SpyCatcher-SpyTagged ApxIA Toxoid and the Immune-Modulating Yeast Ghost Shells

2020 ◽  
Vol 16 (11) ◽  
pp. 1644-1657
Author(s):  
Seonhyung Lee ◽  
Beom-Ku Han ◽  
Yang-Hoon Kim ◽  
Ji-Young Ahn
Keyword(s):  
Immune Responses ◽  
Innate Immune ◽  
Mass Spectrometry Analysis ◽  
Cytotoxic Activities ◽  
Raw 264.7 Macrophages ◽  
Spectrometry Analysis ◽  
Cellular Immune Responses ◽  
Histocompatibility Complex ◽  
Tnf Α ◽  
Cellular Immune

Actinobacillus pleuropneumoniaesecretes the hemolytic cytotoxins ApxI, ApxII, ApxIII, and ApxIV, which cause pleurop- neumonia in swine. Of these, ApxI is the most toxic. ApxIA, a repeats-in-toxin toxin-like protein, has strong hemolytic and cytotoxic activities. This study aimed to develop an immune modulator ApxIA toxoid, with a Spytag/Spycatcher pair (SC::ST pair), in yeast ghost shells (YGSs). These YGSs were utilized as ApxIA toxoid delivery platforms for -glucan components that can be recognized by the innate immune system. The SC::ST pair was used to conjugate the ApxIA toxoid to YGSs. The YGS-SC::ST-ToxApxIA was successfully phagocytosed by RAW 264.7 macrophages cells, without any toxicity. Further investigation revealed that YGS-SC::ST-ToxApxIA led to defective immune responses, in addition to increased levels of cytokines IL-1β, TNF-α, and IL-10. A membrane proteomic analysis, to determine preferential major histocompatibility complex binding of ApxIA-derived peptides, was performed and four ApxIA peptides were successfully identified by liquid chromatography with tandem mass spectrometry analysis. The identified peptides may serve as poten- tial vaccine candidates in immunobiology studies of A. pleuropneumoniae. Our results indicate that YGS-SC::ST-ToxApxIA can prevent A. pleuropneumoniae pleuropneumonia (APP) by inducing both humoral and cellular immune responses.

scholarly journals MicroRNAs from Snellenius manilae bracovirus regulate innate and cellular immune responses of its host Spodoptera litura

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Cheng-Kang Tang ◽  
Chih-Hsuan Tsai ◽  
Carol-P. Wu ◽  
Yu-Hsien Lin ◽  
Sung-Chan Wei ◽  
...  
Keyword(s):  
Immune Responses ◽  
Spodoptera Litura ◽  
Molecular Mechanisms ◽  
Innate Immune ◽  
Sequencing Analysis ◽  
Innate Immune Responses ◽  
Cellular Immune Responses ◽  
Next Generation Sequencing Analysis ◽  
Cellular Immune ◽  
Generation Sequencing

AbstractTo avoid inducing immune and physiological responses in insect hosts, parasitoid wasps have developed several mechanisms to inhibit them during parasitism, including the production of venom, specialized wasp cells, and symbioses with polydnaviruses (PDVs). These mechanisms alter the host physiology to give the wasp offspring a greater chance of survival. However, the molecular mechanisms for most of these alterations remain unclear. In the present study, we applied next-generation sequencing analysis and identified several miRNAs that were encoded in the genome of Snellenius manilae bracovirus (SmBV), and expressed in the host larvae, Spodoptera litura, during parasitism. Among these miRNAs, SmBV-miR-199b-5p and SmBV-miR-2989 were found to target domeless and toll-7 in the host, which are involved in the host innate immune responses. Microinjecting the inhibitors of these two miRNAs into parasitized S. litura larvae not only severely decreased the pupation rate of Snellenius manilae, but also restored the phagocytosis and encapsulation activity of the hemocytes. The results demonstrate that these two SmBV-encoded miRNAs play an important role in suppressing the immune responses of parasitized hosts. Overall, our study uncovers the functions of two SmBV-encoded miRNAs in regulating the host innate immune responses upon wasp parasitism.

scholarly journals Polyamine Transport Protein PotD Protects Mice against Haemophilus parasuis and Elevates the Secretion of Pro-Inflammatory Cytokines of Macrophage via JNK–MAPK and NF–κB Signal Pathways through TLR4

Vaccines ◽  
2019 ◽  
Vol 7 (4) ◽  
pp. 216 ◽  
Author(s):  
Ke Dai ◽  
Xiaoyu Ma ◽  
Zhen Yang ◽  
Yung-Fu Chang ◽  
Sanjie Cao ◽  
...  
Keyword(s):  
Immune Responses ◽  
Inflammatory Cytokines ◽  
Transport System ◽  
Signal Pathways ◽  
Raw 264.7 ◽  
Raw 264.7 Macrophages ◽  
Cellular Immune Responses ◽  
Polyamine Transport ◽  
Cellular Immune ◽  
Pro Inflammatory Cytokines

The potD gene, belonging to the well-conserved ABC (ATP-binding cassette) transport system potABCD, encodes the bacterial substrate-binding subunit of the polyamine transport system. In this study, we found PotD in Haemophilus (Glaesserella) parasuis could actively stimulate both humoral immune and cellular immune responses and elevate lymphocyte proliferation, thus eliciting a Th1-type immune response in a murine immunity and infection model. Stimulation of Raw 264.7 macrophages with PotD validated that Toll-like receptor 4, rather than 2, participated in the positive transcription and expression of pro-inflammatory cytokines IL–1β, IL–6, and TNF–α using qPCR and ELISA. Blocking signal-regulated JNK–MAPK and RelA(p65) pathways significantly decreased PotD-induced pro-inflammatory cytokine production. Overall, we conclude that vaccination of PotD could induce both humoral and cellular immune responses and provide immunoprotection against H. parasuis challenge. The data also suggest that Glaesserella PotD is a novel pro-inflammatory mediator and induces TLR4-dependent pro-inflammatory activity in Raw 264.7 macrophages through JNK–MAPK and RelA(p65) pathways.

scholarly journals Molecular and Immunological Significance of Chimpanzee Major Histocompatibility Complex Haplotypes for Hepatitis C Virus Immune Response and Vaccination Studies

2002 ◽  
Vol 76 (12) ◽  
pp. 6093-6103 ◽  
Author(s):  
Eishiro Mizukoshi ◽  
Michelina Nascimbeni ◽  
Joshua B. Blaustein ◽  
Kathleen Mihalik ◽  
Charles M. Rice ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Major Histocompatibility Complex ◽  
Hepatitis C ◽  
Immune Responses ◽  
Cellular Immune Responses ◽  
Functional Homology ◽  
Histocompatibility Complex ◽  
Ifn Γ ◽  
Cellular Immune

ABSTRACT The chimpanzee is a critical animal model for studying cellular immune responses to infectious pathogens such as hepatitis B and C viruses, human immunodeficiency virus, and malaria. Several candidate vaccines and immunotherapies for these infections aim at the induction or enhancement of cellular immune responses against viral epitopes presented by common human major histocompatibility complex (MHC) alleles. To identify and characterize chimpanzee MHC class I molecules that are functionally related to human alleles, we sequenced 18 different Pan troglodytes (Patr) alleles of 14 chimpanzees, 2 of them previously unknown and 3 with only partially reported sequences. Comparative analysis of Patr binding pockets and binding assays with biotinylated peptides demonstrated a molecular homology between the binding grooves of individual Patr alleles and the common human alleles HLA-A1, -A2, -A3, and -B7. Using cytotoxic T cells isolated from the blood of hepatitis C virus (HCV)-infected chimpanzees, we then mapped the Patr restriction of these HCV peptides and demonstrated functional homology between the Patr-HLA orthologues in cytotoxicity and gamma interferon (IFN-γ) release assays. Based on these results, 21 HCV epitopes were selected to characterize the chimpanzees' cellular immune response to HCV. In each case, IFN-γ-producing T cells were detectable in the blood after but not prior to HCV infection and were specifically targeted against those HCV peptides predicted by Patr-HLA homology. This study demonstrates a close functional homology between individual Patr and HLA alleles and shows that HCV infection generates HCV peptides that are recognized by both chimpanzees and humans with Patr and HLA orthologues. These results are relevant for the design and evaluation of vaccines in chimpanzees that can now be selected according to the most frequent human MHC haplotypes.

scholarly journals Resistance of Major Histocompatibility Complex Class B (MHC-B) to Nef-Mediated Downregulation Relative to that of MHC-A Is Conserved among Primate Lentiviruses and Influences Antiviral T Cell Responses in HIV-1-Infected Individuals

2017 ◽  
Vol 92 (1) ◽  
Author(s):  
Francis Mwimanzi ◽  
Mako Toyoda ◽  
Macdonald Mahiti ◽  
Jaclyn K. Mann ◽  
Jeffrey N. Martin ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Immune Responses ◽  
Complex Class ◽  
Subtype C ◽  
Cell Responses ◽  
Cellular Immune Responses ◽  
Histocompatibility Complex ◽  
Primate Lentiviruses ◽  
Cellular Immune ◽  
Hiv 1

ABSTRACTPatient-derived HIV-1 subtype B Nef clones downregulate HLA-A more efficiently than HLA-B. However, it remains unknown whether this property is common to Nef proteins across primate lentiviruses and how antiviral immune responses may be affected. We examined 263 Nef clones from diverse primate lentiviruses including different pandemic HIV-1 group M subtypes for their ability to downregulate major histocompatibility complex class A (MHC-A) and MHC-B from the cell surface. Though lentiviral Nef proteins differed markedly in their absolute MHC-A and MHC-B downregulation abilities, all lentiviral Nef lineages downregulated MHC-A, on average, 11 to 32% more efficiently than MHC-B. Nef genotype/phenotype analyses in a cohort of HIV-1 subtype C-infected patients (n= 168), together with site-directed mutagenesis, revealed Nef position 9 as a subtype-specific determinant of differential HLA-A versus HLA-B downregulation activity. Nef clones harboring nonconsensus variants at codon 9 downregulated HLA-B (though not HLA-A) significantly better than those harboring the consensus sequence at this site, resulting in reduced recognition of infected target cells by HIV-1-specific CD8+effector cellsin vitro. Among persons expressing protective HLA class I alleles, carriage of Nef codon 9 variants was also associated with reducedex vivoHIV-specific T cell responses. Our results demonstrate that Nef's inferior ability to downregulate MHC-B compared to that of MHC-A is conserved across primate lentiviruses and suggest that this property influences antiviral cellular immune responses.IMPORTANCEPrimate lentiviruses encode the Nef protein that plays an essential role in establishing persistent infection in their respective host species. Nef interacts with the cytoplasmic region of MHC-A and MHC-B molecules and downregulates them from the infected cell surface to escape recognition by host cellular immunity. Using a panel of Nef alleles isolated from diverse primate lentiviruses including pandemic HIV-1 group M subtypes, we demonstrate that Nef proteins across all lentiviral lineages downregulate MHC-A approximately 20% more effectively than MHC-B. We further identify a naturally polymorphic site at Nef position 9 that contributes to the MHC-B downregulation function in HIV-1 subtype C and show that carriage of Nef variants with enhanced MHC-B downregulation ability is associated with reduced breadth and magnitude of MHC-B-restricted cellular immune responses in HIV-infected individuals. Our study underscores an evolutionarily conserved interaction between lentiviruses and primate immune systems that may contribute to pathogenesis.

scholarly journals Magnitude and Phenotype of Cellular Immune Responses Elicited by Recombinant Adenovirus Vectors and Heterologous Prime-Boost Regimens in Rhesus Monkeys

2008 ◽  
Vol 82 (10) ◽  
pp. 4844-4852 ◽  
Author(s):  
Jinyan Liu ◽  
Bonnie A. Ewald ◽  
Diana M. Lynch ◽  
Matthew Denholtz ◽  
Peter Abbink ◽  
...  
Keyword(s):  
Immune Responses ◽  
T Lymphocyte ◽  
Rhesus Monkeys ◽  
Recombinant Adenovirus ◽  
Interleukin 2 ◽  
Cellular Immune Responses ◽  
Tnf Α ◽  
Ifn Γ ◽  
Cellular Immune ◽  
Lymphocyte Responses

ABSTRACT Recombinant adenovirus serotype 5 (rAd5) vaccine vectors for human immunodeficiency virus type 1 (HIV-1) and other pathogens have been shown to elicit antigen-specific cellular immune responses. Rare serotype rAd vectors have also been constructed to circumvent preexisting anti-Ad5 immunity and to facilitate the development of novel heterologous rAd prime-boost regimens. Here we show that rAd5, rAd26, and rAd48 vectors elicit qualitatively distinct phenotypes of cellular immune responses in rhesus monkeys and can be combined as potent heterologous prime-boost vaccine regimens. While rAd5-Gag induced primarily gamma interferon-positive (IFN-γ+) and IFN-γ+/tumor necrosis factor alpha+ (TNF-α+) T-lymphocyte responses, rAd26-Gag and rAd48-Gag induced higher proportions of interleukin-2+ (IL-2+) and polyfunctional IFN-γ+/TNF-α+/IL-2+ T-lymphocyte responses. Priming with the rare serotype rAd vectors proved remarkably effective for subsequent boosting with rAd5 vectors. These data demonstrate that the rare serotype rAd vectors elicited T-lymphocyte responses that were phenotypically distinct from those elicited by rAd5 vectors and suggest the functional relevance of polyfunctional CD8+ and CD4+ T-lymphocyte responses. Moreover, qualitative differences in cellular immune responses may prove critical in determining the overall potency of heterologous rAd prime-boost regimens.

scholarly journals Simian Immunodeficiency Virus SIVmac239 Infection of Major Histocompatibility Complex-Identical Cynomolgus Macaques from Mauritius

2006 ◽  
Vol 81 (1) ◽  
pp. 349-361 ◽  
Author(s):  
Roger W. Wiseman ◽  
Jason A. Wojcechowskyj ◽  
Justin M. Greene ◽  
Alex J. Blasky ◽  
Tobias Gopon ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Immune Responses ◽  
Simian Immunodeficiency Virus ◽  
Major Histocompatibility ◽  
Cellular Immune Responses ◽  
Histocompatibility Complex ◽  
Immunodeficiency Virus ◽  
Cynomolgus Macaques ◽  
Feral Animals ◽  
Cellular Immune

ABSTRACT Nonhuman primates are widely used to study correlates of protective immunity in AIDS research. Successful cellular immune responses have been difficult to identify because heterogeneity within macaque major histocompatibility complex (MHC) genes results in quantitative and qualitative differences in immune responses. Here we use microsatellite analysis to show that simian immunodeficiency virus (SIV)-susceptible cynomolgus macaques (Macaca fascicularis) from the Indian Ocean island of Mauritius have extremely simple MHC genetics, with six common haplotypes accounting for two-thirds of the MHC haplotypes in feral animals. Remarkably, 39% of Mauritian cynomolgus macaques carry at least one complete copy of the most frequent MHC haplotype, and 8% of these animals are homozygous. In stark contrast, entire MHC haplotypes are rarely conserved in unrelated Indian rhesus macaques. After intrarectal infection with highly pathogenic SIVmac239 virus, a pair of MHC-identical Mauritian cynomolgus macaques mounted concordant cellular immune responses comparable to those previously reported for a pair of monozygotic twins infected with the same strain of human immunodeficiency virus. Our identification of relatively abundant SIV-susceptible, MHC-identical macaques will facilitate research into protective cellular immunity.

scholarly journals Complement C3 Plays a Key Role in Inducing Humoral and Cellular Immune Responses to Influenza Virus Strain-Specific Hemagglutinin-Based or Cross-Protective M2 Extracellular Domain-Based Vaccination

2018 ◽  
Vol 92 (20) ◽  
Author(s):  
Yu-Jin Kim ◽  
Ki-Hye Kim ◽  
Eun-Ju Ko ◽  
Min-Chul Kim ◽  
Yu-Na Lee ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Immune Responses ◽  
Adaptive Immunity ◽  
Immune Defense ◽  
Innate Immune ◽  
Complement C3 ◽  
Complement Protein ◽  
Cellular Immune Responses ◽  
Homologous Virus ◽  
Cellular Immune

ABSTRACTThe complement pathway is involved in eliminating antigen immune complexes. However, the role of the C3 complement system remains largely unknown in influenza virus M2 extracellular (M2e) domain or hemagglutinin (HA) vaccine-mediated protection after vaccination. Using a C3 knockout (C3 KO) mouse model, we found that complement protein C3 was required for effective induction of immune responses to vaccination with M2e-based or HA-based vaccines, which include isotype class-switched antibodies and effector CD4 and CD8 T cell responses. C3 KO mice after active immunization with cross-protective nonneutralizing M2e-based vaccine were not protected against influenza virus, although low levels of M2e-specific antibodies were protective after passive coadministration with virus in wild-type mice. In contrast, C3 KO mice that were immunized with strain-specific neutralizing HA-based vaccine were protected against homologous virus challenge despite lower levels of HA antibody responses. C3 KO mice showed impaired maintenance of innate immune cells and a defect in innate immune responses upon exposure to antigens. The findings in this study suggest that C3 is required for effective induction of humoral and cellular adaptive immune responses as well as protective immunity after nonneutralizing influenza M2e vaccination.IMPORTANCEComplement is the well-known innate immune defense system involved in the opsonization and lysis of pathogens but is less studied in establishing adaptive immunity after vaccination. Influenza virus HA-based vaccination confers protection via strain-specific neutralizing antibodies, whereas M2e-based vaccination induces a broad spectrum of protection by immunity against the conserved M2e epitopes. This study revealed the critical roles of C3 complement in inducing humoral and cellular immune responses after immunization with M2e or HA vaccines. C3 was found to be required for protection by M2e-based but not by HA-based active vaccination as well as for maintaining innate antigen-presenting cells. Findings in this study have insight into better understanding the roles of C3 complement in inducing effective innate and adaptive immunity as well as in conferring protection by cross-protective conserved M2e vaccination.

scholarly journals Differentiation, Maturation, and Survival of Dendritic Cells by Osteopontin Regulation

2005 ◽  
Vol 12 (1) ◽  
pp. 206-212 ◽  
Author(s):  
Kodai Kawamura ◽  
Kazuhiro Iyonaga ◽  
Hidenori Ichiyasu ◽  
Junji Nagano ◽  
Moritaka Suga ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
Human Monocyte ◽  
Matrix Component ◽  
Cellular Immune Responses ◽  
Histocompatibility Complex ◽  
Important Interaction ◽  
Cellular Immune ◽  
Antigen Presenting ◽  
Class Ii Antigens

ABSTRACT Dendritic cells (DCs) are antigen-presenting cells with the ability to induce primary immune responses necessary in innate immunity and adaptive immunity. Osteopontin (OPN) is a secreted acidic phosphoprotein containing an arginine-glycine-aspartate sequence and has been suggested to play an important role in early cellular immune responses. The interaction between DCs and OPN has not been clarified. We hypothesized that there is an important interaction between DCs and OPN, which is an indispensable extracellular matrix component in early cellular immune responses. Human monocyte-derived DCs synthesized OPN especially during the differentiation from monocytes to immature DCs. By blocking of OPN with anti-OPN antibody, cultured DCs became smaller and expressed lower levels of costimulatory molecules and major histocompatibility complex class II antigens than untreated DCs. Furthermore, DCs treated with anti-OPN antibody easily underwent apoptosis. These results suggest that human DCs can produce OPN and that OPN may play a role in the differentiation, maturation, and survival of DCs by autocrine and/or paracrine pathways.

scholarly journals Vaccine Vectors Harnessing the Power of Cytomegaloviruses

Vaccines ◽  
2019 ◽  
Vol 7 (4) ◽  
pp. 152 ◽  
Author(s):  
Ynga-Durand ◽  
Dekhtiarenko ◽  
Cicin-Sain
Keyword(s):  
Immune Responses ◽  
Vaccine Vectors ◽  
Mhc Molecules ◽  
Cell Responses ◽  
Cellular Immune Responses ◽  
Mature Phase ◽  
Histocompatibility Complex ◽  
Technological Platform ◽  
Cellular Immune ◽  
Antigenic Epitopes

Cytomegalovirus (CMV) species have been gaining attention as experimental vaccine vectors inducing cellular immune responses of unparalleled strength and protection. This review outline the strengths and the restrictions of CMV-based vectors, in light of the known aspects of CMV infection, pathogenicity and immunity. We discuss aspects to be considered when optimizing CMV based vaccines, including the innate immune response, the adaptive humoral immunity and the T-cell responses. We also discuss the antigenic epitopes presented by unconventional major histocompatibility complex (MHC) molecules in some CMV delivery systems and considerations about routes for delivery for the induction of systemic or mucosal immune responses. With the first clinical trials initiating, CMV-based vaccine vectors are entering a mature phase of development. This impetus needs to be maintained by scientific advances that feed the progress of this technological platform.

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