth antigen (Ag), and efficient migration to, and localization with, T cells in the draining lymph node (dLN). Importantly, DCs generated from Ifnar1-/- mice were incapable of initiating Th2 responses in vivo. These data demonstrate for the first time that the influence of IFN-I is not limited to antiviral or bacterial settings but also has a central role to play in DC initiation of Th2 responses.

Published
2017

29. Parasite-derived microRNAs in host serum as novel biomarkers of helminth infection

Author

Hoy, Anna M., Lundie, Rachel J., Ivens, Alasdair, Quintana, Juan F., Nausch, Norman, Forster, Thorsten, Jones, Frances, Kabatereine, Narcis B., Dunne, David W., Mutapi, Francisca, MacDonald, Andrew S., Buck, Amy H., Dunne, David [0000-0002-8940-9886], and Apollo - University of Cambridge Repository

Subjects
Adult, Male, lcsh:Arctic medicine. Tropical medicine, Adolescent, lcsh:RC955-962, Mice, Young Adult, Diagnostic Medicine, Pathology, Parasitic Diseases, Animals, Humans, Child, lcsh:Public aspects of medicine, lcsh:RA1-1270, Schistosoma mansoni, Middle Aged, Schistosomiasis mansoni, Mice, Inbred C57BL, MicroRNAs, Infectious Diseases, Liver, Child, Preschool, Medicine, Female, RNA, Helminth, Biomarkers, Research Article, General Pathology
Abstract

Background MicroRNAs (miRNAs) are a class of short non-coding RNA that play important roles in disease processes in animals and are present in a highly stable cell-free form in body fluids. Here, we examine the capacity of host and parasite miRNAs to serve as tissue or serum biomarkers of Schistosoma mansoni infection. Methods/Principal Findings We used Exiqon miRNA microarrays to profile miRNA expression in the livers of mice infected with S. mansoni at 7 weeks post-infection. Thirty-three mouse miRNAs were differentially expressed in infected compared to naïve mice (>2 fold change, p, Author Summary Schistosomiasis is a chronic disease caused by blood flukes that affects over 200 million people worldwide, of which 90% live in Sub-Saharan Africa. In the field setting schistosomiasis caused by S. mansoni is diagnosed by detection of parasite eggs in stool samples using microscopic techniques. Here we investigate the potential of microRNAs (miRNAs), a class of short noncoding RNAs, to act as biomarkers of S. mansoni infection. We have identified a specific subset of murine miRNAs whose expression is significantly altered in the liver between 6–12 weeks post infection. However their abundance in serum is not significantly different between naïve and S. mansoni-infected mice until twelve weeks post infection and they do not display consistent differential abundance in the serum of infected versus uninfected humans. In contrast, three parasite-derived miRNAs (miR-277, bantam and miR-3479-3p) were detected in the serum of infected mice and human patients and the combined detection of these miRNAs could distinguish S. mansoni infected from uninfected individuals from low and high infection intensity areas with 89%/80% or 80%/90% specificity/sensitivity, respectively. These results demonstrate that miRNAs of parasite origin are a new class of serum biomarker for detecting S. mansoni and likely other helminth infections.

Published
2014
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31. A dominant role for the methyl-CpG-binding protein Mbd2 in controlling Th2 induction by dendritic cells

Author

Cook, Peter C, Owen, Heather, Deaton, Aimée M, Borger, Jessica G, Brown, Sheila L, Clouaire, Thomas, Jones, Gareth-Rhys, Jones, Lucy H, Lundie, Rachel J, Marley, Angela K, Morrison, Vicky L, Phythian-Adams, Alexander T, Wachter, Elisabeth, Webb, Lauren M, Sutherland, Tara E, Thomas, Graham D, Grainger, John R, Selfridge, Jim, McKenzie, Andrew N J, Allen, Judith E, Fagerholm, Susanna C, Maizels, Rick M, Ivens, Alasdair C, Bird, Adrian, MacDonald, Andrew S, Cook, Peter C, Owen, Heather, Deaton, Aimée M, Borger, Jessica G, Brown, Sheila L, Clouaire, Thomas, Jones, Gareth-Rhys, Jones, Lucy H, Lundie, Rachel J, Marley, Angela K, Morrison, Vicky L, Phythian-Adams, Alexander T, Wachter, Elisabeth, Webb, Lauren M, Sutherland, Tara E, Thomas, Graham D, Grainger, John R, Selfridge, Jim, McKenzie, Andrew N J, Allen, Judith E, Fagerholm, Susanna C, Maizels, Rick M, Ivens, Alasdair C, Bird, Adrian, and MacDonald, Andrew S

Abstract

Dendritic cells (DCs) direct CD4(+) T-cell differentiation into diverse helper (Th) subsets that are required for protection against varied infections. However, the mechanisms used by DCs to promote Th2 responses, which are important both for immunity to helminth infection and in allergic disease, are currently poorly understood. We demonstrate a key role for the protein methyl-CpG-binding domain-2 (Mbd2), which links DNA methylation to repressive chromatin structure, in regulating expression of a range of genes that are associated with optimal DC activation and function. In the absence of Mbd2, DCs display reduced phenotypic activation and a markedly impaired capacity to initiate Th2 immunity against helminths or allergens. These data identify an epigenetic mechanism that is central to the activation of CD4(+) T-cell responses by DCs, particularly in Th2 settings, and reveal methyl-CpG-binding proteins and the genes under their control as possible therapeutic targets for type-2 inflammation.

Published
2015

32. Immune-mediated mechanisms of parasite tissue sequestration during experimental cerebral malaria

Author

Amante, Fiona H., Haque, Ashraful, Stanley, Amanda C., de Labastida Rivera, Fabian, Randall, Louise M., Wilson, Yana A., Yeo, Gladys, Pieper, Christian, Crabb, Brendan S., de Koning-Ward, Tania F., Lundie, Rachel J., Good, Michael F., Pinzon-Charry, Alberto, Pearson, Mark S., Duke, Mary G., McManus, Donald P., Loukas, Alex, Hill, Geoff R., Engwerda, Christian R., Amante, Fiona H., Haque, Ashraful, Stanley, Amanda C., de Labastida Rivera, Fabian, Randall, Louise M., Wilson, Yana A., Yeo, Gladys, Pieper, Christian, Crabb, Brendan S., de Koning-Ward, Tania F., Lundie, Rachel J., Good, Michael F., Pinzon-Charry, Alberto, Pearson, Mark S., Duke, Mary G., McManus, Donald P., Loukas, Alex, Hill, Geoff R., and Engwerda, Christian R.

Abstract

Cerebral malaria is a severe complication of malaria. Sequestration of parasitized RBCs in brain microvasculature is associated with disease pathogenesis, but our understanding of this process is incomplete. In this study, we examined parasite tissue sequestration in an experimental model of cerebral malaria (ECM). We show that a rapid increase in parasite biomass is strongly associated with the induction of ECM, mediated by IFN-γ and lymphotoxin α, whereas TNF and IL-10 limit this process. Crucially, we discovered that host CD4+ and CD8+ T cells promote parasite accumulation in vital organs, including the brain. Modulation of CD4+ T cell responses by helminth coinfection amplified CD4+ T cell-mediated parasite sequestration, whereas vaccination could generate CD4+ T cells that reduced parasite biomass and prevented ECM. These findings provide novel insights into immune-mediated mechanisms of ECM pathogenesis and highlight the potential of T cells to both prevent and promote infectious diseases.

Published
2010

36. Immune-Mediated Mechanisms of Parasite Tissue Sequestration during Experimental Cerebral Malaria

Author

Amante, Fiona H., primary, Haque, Ashraful, additional, Stanley, Amanda C., additional, Rivera, Fabian de Labastida, additional, Randall, Louise M., additional, Wilson, Yana A., additional, Yeo, Gladys, additional, Pieper, Christian, additional, Crabb, Brendan S., additional, de Koning-Ward, Tania F., additional, Lundie, Rachel J., additional, Good, Michael F., additional, Pinzon-Charry, Alberto, additional, Pearson, Mark S., additional, Duke, Mary G., additional, McManus, Donald P., additional, Loukas, Alex, additional, Hill, Geoff R., additional, and Engwerda, Christian R., additional

Published
2010
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37. CD11c depletion severely disrupts Th2 induction and development in vivo

Author

Phythian-Adams, Alexander T., primary, Cook, Peter C., additional, Lundie, Rachel J., additional, Jones, Lucy H., additional, Smith, Katherine A., additional, Barr, Tom A., additional, Hochweller, Kristin, additional, Anderton, Stephen M., additional, Hämmerling, Günter J., additional, Maizels, Rick M., additional, and MacDonald, Andrew S., additional

Published
2010
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39. IP-10-Mediated T Cell Homing Promotes Cerebral Inflammation over Splenic Immunity to Malaria Infection

Author

Nie, Catherine Q., primary, Bernard, Nicholas J., additional, Norman, M. Ursula, additional, Amante, Fiona H., additional, Lundie, Rachel J., additional, Crabb, Brendan S., additional, Heath, William R., additional, Engwerda, Christian R., additional, Hickey, Michael J., additional, Schofield, Louis, additional, and Hansen, Diana S., additional

Published
2009
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40. Blood-stage Plasmodium infection induces CD8 + T lymphocytes to parasite-expressed antigens, largely regulated by CD8α + dendritic cells

Author

Lundie, Rachel J., primary, de Koning-Ward, Tania F., additional, Davey, Gayle M., additional, Nie, Catherine Q., additional, Hansen, Diana S., additional, Lau, Lei Shong, additional, Mintern, Justine D., additional, Belz, Gabrielle T., additional, Schofield, Louis, additional, Carbone, Francis R., additional, Villadangos, Jose A., additional, Crabb, Brendan S., additional, and Heath, William R., additional

Published
2008
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41. Systemic activation of dendritic cells by Toll-like receptor ligands or malaria infection impairs cross-presentation and antiviral immunity

Author

Wilson, Nicholas S, primary, Behrens, Georg M N, additional, Lundie, Rachel J, additional, Smith, Christopher M, additional, Waithman, Jason, additional, Young, Louise, additional, Forehan, Simon P, additional, Mount, Adele, additional, Steptoe, Raymond J, additional, Shortman, Ken D, additional, de Koning-Ward, Tania F, additional, Belz, Gabrielle T, additional, Carbone, Francis R, additional, Crabb, Brendan S, additional, Heath, William R, additional, and Villadangos, Jose A, additional

Published
2006
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42. RNA: DNA hybrids are a novel molecular pattern sensed by TLR9.

Author

Rigby, Rachel E, Webb, Lauren M, Mackenzie, Karen J, Li, Yue, Leitch, Andrea, Reijns, Martin A M, Lundie, Rachel J, Revuelta, Ailsa, Davidson, Donald J, Diebold, Sandra, Modis, Yorgo, MacDonald, Andrew S, and Jackson, Andrew P

Subjects
RNA, DNA, MOLECULAR genetics, TOLL-like receptors, NATURAL immunity, ANTI-infective agents, ANTIVIRAL agents
Abstract

The sensing of nucleic acids by receptors of the innate immune system is a key component of antimicrobial immunity. RNA: DNA hybrids, as essential intracellular replication intermediates generated during infection, could therefore represent a class of previously uncharacterised pathogen-associated molecular patterns sensed by pattern recognition receptors. Here we establish that RNA: DNA hybrids containing viral-derived sequences efficiently induce pro-inflammatory cytokine and antiviral type I interferon production in dendritic cells. We demonstrate that MyD88-dependent signalling is essential for this cytokine response and identify TLR9 as a specific sensor of RNA: DNA hybrids. Hybrids therefore represent a novel molecular pattern sensed by the innate immune system and so could play an important role in host response to viruses and the pathogenesis of autoimmune disease. [ABSTRACT FROM AUTHOR]

Published
2014
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43. Blood-stage Plasmodium infection induces CD8+ T lymphocytes to parasite-expressed antigens, largely regulated by CD8α+ dendritic cells.

Author

Lundie, Rachel J., de Koning-Ward, Tania F., Davey, Gayle M., Nie, Catherine Q., Hansen, Diana S., Lei Shong Lau, Mintern, Justine D., Belz, Gabrielle T., Schofield, Louis, Carbone, Francis R., Villadangos, Jose A., Crabb, Brendan S., and Heath, William R.

Subjects
*T cells, *LYMPHOCYTES, *MALARIA, *CEREBRAL malaria, *LEUCOCYTES
Abstract

Although CD8+ T cells do not contribute to protection against the blood stage of Plasmodium infection, there is mounting evidence that they are principal mediators of murine experimental cerebral malaria (ECM). At present, there is no direct evidence that the CD8+ T cells mediating ECM are parasite-specific or, for that matter, whether parasite-specific CD8+ T cells are generated in response to blood-stage infection. To resolve this and to define the cellular requirements for such priming, we generated transgenic P. berghei parasites expressing model T cell epitopes. This approach was necessary as MHC class I-restricted antigens to blood-stage infection have not been defined. Here, we show that blood-stage infection leads to parasite-specific CD8+ and CD4+ T cell responses. Furthermore, we show that P. berghei-expressed antigens are cross-presented by the CD8+ subset of dendritic cells (DC), and that this induces pathogen-specific cytotoxic T lymphocytes (CTL) capable of lysing cells presenting antigens expressed by blood-stage parasites. Finally, using three different experimental approaches, we provide evidence that CTL specific for parasite-expressed antigens contribute to ECM. [ABSTRACT FROM AUTHOR]

Published
2008
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44. Novel roles for erythroid Ankyrin-1revealed through an ENU-induced null mouse mutant

Author

Rank, Gerhard, Sutton, Rosemary, Marshall, Vikki, Lundie, Rachel J., Caddy, Jacinta, Romeo, Tony, Fernandez, Kate, McCormack, Matthew P., Cooke, Brian M., Foote, Simon J., Crabb, Brendan S., Curtis, David J., Hilton, Douglas J., Kile, Benjamin T., and Jane, Stephen M.

Abstract

Insights into the role of ankyrin-1 (ANK-1) in the formation and stabilization of the red cell cytoskeleton have come from studies on the nb/nbmice, which carry hypomorphic alleles of Ank-1. Here, we revise several paradigms established in the nb/nbmice through analysis of an N-ethyl-N-nitrosourea (ENU)–induced Ank-1–null mouse. Mice homozygous for the Ank-1mutation are profoundly anemic in utero and most die perinatally, indicating that Ank-1plays a nonredundant role in erythroid development. The surviving pups exhibit features of severe hereditary spherocytosis (HS), with marked hemolysis, jaundice, compensatory extramedullary erythropoiesis, and tissue iron overload. Red cell membrane analysis reveals a complete loss of ANK-1 protein and a marked reduction in β-spectrin. As a consequence, the red cells exhibit total disruption of cytoskeletal architecture and severely altered hemorheologic properties. Heterozygous mutant mice, which have wild-type levels of ANK-1 and spectrin in their RBC membranes and normal red cell survival and ultrastructure, exhibit profound resistance to malaria, which is not due to impaired parasite entry into RBC. These findings provide novel insights into the role of Ank-1, and define an ideal model for the study of HS and malarial resistance.

Published
2009
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45. RNA:DNA hybrids are a novel molecular pattern sensed by TLR9

Author

Rigby, Rachel E, Webb, Lauren M, Mackenzie, Karen J, Li, Yue, Leitch, Andrea, Reijns, Martin AM, Lundie, Rachel J, Revuelta, Ailsa, Davidson, Donald J, Diebold, Sandra, Modis, Yorgo, MacDonald, Andrew S, and Jackson, Andrew P

Subjects
Blotting, Western, Immunoblotting, Models, Immunological, Nucleic Acid Heteroduplexes, Fluorescent Antibody Technique, Enzyme-Linked Immunosorbent Assay, Fluorescence Polarization, Dendritic Cells, Endosomes, Flow Cytometry, Real-Time Polymerase Chain Reaction, Immunity, Innate, 3. Good health, Mice, Inbred C57BL, Mice, Toll-Like Receptor 9, Myeloid Differentiation Factor 88, Animals, Humans, Signal Transduction
Abstract

The sensing of nucleic acids by receptors of the innate immune system is a key component of antimicrobial immunity. RNA:DNA hybrids, as essential intracellular replication intermediates generated during infection, could therefore represent a class of previously uncharacterised pathogen-associated molecular patterns sensed by pattern recognition receptors. Here we establish that RNA:DNA hybrids containing viral-derived sequences efficiently induce pro-inflammatory cytokine and antiviral type I interferon production in dendritic cells. We demonstrate that MyD88-dependent signalling is essential for this cytokine response and identify TLR9 as a specific sensor of RNA:DNA hybrids. Hybrids therefore represent a novel molecular pattern sensed by the innate immune system and so could play an important role in host response to viruses and the pathogenesis of autoimmune disease.

46. Parasite-derived microRNAs in host serum as novel biomarkers of helminth infection

Author

Hoy, Anna M, Lundie, Rachel J, Ivens, Alasdair, Quintana, Juan F, Nausch, Norman, Forster, Thorsten, Jones, Frances, Kabatereine, Narcis B, Dunne, David W, Mutapi, Francisca, Macdonald, Andrew S, and Buck, Amy H

Subjects
Adult, Male, Adolescent, Schistosoma mansoni, Middle Aged, Schistosomiasis mansoni, 3. Good health, Mice, Inbred C57BL, Mice, MicroRNAs, Young Adult, Liver, Child, Preschool, Animals, Humans, Female, RNA, Helminth, Child, Biomarkers
Abstract

BACKGROUND: MicroRNAs (miRNAs) are a class of short non-coding RNA that play important roles in disease processes in animals and are present in a highly stable cell-free form in body fluids. Here, we examine the capacity of host and parasite miRNAs to serve as tissue or serum biomarkers of Schistosoma mansoni infection. METHODS/PRINCIPAL FINDINGS: We used Exiqon miRNA microarrays to profile miRNA expression in the livers of mice infected with S. mansoni at 7 weeks post-infection. Thirty-three mouse miRNAs were differentially expressed in infected compared to naïve mice (>2 fold change, p

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