Use of Proteins Identified through a Functional Genomic Screen To Develop a Protein Subunit Vaccine That Provides Significant Protection against Virulent
                    Streptococcus suis
                    in Pigs

ABSTRACT Streptococcus suis is a bacterium that is commonly carried in the respiratory tract and that is also one of the most important invasive pathogens of swine, commonly causing meningitis, arthritis, and septicemia. Due to the existence of many serotypes and a wide range of immune evasion capabilities, efficacious vaccines are not readily available. The selection of S. suis protein candidates for inclusion in a vaccine was accomplished by identifying fitness genes through a functional genomics screen and selecting conserved predicted surface-associated proteins. Five candidate proteins were selected for evaluation in a vaccine trial and administered both intranasally and intramuscularly with one of two different adjuvant formulations. Clinical protection was evaluated by subsequent intranasal challenge with virulent S. suis . While subunit vaccination with the S. suis proteins induced IgG antibodies to each individual protein and a cellular immune response to the pool of proteins and provided substantial protection from challenge with virulent S. suis , the immune response elicited and the degree of protection were dependent on the parenteral adjuvant given. Subunit vaccination induced IgG reactive against different S. suis serotypes, indicating a potential for cross protection.

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Does gamma knife surgery stimulate cellular immune response to metastatic brain tumors? A histopathological and immunohistochemical study

Journal of Neurosurgery ◽

10.3171/sup.2005.102.s_supplement.0180 ◽

2005 ◽

Vol 102 (Special_Supplement) ◽

pp. 180-184 ◽

Cited By ~ 3

Author(s):

György T. Szeifert ◽

Isabelle Salmon ◽

Sandrine Rorive ◽

Nicolas Massager ◽

Daniel Devriendt ◽

...

Keyword(s):

Immune Response ◽

Brain Tumors ◽

Gamma Knife ◽

Cellular Immune Response ◽

Lymphocytic Infiltration ◽

Gamma Knife Surgery ◽

Metastatic Brain Tumors ◽

Content Type ◽

Cellular Immune ◽

Fine Print

Object. The aim of this study was to analyze the cellular immune response and histopathological changes in secondary brain tumors after gamma knife surgery (GKS). Methods. Two hundred ten patients with cerebral metastases underwent GKS. Seven patients underwent subsequent craniotomy for tumor removal between 1 and 33 months after GKS. Four of these patients had one tumor, two patients had two tumors, and one patient had three. Histological and immunohistochemical investigations were performed. In addition to routine H & E and Mallory trichrome staining, immunohistochemical reactions were conducted to characterize the phenotypic nature of the cell population contributing to the tissue immune response to neoplastic deposits after radiosurgery. Light microscopy revealed an intensive lymphocytic infiltration in the parenchyma and stroma of tumor samples obtained in patients in whom surgery was performed over 6 months after GKS. Contrary to this, extensive areas of tissue necrosis with either an absent or scanty lymphoid population were observed in the poorly controlled neoplastic specimens obtained in cases in which surgery was undertaken in patients less than 6 months after GKS. Immunohistochemical characterization demonstrated the predominance of CD3-positive T cells in the lymphoid infiltration. Conclusions. Histopathological findings of the present study are consistent with a cellular immune response of natural killer cells against metastatic brain tumors, presumably stimulated by the ionizing energy of focused radiation.

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Variation in the Susceptibility of Drosophila to Different Entomopathogenic Nematodes

Infection and Immunity ◽

10.1128/iai.02740-14 ◽

2015 ◽

Vol 83 (3) ◽

pp. 1130-1138 ◽

Cited By ~ 38

Author(s):

Jennifer M. Peña ◽

Mayra A. Carrillo ◽

Elissa A. Hallem

Keyword(s):

Immune Response ◽

Entomopathogenic Nematodes ◽

Parasitic Nematode ◽

Insect Pests ◽

Model System ◽

Nematode Infection ◽

Xenorhabdus Nematophila ◽

Content Type ◽

Wide Range ◽

Insect Immune Response

Entomopathogenic nematodes (EPNs) in the generaHeterorhabditisandSteinernemaare lethal parasites of insects that are of interest as models for understanding parasite-host interactions and as biocontrol agents for insect pests. EPNs harbor a bacterial endosymbiont in their gut that assists in insect killing. EPNs are capable of infecting and killing a wide range of insects, yet how the nematodes and their bacterial endosymbionts interact with the insect immune system is poorly understood. Here, we develop a versatile model system for understanding the insect immune response to parasitic nematode infection that consists of seven species of EPNs as model parasites and five species ofDrosophilafruit flies as model hosts. We show that the EPNSteinernema carpocapsae, which is widely used for insect control, is capable of infecting and killingD. melanogasterlarvae.S. carpocapsaeis associated with the bacteriumXenorhabdus nematophila, and we show thatX. nematophilainduces expression of a subset of antimicrobial peptide genes and suppresses the melanization response to the nematode. We further show that EPNs vary in their virulence towardD. melanogasterand thatDrosophilaspecies vary in their susceptibilities to EPN infection. Differences in virulence among different EPN-host combinations result from differences in both rates of infection and rates of postinfection survival. Our results establish a powerful model system for understanding mechanisms of host-parasite interactions and the insect immune response to parasitic nematode infection.

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Live Attenuated Salmonella Vaccines Displaying Regulated Delayed Lysis and Delayed Antigen Synthesis To Confer Protection against Mycobacterium tuberculosis

Infection and Immunity ◽

10.1128/iai.05526-11 ◽

2011 ◽

Vol 80 (2) ◽

pp. 815-831 ◽

Cited By ~ 22

Author(s):

María Dolores Juárez-Rodríguez ◽

Jiseon Yang ◽

Rebin Kader ◽

Praveen Alamuri ◽

Roy Curtiss ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Signal Sequence ◽

Secretion System ◽

Type Ii Secretion ◽

Content Type ◽

Degree Of Protection ◽

Amino Terminal ◽

Type Ii Secretion System ◽

Cellular Immune

ABSTRACTLive recombinant attenuatedSalmonellavaccine (RASV) strains have great potential to induce protective immunity againstMycobacterium tuberculosisby deliveringM. tuberculosisantigens. Recently, we reported that, in orally immunized mice, RASV strains delivering theM. tuberculosisearly secreted antigenic target 6-kDa (ESAT-6) protein and culture filtrate protein 10 (CFP-10) antigens via theSalmonellatype III secretion system (SopE amino-terminal region residues 1 to 80 with two copies of ESAT-6 and one copy of CFP-10 [SopENt80-E2C]) afforded protection against aerosol challenge withM. tuberculosis. Here, we constructed and evaluated an improvedSalmonellavaccine againstM. tuberculosis. We constructed translational fusions for the synthesis of two copies of ESAT-6 plus CFP-10 fused to the OmpC signal sequence (OmpCSS-E2C) and amino acids 44 to 338 of antigen 85A (Ag85A294) flanked by the signal sequence (SS) and C-terminal peptide (CT) of β-lactamase (BlaSS-Ag85A294-BlaCT) to enable delivery via theSalmonellatype II secretion system. The genes expressing these proteins were cloned as an operon transcribed from Ptrcinto isogenic Asd+/MurA+pYA3681 lysis vector derivatives with different replication origins (pBR, p15A, pSC101), resulting in pYA4890, pYA4891, and pYA4892 for SopENt80-E2C/Ag85A294synthesis and pYA4893 and pYA4894 for OmpCSS-E2C/Ag85A294synthesis. Mice orally immunized with the RASV χ11021 strain engineered to display regulated delayed lysis and regulated delayed antigen synthesisin vivoand harboring pYA4891, pYA4893, or pYA4894 elicited significantly greater humoral and cellular immune responses, and the RASV χ11021 strain afforded a greater degree of protection againstM. tuberculosisaerosol challenge in mice than RASVs harboring any other Asd+/MurA+lysis plasmid and immunization withM. bovisBCG, demonstrating that RASV strains displaying regulated delayed lysis with delayed antigen synthesis resulted in highly immunogenic delivery vectors for oral vaccination againstM. tuberculosisinfection.

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Studies in experimental spinal cord trauma

Journal of Neurosurgery ◽

10.3171/jns.1974.40.1.0044 ◽

1974 ◽

Vol 40 (1) ◽

pp. 44-51 ◽

Cited By ~ 53

Author(s):

Lynn S. Hedeman ◽

Ranajit Sil

Keyword(s):

Clinical Result ◽

Post Injury ◽

Synthesis Inhibitor ◽

Content Type ◽

Degree Of Protection ◽

Therapeutic Value ◽

Clinical Protection ◽

Receptor Blockers ◽

Central Gray ◽

High Degree

✓ A chronic clinicopathological study in 43 mongrel dogs evaluates the therapeutic effect of microcirculatory augmentation, an anti-edema agent, catecholamine (CA) receptor blockers, and a CA synthesis inhibitor. Results showed a high degree of clinical protection conferred by phenoxybenzamine, an alpha-adrenergic receptor blocker, and a lesser degree of protection from haloperidol, a domaminergic blocker, and low molecular weight dextran. Alpha-methyltyrosine given post-injury and steroids were of no therapeutic value. There was a correlation between microscopic white matter protection and clinical result. The presence of central gray necrosis was rather constant irrespective of therapy or clinical result.

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Vibrio cholerae O1 Infection Induces Proinflammatory CD4+T-Cell Responses in Blood and Intestinal Mucosa of Infected Humans

Clinical and Vaccine Immunology ◽

10.1128/cvi.05088-11 ◽

2011 ◽

Vol 18 (8) ◽

pp. 1371-1377 ◽

Cited By ~ 19

Author(s):

Alison Kuchta ◽

Taibur Rahman ◽

Erica L. Sennott ◽

Taufiqur R. Bhuyian ◽

Taher Uddin ◽

...

Keyword(s):

Immune Response ◽

T Cell ◽

Vibrio Cholerae ◽

Cellular Immune Response ◽

T Cell Responses ◽

Apparent Lack ◽

Whole Cell ◽

Content Type ◽

Cell Responses ◽

Cellular Immune

ABSTRACTVibrio choleraeO1 is a noninvasive enteric pathogen and serves as a model for studies of mucosal immunity. Although symptomaticV. choleraeinfection induces durable protection against subsequent disease, vaccination with oral killed whole-cellV. choleraestimulates less long-lasting protection against cholera. In this study, we demonstrated that cholera induces an early proinflammatory cellular immune response that results in priming of Th1- and Th17-type cytokine responses toex vivoantigenic stimulation and an increase in the ratio of Th1 to Th2 CD4+T-cell responses. Comparable priming of Th1 and Th17 responses, with an increased ratio of Th1 to Th2 CD4+T-cell responses, was not observed in subjects who received two doses of the oral cholera vaccine Dukoral (a whole-cell cholera toxin B subunit containing [WC-CTB] vaccine). These findings suggest that naturalV. choleraeinfection induces an early, proinflammatory cellular immune response, despite the apparent lack of clinical signs of inflammation. The failure of the WC-CTB vaccine to activate equivalent, CD4+T-cell responses is a potential explanation for the shorter duration of protection following immunization with this vaccine. Additional studies are needed to determine whether these early T-cell-mediated events predict the subsequent duration of immunologic memory.

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Brucella Hijacks Host-Mediated Palmitoylation To Stabilize and Localize PrpA to the Plasma Membrane

Infection and Immunity ◽

10.1128/iai.00402-18 ◽

2018 ◽

Vol 86 (11) ◽

Cited By ~ 2

Author(s):

Juan M. Spera ◽

Francisco Guaimas ◽

María M. Corvi ◽

Juan E. Ugalde

Keyword(s):

Immune Response ◽

Plasma Membrane ◽

Host Cell ◽

Virulence Factors ◽

Cell Activity ◽

Host Immune Response ◽

Content Type ◽

Cell Plasma ◽

The Individual ◽

Cellular Immune

ABSTRACT Brucellaceae are a group of pathogenic intracellular bacteria with the ability to modulate the host response, both at the individual cell level and systemically. One of the hallmarks of the virulence process is the capacity of the bacteria to downregulate the adaptive and acquired host immune response through a plethora of virulence factors that directly impact several key signaling cascades. PrpA is one of those virulence factors that alters, via its polyclonal B-cell activity, the humoral and cellular immune responses of the host, ultimately favoring the establishment of a chronic infection. Even though PrpA affects B cells, it directly targets macrophages, triggering a response that ultimately affects B lymphocytes. In the present article we report that PrpA is S-palmitoylated in two N-terminal cysteine residues by the host cell and that this modification is necessary for its biological activity. Our results demonstrate that S-palmitoylation promotes PrpA migration to the host cell plasma membrane and stabilizes the protein during infection. These findings add a new mechanism exploited by this highly evolved pathogen to modulate the host immune response.

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Does gamma knife surgery stimulate cellular immune response to metastatic brain tumors? A histopathological and immunohistochemical study

Journal of Neurosurgery ◽

10.3171/jns.2005.102.s_supplement.0180 ◽

2005 ◽

Vol 102 ◽

pp. 180-184 ◽

Cited By ~ 9

Author(s):

György T. Szeifert ◽

Isabelle Salmon ◽

Sandrine Rorive ◽

Nicolas Massager ◽

Daniel Devriendt ◽

...

Keyword(s):

Immune Response ◽

Brain Tumors ◽

Gamma Knife ◽

Cellular Immune Response ◽

Lymphocytic Infiltration ◽

Gamma Knife Surgery ◽

Metastatic Brain Tumors ◽

Content Type ◽

Cellular Immune ◽

Fine Print

Object.The aim of this study was to analyze the cellular immune response and histopathological changes in secondary brain tumors after gamma knife surgery (GKS).Methods.Two hundred ten patients with cerebral metastases underwent GKS. Seven patients underwent subsequent craniotomy for tumor removal between 1 and 33 months after GKS. Four of these patients had one tumor, two patients had two tumors, and one patient had three. Histological and immunohistochemical investigations were performed. In addition to routine H & E and Mallory trichrome staining, immunohistochemical reactions were conducted to characterize the phenotypic nature of the cell population contributing to the tissue immune response to neoplastic deposits after radiosurgery.Light microscopy revealed an intensive lymphocytic infiltration in the parenchyma and stroma of tumor samples obtained in patients in whom surgery was performed over 6 months after GKS. Contrary to this, extensive areas of tissue necrosis with either an absent or scanty lymphoid population were observed in the poorly controlled neoplastic specimens obtained in cases in which surgery was undertaken in patients less than 6 months after GKS. Immunohistochemical characterization demonstrated the predominance of CD3-positive T cells in the lymphoid infiltration.Conclusions.Histopathological findings of the present study are consistent with a cellular immune response of natural killer cells against metastatic brain tumors, presumably stimulated by the ionizing energy of focused radiation.

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Gamma Interferon Assays Used in the Diagnosis of Tuberculosis

Clinical and Vaccine Immunology ◽

10.1128/cvi.00199-15 ◽

2015 ◽

Vol 22 (8) ◽

pp. 845-849 ◽

Cited By ~ 4

Author(s):

Rebecca T. Horvat

Keyword(s):

Immune Response ◽

Mycobacterium Tuberculosis ◽

Skin Test ◽

Blood Cells ◽

Diagnostic Tests ◽

Young Patients ◽

Active Tuberculosis ◽

Peripheral Blood Cells ◽

Content Type ◽

Cellular Immune

ABSTRACTTuberculosis (TB) is an ancient disease that has infected humans for thousands of years. However, despite diagnostic tests that detect the disease and effective therapy, there are still millions of people worldwide who are infected with TB. The first TB test used to detect infected patients was a skin test that identifies individuals actively infected with TB. This test used a mix of proteins from culture filtrates of the bacteriaMycobacterium tuberculosis. Recently, two new diagnostic tests have been introduced; these two new tests can detect TB infection in patients by challenging peripheral blood cells with specific TB proteins. These assays measure the cellular immune response to these proteins. This minireview evaluates the new assays and compares them to the use of the TB skin test. The use of these new assays may have some advantages in detecting individuals with active tuberculosis. However, there is still a role for the use of the skin test, especially in young patients.

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Engineering Mycobacteria for the Production of Self-Assembling Biopolyesters Displaying Mycobacterial Antigens for Use as a Tuberculosis Vaccine

Applied and Environmental Microbiology ◽

10.1128/aem.02289-16 ◽

2017 ◽

Vol 83 (5) ◽

Cited By ~ 4

Author(s):

Jason W. Lee ◽

Natalie A. Parlane ◽

Bernd H. A. Rehm ◽

Bryce M. Buddle ◽

Axel Heiser

Keyword(s):

Immune Response ◽

Mycobacterium Tuberculosis ◽

Global Health ◽

Mycobacterium Bovis ◽

Cellular Immune Response ◽

Pha Synthase ◽

Content Type ◽

Cellular Immune ◽

Mycobacterial Antigens ◽

Health Burdens

ABSTRACT Tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis or Mycobacterium bovis and still remains one of the world's biggest global health burdens. Recently, engineered polyhydroxyalkanoate (PHA) biobeads that were produced in both Escherichia coli and Lactococcus lactis and displayed mycobacterial antigens were found to induce significant cell-mediated immune responses in mice. We observed that such PHA beads contained host cell proteins as impurities, which we hypothesized to have the potential to induce immunity. In this study, we aimed to develop PHA beads produced in mycobacteria (mycobacterial PHA biobeads [MBB]) and test their potential as a TB vaccine in a mouse model. As a model organism, nonpathogenic Mycobacterium smegmatis was engineered to produce MBB or MBB with immobilized mycobacterial antigens Ag85A and ESAT-6 on their surface (A:E-MBB). Three key enzymes involved in the poly(3-hydroxybutyric acid) pathway, namely, β-ketothiolase (PhaA), acetoacetyl-coenzyme A reductase (PhaB), and PHA synthase (PhaC), were engineered into E. coli-Mycobacterium shuttle plasmids and expressed in trans. Immobilization of specific antigens to the surface of the MBB was achieved by creating a fusion with the PHA synthase which remains covalently attached to the polyester core, resulting in PHA biobeads displaying covalently immobilized antigens. MBB, A:E-MBB, and an M. smegmatis vector control (MVC) were used in a mouse immunology trial, with comparison to phosphate-buffered saline (PBS)-vaccinated and Mycobacterium bovis BCG-vaccinated groups. We successfully produced MBB and A:E-MBB and used them as vaccines to induce a cellular immune response to mycobacterial antigens. IMPORTANCE Tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis or Mycobacterium bovis and still remains one of the world's biggest global health burdens. In this study, we produced polyhydroxyalkanoate (PHA) biobeads in mycobacteria and used them as vaccines to induce a cellular immune response to mycobacterial antigens.

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