J Oriol Sunyer

University of Pennsylvania, Philadelphia, Pennsylvania, United States

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Publications (57)286.68 Total impact

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    ABSTRACT: C5a, the most potent anaphylatoxin generated during complement activation, has important pro-inflammatory actions and has also been shown to enhance antigen-specific antibody response in mammals, thereby acting as a molecular adjuvant. In rainbow trout, C5a has been shown to have a chemoattractant ability and its receptor has also been found on potential APCs. In this study, we tested the possible role of trout C5a as a molecular adjuvant. We demonstrated the presence of native C5a in trout serum using the antibody generated by recombinant trout C5a, and then we generated recombinant infectious hematopoietic necrosis virus glycoprotein (G), and a G-C5a fusion protein to test the adjuvant activity of trout C5a. Recombinant G-C5a displayed a potent chemoattractant activity in contrast to G alone, indicating that the C5a portion of the fusion protein was functional. Thereafter, G-C5a, partially emulsified in a small quantity of IFA, was injected into one group of trout, while the other group of trout was inoculated with the same dose of recombinant G. At four to sixteen weeks post-injection, the serum IgM antibody levels of the fish injected with recombinant G-C5a were obviously higher than those injected with G protein alone. Thus, these results suggest, for the first time, that C5a acts as molecular adjuvant in teleost fish by enhancing antibody response to a soluble antigen.
    Fish &amp Shellfish Immunology 08/2014; · 2.96 Impact Factor
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    ABSTRACT: We investigated intra-specific variation in the response of salmon to infection with the myxozoan Ceratomyxa shasta by comparing the progress of parasite infection and measures of host immune response in susceptible and resistant Chinook salmon Oncorhynchus tshawytscha at days 12, 25 and 90 post exposure. There were no differences in invasion of the gills indicating that resistance does not occur at the site of entry. In the intestine on day 12, infection intensity and Ig+ cell numbers were higher in susceptible than resistant fish, but histological examination at that timepoint showed more severe inflammation in resistant fish This suggests a role for the immune response in resistant fish that eliminates some parasites prior to or soon after reaching the intestine. Susceptible fish had a higher IFNγ, IL-6 and IL-10 response at day 12, but all died of fatal enteronecrosis by day 25. The greatest fold change in IFNγ expression was detected at day 25 in resistant Chinook. In addition, the number of Ig+ cells in resistant Chinook also increased by day 25. By day 90, resistant Chinook had resolved the inflammation, cytokine expression had decreased and Ig+ cell numbers were similar to uninfected controls. Thus, it appears that the susceptible strain was incapable of containing or eliminating C. shasta but resistant fish: 1) reduced infection intensity during early intestinal infection 2) elicited an effective inflammatory response in the intestine that eliminated C. shasta 3) resolved the inflammation and recovered from infection.
    Fish &amp Shellfish Immunology 01/2014; · 2.96 Impact Factor
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    ABSTRACT: Infectious Pancreatic Necrosis Virus (IPNV) is the agent of a well-characterized acute disease that produces a systemic infection and high mortality in farmed fish species but also persistent infection in surviving fish after outbreaks. Because viral persistence of susceptible mammal hosts appears to be associated with the modulation of anti-inflammatory cytokine expression, in this study we examined the expression levels of key pro- and anti-inflammatory cytokines in kidney and spleen of trout, as well as humoral immune response (IgM and IgT) during experimental persistent viral infection and in the acute phase of infection as a comparison. IPNV infection in rainbow trout resulted in a distinct profile of cytokine expression depending on the type of infection, acute or persistent. Levels of early pro-inflammatory cytokines, IL-1β and IL-8, did not increase in the head kidney of the fish with persistent asymptomatic infection but increased in some of the symptomatic infected fish. The antiviral cytokine IFNα was not significantly induced in any of the infected fish groups. The level of expression of the Th1-related cytokine IL-12 was significantly higher in trout with persistent asymptomatic infection than in symptomatic fish. This was also accompanied by an increase in IFNγ. The anti-inflammatory cytokines IL-10 and TGF-β1 had distinct expression profiles. While IL-10 expression increased in all infected fish, TGF-β1 was only up-regulated in fish with persistent infection. All infected fish had significantly lower total IgM levels than the non-infected fish whereas IgT levels did not change. Specific and neutralizing antibodies against IPNV were not observed in acute and persistent infection except in the group of fish with the lowest degree of clinical signs. Interestingly, the lack of humoral immune response could be associated with the high expression of anti-inflammatory cytokines, which might inhibit antibody production. The balance between pro-inflammatory Th1 type cytokines and the regulatory cytokines could explain the high percentage of survival and the resolution of the inflammatory response in the IPNV-infected fish but also the establishment of viral persistence.
    Fish &amp Shellfish Immunology 01/2014; · 2.96 Impact Factor
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    Daniela Gomez, J Oriol Sunyer, Irene Salinas
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    ABSTRACT: The field of mucosal immunology research has grown fast over the past few years, and our understanding on how mucosal surfaces respond to complex antigenic cocktails is expanding tremendously. With the advent of new molecular sequencing techniques, it is easier to understand how the immune system of vertebrates is, to a great extent, orchestrated by the complex microbial communities that live in symbiosis with their hosts. The commensal microbiota is now seen as the "extended self" by many scientists. Similarly, fish immunologist are devoting important research efforts to the field of mucosal immunity and commensals. Recent breakthroughs on our understanding of mucosal immune responses in teleost fish open up the potential of teleosts as animal research models for the study of human mucosal diseases. Additionally, this new knowledge places immunologists in a better position to specifically target the fish mucosal immune system while rationally designing mucosal vaccines and other immunotherapies. In this review, an updated view on how teleost skin, gills and gut immune cells and molecules, function in response to pathogens and commensals is provided. Finally, some of the future avenues that the field of fish mucosal immunity may follow in the next years are highlighted.
    Fish &amp Shellfish Immunology 10/2013; · 2.96 Impact Factor
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    ABSTRACT: Myxozoans are among the most abundant parasites in nature. Their life cycles involve two hosts: an invertebrate, usually an annelid, and a vertebrate, usually a fish. They affect species in their natural habitats but also constitute a great menace for fish aquaculture. Using different strategies they are able to parasitize and cause damage in multiple organs, including mucosal tissues, which they use also as portals of entry. In fish, the main mucosal sites include the intestine, skin and gills. Recently the finding of a specific mucosal immunoglobulin in teleost (IgT), analogous to mammalian IgA, and the capacity of fish to develop a specific mucosal immune response against different pathogens, has highlighted the importance of studying immune responses at mucosal sites. In this review, we describe the major biological characteristics of myxozoan parasites and present the data available regarding immune responses for species that infect mucosal sites. As models for mucosal immunity we review the responses to Enteromyxum spp. and Ceratomyxa shasta, both of which parasitize the intestine. The immune response at the skin and gills is also described, as these mucosal tissues are used by myxozoans as attaching surfaces and portal of entry, and some species also parasitize these sites. Finally, the development of immunoprophylactic strategies is discussed.
    Developmental and comparative immunology 08/2013; · 3.29 Impact Factor
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    ABSTRACT: Skin homeostasis is critical to preserve animal integrity. Although the skin of most vertebrates is known to contain a skin-associated lymphoid tissue (SALT), very little is known about skin B-cell responses as well as their evolutionary origins. Teleost fish represent the most ancient bony vertebrates containing a SALT. Due to its lack of keratinization, teleost skin possesses living epithelial cells in direct contact with the water medium. Interestingly, teleost SALT structurally resembles that of the gut-associated lymphoid tissue, and it possesses a diverse microbiota. Thus, we hypothesized that, because teleost SALT and gut-associated lymphoid tissue have probably been subjected to similar evolutionary selective forces, their B-cell responses would be analogous. Confirming this hypothesis, we show that IgT, a teleost immunoglobulin specialized in gut immunity, plays the prevailing role in skin mucosal immunity. We found that IgT(+) B cells represent the major B-cell subset in the skin epidermis and that IgT is mainly present in polymeric form in the skin mucus. Critically, we found that the majority of the skin microbiota are coated with IgT. Moreover, IgT responses against a skin parasite were mainly limited to the skin whereas IgM responses were almost exclusively detected in the serum. Strikingly, we found that the teleost skin mucosa showed key features of mammalian mucosal surfaces exhibiting a mucosa-associated lymphoid tissue. Thus, from an evolutionary viewpoint, our findings suggest that, regardless of their phylogenetic origin and tissue localization, the chief immunoglobulins of all mucosa-associated lymphoid tissue operate under the guidance of primordially conserved principles.
    Proceedings of the National Academy of Sciences 07/2013; · 9.81 Impact Factor
  • Fish &amp Shellfish Immunology 06/2013; 34(6):1653. · 2.96 Impact Factor
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    J Oriol Sunyer
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    ABSTRACT: Recent years have witnessed a renaissance in the study of fish immune systems. Such studies have greatly expanded the knowledge of the evolution and diversification of vertebrate immune systems. Several findings in those studies have overturned old paradigms about the immune system and led to the discovery of novel aspects of mammalian immunity. Here I focus on how findings pertaining to immunity in teleost (bony) fish have led to major new insights about mammalian B cell function in innate and adaptive immunity. Additionally, I illustrate how the discovery of the most ancient mucosal immunoglobulin described thus far will help resolve unsettled paradigms of mammalian mucosal immunity.
    Nature Immunology 03/2013; 14(4):320-326. · 26.20 Impact Factor
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    ABSTRACT: With lymphoid tissue anatomy different than mammals, and diverse adaptations to all aquatic environments, fish constitute a fascinating group of vertebrate to study the biol-ogy of B cell repertoires in a comparative perspective. Fish B lymphocytes express immunoglobulin (Ig) on their surface and secrete antigen-specific antibodies in response to immune challenges. Three antibody classes have been identified in fish, namely IgM, IgD, and IgT, while IgG, IgA, and IgE are absent. IgM and IgD have been found in all fish species analyzed, and thus seem to be primordial antibody classes. IgM and IgD are normally co-expressed from the same mRNA through alternative splicing, as in mammals. Tetrameric IgM is the main antibody class found in serum. Some species of fish also have IgT, which seems to exist only in fish and is specialized in mucosal immunity. IgM/IgD and IgT are expressed by two different sub-populations of B cells. The tools available to investigate B cell responses at the cellular level in fish are limited, but the progress of fish genomics has started to unravel a rich diversity of IgH and immunoglobulin light chain locus organization, which might be related to the succession of genome remodelings that occurred during fish evolution. Moreover, the development of deep sequencing techniques has allowed the investigation of the global features of the expressed fish B cell repertoires in zebrafish and rainbow trout, in steady state or after infection. This review provides a description of the organization of fish Ig loci, with a particular emphasis on their heterogeneity between species, and presents recent data on the structure of the expressed Ig repertoire in healthy and infected fish.
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    ABSTRACT: With lymphoid tissue anatomy different than mammals, and diverse adaptations to all aquatic environments, fish constitute a fascinating group of vertebrate to study the biology of B cell repertoires in a comparative perspective. Fish B lymphocytes express immunoglobulin (Ig) on their surface and secrete antigen-specific antibodies in response to immune challenges. Three antibody classes have been identified in fish, namely IgM, IgD, and IgT, while IgG, IgA, and IgE are absent. IgM and IgD have been found in all fish species analyzed, and thus seem to be primordial antibody classes. IgM and IgD are normally co-expressed from the same mRNA through alternative splicing, as in mammals. Tetrameric IgM is the main antibody class found in serum. Some species of fish also have IgT, which seems to exist only in fish and is specialized in mucosal immunity. IgM/IgD and IgT are expressed by two different sub-populations of B cells. The tools available to investigate B cell responses at the cellular level in fish are limited, but the progress of fish genomics has started to unravel a rich diversity of IgH and immunoglobulin light chain locus organization, which might be related to the succession of genome remodelings that occurred during fish evolution. Moreover, the development of deep sequencing techniques has allowed the investigation of the global features of the expressed fish B cell repertoires in zebrafish and rainbow trout, in steady state or after infection. This review provides a description of the organization of fish Ig loci, with a particular emphasis on their heterogeneity between species, and presents recent data on the structure of the expressed Ig repertoire in healthy and infected fish.
    Frontiers in Immunology 01/2013; 4:28.
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    ABSTRACT: In mammals, CCR7 is the chemokine receptor for the CCL19 and CCL21 chemokines, molecules with a major role in the recruitment of lymphocytes to lymph nodes and Peyer's patches in the intestinal mucosa, especially naïve T lymphocytes. In the current work, we have identified a CCR7 orthologue in rainbow trout (Oncorhynchus mykiss) that shares many of the conserved features of mammalian CCR7. The receptor is constitutively transcribed in the gills, hindgut, spleen, thymus and gonad. When leukocyte populations were isolated, IgM(+) cells, T cells and myeloid cells from head kidney transcribed the CCR7 gene. In blood, both IgM(+) and IgT(+) B cells and myeloid cells but not T lymphocytes were transcribing CCR7, whereas in the spleen, CCR7 mRNA expression was strongly detected in T lymphocytes. In response to infection with viral hemorrhagic septicemia virus (VHSV), CCR7 transcription was down-regulated in spleen and head kidney upon intraperitoneal infection, whereas upon bath infection, CCR7 was up-regulated in gills but remained undetected in the fin bases, the main site of virus entry. Concerning its regulation in the intestinal mucosa, the ex vivo stimulation of hindgut segments with Poly I:C or inactivated bacteria significantly increased CCR7 transcription, while in the context of an infection with Ceratomyxa shasta, the levels of transcription of CCR7 in both IgM(+) and IgT(+) cells from the gut were dramatically increased. All these data suggest that CCR7 plays an important role in lymphocyte trafficking during rainbow trout infections, in which CCR7 appears to be implicated in the recruitment of B lymphocytes into the gut.
    Developmental and comparative immunology 07/2012; 38(2):302-11. · 3.29 Impact Factor
  • David Parra, Fumio Takizawa, J. Oriol Sunyer
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    ABSTRACT: Two types of adaptive immune strategies are known to have evolved in vertebrates: the VLR-based system, which is present in jawless organisms and is mediated by VLRA and VLRB lymphocytes, and the BCR/TCR-based system, which is present in jawed species and is provided by B and T cell receptors expressed on B and T cells, respectively. Here we summarize features of B cells and their predecessors in the different animal phyla, focusing the review on B cells from jawed vertebrates. We point out the critical role of nonclassical species and comparative immunology studies in the understanding of B cell immunity. Because nonclassical models include species relevant to veterinary medicine, basic science research performed in these animals contributes to the knowledge required for the development of more efficacious vaccines against emerging pathogens. Expected final online publication date for the Annual Review of Animal Biosciences Volume 1 is February 08, 2013. Please see http://www.annualreviews.org/catalog/pu...
    Annual review of animal biosciences. 04/2012; 1.
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    J Oriol Sunyer
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    ABSTRACT: The evolutionary origins of Ig-producing B cells appear to be linked to the emergence of fish in this planet. There are three major classes of living fish species, which from most primitive to modern they are referred to as agnathan (e.g., lampreys), Chondrichthyes (e.g., sharks), and teleost fish (e.g., rainbow trout). Agnathans do not have immunoglobulin- producing B cells, however these fish contain a subset of lymphocytes-like cells producing type B variable lymphocyte receptors (VLRBs) that appear to act as functional analogs of immunoglobulins. Chondrichthyes fish represent the most primitive living species containing bona-fide immunoglobulin-producing B cells. Their B cells are known to secrete three types of antibodies, IgM, IgW and IgNAR. Teleost fish are also called bony fish since they represent the most ancient living species containing true bones. Teleost B cells produce three different immunoglobulin isotypes, IgM, IgD and the recently described IgT. While teleost IgM is the principal player in systemic immunity, IgT appears to be a teleost immunoglobulin class specialized in mucosal immune responses. Thus far, three major B cell lineages have been described in teleost, those expressing either IgT or IgD, and the most common lineage which co-expresses IgD and IgM. A few years ago, the study of teleost fish B cells revealed for the first time in vertebrates the existence of B cell subsets with phagocytic and intracellular bactericidal capacities. This finding represented a paradigm shift as professional phagocytosis was believed to be exclusively performed by some cells of the myeloid lineage (i.e., macrophages, monocytes, neutrophils). This phagocytic capacity was also found in amphibians and reptiles, suggesting that this innate capacity was evolutionarily conserved in certain B cell subsets of vertebrates. Recently, the existence of subsets of B cells with phagocytic and bactericidal abilities have also been confirmed in mammals. Moreover, it has been shown that phagocytic B-1 B cells have a potent ability to present particulate antigen to CD4+ T cells. Thus, studies carried out originally on fish B cells have lead to the discovery of new innate and adaptive roles of B cells in mammals. This review will concentrate on the evolutionary and functional relationships of fish and mammalian B cells, focusing mainly on the newly discovered roles of these cells in phagocytosis, intracellular killing and presentation of particulate antigen.
    Infectious disorders drug targets. 03/2012; 12(3):200-12.
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    Irene Salinas, Yong-An Zhang, J Oriol Sunyer
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    ABSTRACT: As physical barriers that separate teleost fish from the external environment, mucosae are also active immunological sites that protect them against exposure to microbes and stressors. In mammals, the sites where antigens are sampled from mucosal surfaces and where stimulation of naïve T and B lymphocytes occurs are known as inductive sites and are constituted by mucosa-associated lymphoid tissue (MALT). According to anatomical location, the MALT in teleost fish is subdivided into gut-associated lymphoid tissue (GALT), skin-associated lymphoid tissue (SALT), and gill-associated lymphoid tissue (GIALT). All MALT contain a variety of leukocytes, including, but not limited to, T cells, B cells, plasma cells, macrophages and granulocytes. Secretory immunoglobulins are produced mainly by plasmablasts and plasma cells, and play key roles in the maintenance of mucosal homeostasis. Until recently, teleost fish B cells were thought to express only two classes of immunoglobulins, IgM and IgD, in which IgM was thought to be the only one responding to pathogens both in systemic and mucosal compartments. However, a third teleost immunoglobulin class, IgT/IgZ, was discovered in 2005, and it has recently been shown to behave as the prevalent immunoglobulin in gut mucosal immune responses. The purpose of this review is to summarise the current knowledge of mucosal immunoglobulins and B cells of fish MALT. Moreover, we attempt to integrate the existing knowledge on both basic and applied research findings on fish mucosal immune responses, with the goal to provide new directions that may facilitate the development of novel vaccination strategies that stimulate not only systemic, but also mucosal immunity.
    Developmental and comparative immunology 11/2011; 35(12):1346-65. · 3.29 Impact Factor
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    ABSTRACT: Breaking the long-held paradigm that primary B cells are not phagocytic, several studies have demonstrated recently that B cells from fish, amphibians, and reptilians have a significant phagocytic capacity. Whether such capacity has remained conserved in certain mammalian B cell subsets is presently an enigma. Here, we report a previously unrecognized ability of PerC B-1a and B-1b lymphocytes to phagocytose latex beads and bacteria. In contrast, B-2 lymphocytes had an almost negligible ability to internalize these particles. Upon phagocytosis, B-1a and B-1b cells were able to mature their phagosomes into phagolysosomes and displayed the ability to kill internalized bacteria. Importantly, B-1a and B-1b cells effectively present antigen recovered from phagocytosed particles to CD4(+) T cells. However, these cells showed a much lower competence to present soluble antigen or antigen from large, noninternalized particles. B-1 B cells presented particulate and soluble antigen to CD4(+) T cells more efficiently than macrophages, whereas DCs were the most potent APCs. The novel phagocytic and microbicidal abilities identified in B-1 B lymphocytes strengthen the innate nature that has long been attributed to these cells. In the context of adaptive immunity, we show that these innate immune processes are relevant, as they enable B-1 B cells to present phagocytosable particulate antigen. These capacities position these cells at the crossroads that link innate with adaptive immune processes. In a broader context, these newly identified capacities of B-1 B cells further support the previously recognized functional, developmental, and evolutionary relationships between these cells and macrophages.
    Journal of leukocyte biology 11/2011; 91(4):525-36. · 4.99 Impact Factor
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    ABSTRACT: Both eicosanoid generation and the complement system have long evolutionary histories predating the emergence of the vertebrates over 500 myr ago. This study investigated the interplay between these two systems in an example of a bony fish, the rainbow trout (Oncorhynchus mykiss). Specifically, it examined whether purified complement fragments including C3a-1 and zymosan-activated serum, stimulate the biosynthesis of any of these eicosanoids by trout macrophages. Incubation of macrophages with zymosan pre-incubated with normal trout serum resulted in the phagocytosis of such particles and the generation of both intra- and extra-cellularly located lipoxygenase and cyclooxygenase products. Both eicosanoid generation and phagocytosis levels were significantly elevated following incubation of zymosan in trout serum in comparison with heat-inactivated (60°C for 30 min) trout serum and saline alone. A combined mass spectrometry/high performance liquid chromatography approach was employed to conclusively demonstrate the presence of the cyclooxygenase product, prostaglandin E (PGE) in the culture supernatants of ionophore-challenged macrophages. Incubation of trout macrophages with zymosan-activated trout serum (i.e. no zymosan present) failed to stimulate PGE generation. Similarly, incubation of these cells for up to 60 min with C3a-1 (4 or 50 nM) failed to generate significant amounts of PGE or lipoxygenase products such as leukotriene B(4/5) or lipoxin A(4/5). Longer term (6 & 24h) incubation of macrophages with C3a-1 (4 nM) resulted in a time dependent increase in the generation of PGE but not leukotriene B in culture supernatants. No conclusive evidence that the increase in PGE generation was caused by changes in the expression of either cyclooxygenase-1 or -2 was found.
    Developmental and comparative immunology 06/2011; 36(1):1-9. · 3.29 Impact Factor
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    Yong-An Zhang, Irene Salinas, J Oriol Sunyer
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    ABSTRACT: As key effector molecules of jawed vertebrate's adaptive immune system, immunoglobulins are produced by B lymphocytes, either as a secretory form (antibody) or as a membrane form (B cell receptor). Until recently, teleost fish B cells were thought to express only two classes of immunoglobulins, IgM and IgD. In addition, IgM in these species was thought to be the only immunoglobulin isotype responding to pathogens both in systemic or mucosal compartments. However, the unexpected discovery of IgT, a new teleost immunoglobulin unearthed in 2005, has provided for new opportunities to analyze further roles of teleost immunoglobulins in these two physiologically distinct compartments. The smoke about the potential function of IgT has cleared recently with the finding that this immunoglobulin appears to be specialized in gut mucosal immunity. Significantly, the new capability of measuring not only IgM but also IgT responses will greatly facilitate the evaluation and understanding of fish immune responses as well as the protective effects of fish vaccines. The purpose of this review is to summarize the molecular characterization of new IgT orthologs and subtypes in teleosts, as well as to describe the new findings concerning the protein structure of IgT, the B cells producing it, and its role in mucosal immunity.
    Fish &amp Shellfish Immunology 04/2011; 31(5):627-34. · 2.96 Impact Factor
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    ABSTRACT: Teleost fish are the most primitive bony vertebrates that contain immunoglobulins. In contrast to mammals and birds, these species are devoid of immunoglobulin A (IgA) or a functional equivalent. This observation suggests that specialization of immunoglobulin isotypes into mucosal and systemic responses took place during tetrapod evolution. Challenging that paradigm, here we show that IgT, an immunoglobulin isotype of unknown function, acts like a mucosal antibody. We detected responses of rainbow trout IgT to an intestinal parasite only in the gut, whereas IgM responses were confined to the serum. IgT coated most intestinal bacteria. As IgT and IgA are phylogenetically distant immunoglobulins, their specialization into mucosal responses probably occurred independently by a process of convergent evolution.
    Nature Immunology 09/2010; 11(9):827-35. · 26.20 Impact Factor
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    ABSTRACT: The filovirus VP40 protein is capable of budding from mammalian cells in the form of virus-like particles (VLPs) that are morphologically indistinguishable from infectious virions. Ebola virus VP40 (eVP40) contains well-characterized overlapping L domains, which play a key role in mediating efficient virus egress. L domains represent only one component required for efficient budding and, therefore, there is a need to identify and characterize additional domains important for VP40 function. We demonstrate here that the (96)LPLGVA(101) sequence of eVP40 and the corresponding (84)LPLGIM(89) sequence of Marburg virus VP40 (mVP40) are critical for efficient release of VP40 VLPs. Indeed, deletion of these motifs essentially abolished the ability of eVP40 and mVP40 to bud as VLPs. To address the mechanism by which the (96)LPLGVA(101) motif of eVP40 contributes to egress, a series of point mutations were introduced into this motif. These mutants were then compared to the eVP40 wild type in a VLP budding assay to assess budding competency. Confocal microscopy and gel filtration analyses were performed to assess their pattern of intracellular localization and ability to oligomerize, respectively. Our results show that mutations disrupting the (96)LPLGVA(101) motif resulted in both altered patterns of intracellular localization and self-assembly compared to wild-type controls. Interestingly, coexpression of either Ebola virus GP-WT or mVP40-WT with eVP40-DeltaLPLGVA failed to rescue the budding defective eVP40-DeltaLPLGVA mutant into VLPs; however, coexpression of eVP40-WT with mVP40-DeltaLPLGIM successfully rescued budding of mVP40-DeltaLPLGIM into VLPs at mVP40-WT levels. In sum, our findings implicate the LPLGVA and LPLGIM motifs of eVP40 and mVP40, respectively, as being important for VP40 structure/stability and budding.
    Journal of Virology 03/2010; 84(5):2294-303. · 5.08 Impact Factor
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    ABSTRACT: In mammals, interaction of CD28 with CD80 or CD86 molecules provides costimulatory signals for T cell activation that leads to increased IL-2 gene and protein expression by activated T cells. Thus far, CD80 and CD86 have been cloned and functionally characterized only in mammals and birds. To shed light into the evolution of CD80 and CD86, we have cloned and functionally characterized a rainbow trout (rt) molecule (rtCD80/86) that shows the highest degree of sequence conservation and phylogenetic relationship with CD80 and CD86 molecules. Moreover, its genomic organization was almost identical to that of human CD86. Rainbow trout possess one membrane-bound and two soluble CD80/86 transcripts, all of which are derived from the same rtCD80/86 gene. The membrane-bound form exhibited its highest degree of expression in lymphoid tissues, particularly on B cells. Incubation of trout leukocytes with LPS and bacteria leads to up-regulation of rtCD80/86 gene expression. Importantly, we show that trout and other teleost fish contain a single CD80/86 gene, thus suggesting that this gene may represent the ancestor from which CD80 and CD86 arose by gene duplication in more evolved species. To gain further insights into the function of rtCD80/86, we have identified and cloned trout IL-2 and have shown that recombinantly produced trout CD80/86 up-regulates the expression of IL-2 in trout blood leukocytes. Significantly, this finding indicates that the capacity to modulate IL-2 expression is a primordial function that has been conserved both in fish and mammalian CD80/CD86 molecules throughout 350 million years of evolution.
    The Journal of Immunology 08/2009; 183(1):83-96. · 5.52 Impact Factor

Publication Stats

2k Citations
286.68 Total Impact Points

Institutions

  • 1995–2014
    • University of Pennsylvania
      • • Department of Pathobiology
      • • Department of Pathology and Laboratory Medicine
      • • Department of Pathology
      Philadelphia, Pennsylvania, United States
    • Autonomous University of Barcelona
      • Facultat de Ciències
      Cerdanyola del Vallès, Catalonia, Spain
  • 2005
    • Hospital of the University of Pennsylvania
      Philadelphia, Pennsylvania, United States
  • 2001
    • University of Patras
      • Department of Biology
      Ríon, Greece