scholarly journals Therapeutic Efficacy of a Conjugate Vaccine Containing a Peptide Mimotope of Cryptococcal Capsular Polysaccharide Glucuronoxylomannan

2008 ◽  
Vol 15 (8) ◽  
pp. 1176-1187 ◽  
Author(s):  
Kausik Datta ◽  
Andrew Lees ◽  
Liise-anne Pirofski
Keyword(s):  
Mouse Strain ◽  
Capsular Polysaccharide ◽  
Interleukin 10 ◽  
Infection Model ◽  
Carrier Protein ◽  
Degree Of Protection ◽  
Protein Conjugates ◽  
Heat Treated ◽  
Ifn Γ ◽  
Established Infection

ABSTRACTVaccination with P13, a peptide mimotope of the cryptococcal capsular polysaccharide glucuronoxylomannan (GXM), has been shown to confer protection against a subsequent lethalCryptococcus neoformanschallenge. In this study, we sought to investigate whether P13-based vaccines could be effective in an already-established infection. To address this question, we developed a systemic chronic cryptococcal infection model. We vaccinated chronically infected mice with P13-protein conjugates and monitored their survival. Compared to the controls, the conjugates prolonged the survival of chronically infected mice. The degree of protection was a function of the mouse strain (BALB/c or C57BL/6), the carrier protein (tetanus toxoid or diphtheria toxoid), and the route of infection (intraperitoneal or intravenous). Serum GXM levels were correlated with the day of death, but the correlation was driven by the carrier protein and mouse strain. The passive transfer of heat-treated sera from P13 conjugate-vaccinated mice conferred protection to naïve BALB/c mice, indicating that antibody immunity could contribute to protection. The measurement of peripheral blood cytokine (gamma interferon [IFN-γ], interleukin-10 [IL-10], and IL-6) gene expression showed that P13 conjugate-vaccinated BALB/c and C57BL/6 mice mounted a strong Th2 (IL-10)-like response relative to the Th1 (IFN-γ)-like response, with the degree depending on the mouse strain and carrier protein. Taken together, our data suggest that a vaccine could hold promise in the setting of chronic cryptococcosis, and that vaccine efficacy could depend on immunomodulation and augmentation of the natural immune response of the host.

scholarly journals Early Cytokine Production Is Associated with Protection from Murine Cerebral Malaria

2005 ◽  
Vol 73 (9) ◽  
pp. 5645-5653 ◽  
Author(s):  
Andrew J. Mitchell ◽  
Anna M. Hansen ◽  
Leia Hee ◽  
Helen J. Ball ◽  
Sarah M. Potter ◽  
...  
Keyword(s):  
Cerebral Malaria ◽  
Cytokine Production ◽  
Nk Cell ◽  
Interleukin 10 ◽  
Infection Model ◽  
Nkt Cell ◽  
Immune Mediated ◽  
Cerebral Pathology ◽  
Early Production ◽  
Ifn Γ

ABSTRACT Cerebral malaria (CM) is an infrequent but serious complication of Plasmodium falciparum infection in humans. Animal and human studies suggest that the pathogenesis of CM is immune mediated, but the precise mechanisms leading to cerebral pathology are unclear. In mice, infection with Plasmodium berghei ANKA results in CM on day 6 postinoculation (p.i.), while infection with the closely related strain P. berghei K173 does not result in CM. Infection with P. berghei K173 was associated with increased plasma gamma interferon (IFN-γ) at 24 h p.i. and with increased splenic and hepatic mRNAs for a range of cytokines (IFN-γ, interleukin-10 [IL-10], and IL-12) as well as the immunoregulatory enzyme indoleamine 2,3-dioxygenase. In contrast, P. berghei ANKA infection was associated with an absence of cytokine production at 24 h p.i. but a surge of IFN-γ production at 3 to 4 days p.i. When mice were coinfected with both ANKA and K173, they produced an early cytokine response, including a burst of IFN-γ at 24 h p.i., in a manner similar to animals infected with P. berghei K173 alone. These coinfected mice failed to develop CM. In addition, in a low-dose P. berghei K173 infection model, protection from CM was associated with early production of IFN-γ. Early IFN-γ production was present in NK-cell-depleted, γδ-cell-depleted, and Jα281−/− (NKT-cell-deficient) mice but absent from β2-microglobulin mice that had been infected with P. berghei K173. Taken together, the results suggest that the absence of a regulatory pathway involving IFN-γ and CD8+ T cells in P. berghei ANKA infection allows the development of cerebral immunopathology.

scholarly journals Synthesis and immunological evaluation of protein conjugates ofNeisseria meningitidisX capsular polysaccharide fragments

2014 ◽  
Vol 10 ◽  
pp. 2367-2376 ◽  
Author(s):  
Laura Morelli ◽  
Damiano Cancogni ◽  
Marta Tontini ◽  
Alberto Nilo ◽  
Sara Filippini ◽  
...  
Keyword(s):  
Neisseria Meningitidis ◽  
Capsular Polysaccharide ◽  
Vaccine Development ◽  
Carrier Protein ◽  
Immunological Activity ◽  
Preclinical Stage ◽  
Protein Conjugates ◽  
Chemical Conjugation ◽  
Immunological Evaluation

A vaccine to prevent infections from the emergingNeisseria meningitidisX (MenX) is becoming an urgent issue. Recently MenX capsular polysaccharide (CPS) fragments conjugated to CRM197as carrier protein have been confirmed at preclinical stage as promising candidates for vaccine development. However, more insights about the minimal epitope required for the immunological activity of MenX CPS are needed. We report herein the chemical conjugation of fully synthetic MenX CPS oligomers (monomer, dimer, and trimer) to CRM197. Moreover, improvements in some crucial steps leading to the synthesis of MenX CPS fragments are described. Following immunization with the obtained neoglycoconjugates, the conjugated trimer was demonstrated as the minimal fragment possessing immunogenic activity, even though significantly lower than a pentadecamer obtained from the native polymer and conjugated to the same protein. This finding suggests that oligomers longer than three repeating units are possibly needed to mimic the activity of the native polysaccharide.

scholarly journals Preparation, characterization, and immunogenicity of Haemophilus influenzae type b polysaccharide-protein conjugates.

1980 ◽  
Vol 152 (2) ◽  
pp. 361-376 ◽  
Author(s):  
R Schneerson ◽  
O Barrera ◽  
A Sutton ◽  
J B Robbins
Keyword(s):  
Haemophilus Influenzae ◽  
Capsular Polysaccharide ◽  
Bactericidal Effect ◽  
Haemophilus Influenzae Type ◽  
Mouse Strains ◽  
Carrier Protein ◽  
Haemophilus Influenzae Type B ◽  
Type B ◽  
Protein Conjugates ◽  
Carrier Molecule

A method is presented for covalently bonding Haemophilus influenzae type b capsular polysaccharide (HIB Ps) to several proteins. The method is efficient and relies upon the use of adipic dihydrazide as a spacer between the capsular polysaccharide and the carrier protein. In contrast to the poor immunogenicity of the purified HIB Ps in mice and rabbits, the HIB Ps-protein conjugates induced serum anti-type b antibodies having bactericidal activity at levels shown to be protective in humans when low doses were injected subcutaneously in a saline solution. The antibody response in mice was related to the dose of the conjugates, increased with the number of injections, and could be primed by the previous injection of the carrier protein. The HIB Ps-protein conjugates were immunogenic in three different mouse strains. The importance of the carrier molecule for the enhanced immunogenicity of the HIB Ps-protein conjugates was shown by the failure of HIB Ps hybrids prepared with either the homologous polysaccharide or pneumococcus type 3 polysaccharide to induce antibodie in mice. Rabbits injected with the HIB Ps-protein conjugates emulsified in Freund's adjuvant produced high levels of serum anti-type b antibodies which induced a bactericidal effect upon H. influenzae type b organisms. It is proposed that the HIB Ps component of the polysaccharide protein conjugates has been converted to a thymic-dependent immunogen. This method may be used to prepare protein-polysaccharide conjugates with HIB Ps and other polysaccharides to be considered for human use.

scholarly journals Phage Resistance Is Associated with Decreased Virulence in KPC-Producing Klebsiella pneumoniae of the Clonal Group 258 Clade II Lineage

2021 ◽  
Vol 9 (4) ◽  
pp. 762
Author(s):  
Lucia Henrici De Angelis ◽  
Noemi Poerio ◽  
Vincenzo Di Pilato ◽  
Federica De Santis ◽  
Alberto Antonelli ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Parental Strain ◽  
Bacterial Infections ◽  
Capsular Polysaccharide ◽  
Galleria Mellonella ◽  
Bacterial Pathogen ◽  
Phage Resistance ◽  
Infection Model ◽  
Lytic Phage ◽  
Susceptible Host

Phage therapy is now reconsidered with interest in the treatment of bacterial infections. A major piece of information for this application is the definition of the molecular targets exploited by phages to infect bacteria. Here, the genetic basis of resistance to the lytic phage φBO1E by its susceptible host Klebsiella pneumoniae KKBO-1 has been investigated. KKBO-1 phage-resistant mutants were obtained by infection at high multiplicity. One mutant, designated BO-FR-1, was selected for subsequent experiments, including virulence assessment in a Galleria mellonella infection model and characterization by whole-genome sequencing. Infection with BO-FR-1 was associated with a significantly lower mortality when compared to that of the parental strain. The BO-FR-1 genome differed from KKBO-1 by a single nonsense mutation into the wbaP gene, which encodes a glycosyltransferase involved in the first step of the biosynthesis of the capsular polysaccharide (CPS). Phage susceptibility was restored when BO-FR-1 was complemented with the constitutive wbaP gene. Our results demonstrated that φBO1E infects KKBO-1 targeting the bacterial CPS. Interestingly, BO-FR-1 was less virulent than the parental strain, suggesting that in the context of the interplay among phage, bacterial pathogen and host, the emergence of phage resistance may be beneficial for the host.

scholarly journals Stimulation of Interleukin-10 Production by Acidic β-Lactoglobulin-Derived Peptides Hydrolyzed with Lactobacillus paracasei NCC2461 Peptidases

2004 ◽  
Vol 11 (2) ◽  
pp. 266-271 ◽  
Author(s):  
Guénolée Prioult ◽  
Sophie Pecquet ◽  
Ismail Fliss
Keyword(s):  
Oral Tolerance ◽  
Immunosuppressive Agents ◽  
Interleukin 10 ◽  
Lactobacillus Paracasei ◽  
In Vitro Hydrolysis ◽  
Ifn Γ ◽  
Immunomodulatory Peptides ◽  
Β Lactoglobulin

ABSTRACT We have previously demonstrated that Lactobacillus paracasei NCC2461 may help to prevent cow's milk allergy in mice by inducing oral tolerance to β-lactoglobulin (BLG). To investigate the mechanisms involved in this beneficial effect, we examined the possibility that L. paracasei induces tolerance by hydrolyzing BLG-derived peptides and liberating peptides that stimulate interleukin-10 (IL-10) production. L. paracasei peptidases have been shown to hydrolyze tryptic-chymotryptic peptides from BLG, releasing numerous small peptides with immunomodulating properties. We have now shown that acidic tryptic-chymotryptic peptides stimulate splenocyte proliferation and gamma interferon (IFN-γ) production in vitro. Hydrolysis of these peptides with L. paracasei peptidases repressed the lymphocyte stimulation, up-regulated IL-10 production, and down-regulated IFN-γ and IL-4 secretion. L. paracasei NCC2461 may therefore induce oral tolerance to BLG in vivo by degrading acidic peptides and releasing immunomodulatory peptides stimulating regulatory T cells, which function as major immunosuppressive agents by secreting IL-10.

Analysis of hapten-carrier protein conjugates by nondenaturing gel electrophoresis

1993 ◽  
Vol 164 (2) ◽  
pp. 245-253 ◽  
Author(s):  
C. Kamps-Holtzapple ◽  
R.J. Carlin ◽  
C. Sheffield ◽  
L. Kubena ◽  
L. Stanker ◽  
...  
Keyword(s):  
Gel Electrophoresis ◽  
Carrier Protein ◽  
Protein Conjugates

Variable linking region immunogenicity using malarial peptide carrier protein conjugates of defined composition

1990 ◽  
Vol 26 (3) ◽  
pp. 285-290 ◽  
Author(s):  
Graham Lloyd Jones ◽  
Lisa Spencer ◽  
Rodney Mollard ◽  
Allan Saul
Keyword(s):  
Carrier Protein ◽  
Protein Conjugates ◽  
Peptide Carrier

scholarly journals Interdependency of Interleukin-10 and Interleukin-12 in Regulation of T-Cell Differentiation and Effector Function of Monocytes in Response to Stimulation withCryptococcus neoformans

2001 ◽  
Vol 69 (10) ◽  
pp. 6064-6073 ◽  
Author(s):  
Cinzia Retini ◽  
Thomas R. Kozel ◽  
Donatella Pietrella ◽  
Claudia Monari ◽  
Francesco Bistoni ◽  
...  
Keyword(s):  
T Cells ◽  
Critical Role ◽  
Principal Component ◽  
Interleukin 10 ◽  
Interleukin 12 ◽  
T Helper ◽  
Ifn Γ ◽  
Capsular Material ◽  
Type Response

ABSTRACT We previously demonstrated that the principal component of capsular material of Cryptococcus neoformans, glucuronoxylomannan (GXM), induces interleukin-10 (IL-10) secretion from human monocytes. Here we report that encapsulation of the yeast with GXM is able to down-regulate interleukin-12 (IL-12) production by monocytes that would normally occur in the absence of encapsulation. This phenomenon appeared to be the result of inhibition of the phagocytic process by encapsulation with GXM as well as of negative signals such as IL-10 secretion produced by interaction of GXM with leukocytes. Decreased secretion of IL-12 correlated with decreased release of gamma interferon (IFN-γ) from T cells, suggesting a role for encapsulation with GXM in hindering a T helper type 1 (Th1) response. This is supported by the ability of encapsulation with GXM to limit increased expression of B7-1 costimulatory molecules that otherwise might limit IL-10 secretion. Endogenous IL-10 played a critical role in modulatory activity associated with encapsulation with GXM. Blocking IL-10 with monoclonal antibody to IL-10 resulted in increased (i) IL-12 secretion, (ii) IFN-γ release from T cells, and (iii) killing of C. neoformans by monocytes. These results suggest that encapsulation with GXM limits development of a protective Th1-type response, an inhibitory process in which IL-10 plays a critical role. Scavengers of GXM and/or IL-10 could be useful in a protective Th1-type response in patients with cryptococcosis.

scholarly journals Expression of the Nitric Oxide Synthase 2 Gene Is Not Essential for Early Control of Mycobacterium tuberculosis in the Murine Lung

2000 ◽  
Vol 68 (12) ◽  
pp. 6879-6882 ◽  
Author(s):  
Andrea M. Cooper ◽  
John E. Pearl ◽  
Jason V. Brooks ◽  
Stefan Ehlers ◽  
Ian M. Orme
Keyword(s):  
Nitric Oxide ◽  
Mycobacterium Tuberculosis ◽  
Nitric Oxide Synthase ◽  
Low Dose ◽  
Interleukin 12 ◽  
Infection Model ◽  
Rapid Progression ◽  
Ifn Γ ◽  
Nitric Oxide Synthase 2 ◽  
Oxide Synthase

ABSTRACT The interleukin-12 and gamma interferon (IFN-γ) pathway of macrophage activation plays a pivotal role in controlling tuberculosis. In the murine model, the generation of supplementary nitric oxide by the induction of the nitric oxide synthase 2 (NOS2) gene product is considered the principal antimicrobial mechanism of IFN-γ-activated macrophages. Using a low-dose aerosol-mediated infection model in the mouse, we have investigated the role of nitric oxide in controllingMycobacterium tuberculosis in the lung. In contrast to the consequences of a systemic infection, a low dose of bacteria introduced directly into the lungs of mice lacking the NOS2 gene is controlled almost as well as in intact animals. This is in contrast to the rapid progression of disease in mice lacking IFN-γ or a key member of the IFN signaling pathway, interferon regulatory factor 1. Thus while IFN-γ is pivotal in early control of bacterial growth in the lung, this control does not completely depend upon the expression of the NOS2 gene. The absence of inducible nitric oxide in the lung does, however, result in increased polymorphonuclear cell involvement and eventual necrosis in the pulmonary granulomas of the infected mice lacking the NOS2 gene.

scholarly journals A Defect in Interleukin-10 Leads to Enhanced Malarial Disease in Plasmodium chabaudi chabaudi Infection in Mice

1999 ◽  
Vol 67 (9) ◽  
pp. 4435-4442 ◽  
Author(s):  
Ching Li ◽  
Inés Corraliza ◽  
Jean Langhorne
Keyword(s):  
Body Weight ◽  
Knockout Mice ◽  
Interleukin 10 ◽  
Plasmodium Chabaudi ◽  
Double Knockout ◽  
Direct Stimulation ◽  
Necrosis Factor Alpha ◽  
Glucose Levels ◽  
Tnf Α ◽  
Ifn Γ

ABSTRACT Infection of interleukin-10 (IL-10)-nonexpressing (IL-10−/−) mice with Plasmodium chabaudi chabaudi (AS) leads to exacerbated pathology in female mice and death in a proportion of them. Hypoglycemia, hypothermia, and loss in body weight were significantly greater in female IL-10−/−mice than in male knockout mice and all wild-type (WT) mice during the acute phase of infection. At this time, both female and male IL-10−/− mice produced more gamma interferon (IFN-γ), tumor necrosis factor alpha (TNF-α), and IL-12p40 mRNA than their respective WT counterparts. Inactivation of IFN-γ in IL-10−/− mice by the injection of anti-IFN-γ antibodies or by the generation of IL-10−/− IFN-γ receptor−/− double-knockout mice resulted in reduced mortality but did not affect body weight, temperature, or blood glucose levels. The data suggest that IFN-γ-independent pathways may be responsible for these pathological features of P. chabaudimalaria and may be due to direct stimulation of TNF-α by the parasite. Since male and female knockout mice both produce more inflammatory cytokines than their WT counterparts, it is likely that the mortality seen in females is due to the nature or magnitude of the response to these cytokines rather than the amount of IFN-γ or TNF-α produced.

Sign in / Sign up

Export Citation Format

Share Document