ORCID Profile
0000-0002-5690-2551
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Infectious Agents | Cellular Immunology | Medical Infection Agents (incl. Prions) | Animal Immunology | Microbiology |
Expanding Knowledge in the Agricultural and Veterinary Sciences | Zoonoses | Immune System and Allergy | Expanding Knowledge in the Medical and Health Sciences | Infectious Diseases
Publisher: Elsevier BV
Date: 02-2016
DOI: 10.1016/J.VACCINE.2016.01.030
Abstract: Influenza viruses are promising mucosal vaccine vectors for HIV but their use has been limited by difficulties in engineering the expression of large amounts of foreign protein. We developed recombinant influenza viruses incorporating the HIV-1 p24 gag capsid into the NS-segment of PR8 (H1N1) and X31 (H3N2) influenza viruses with the use of multiple 2A ribosomal skip sequences. Despite the insertion of a sizable HIV-1 gene into the influenza genome, recombinant viruses were readily rescued to high titers. Intracellular expression of p24 capsid was confirmed by in vitro infection assays. The recombinant influenza viruses were subsequently tested as mucosal vaccines in BALB/c mice. Recombinant viruses were attenuated and safe in immunized mice. Systemic and mucosal HIV-specific CD8 T-cell responses were elicited in mice that were immunized via intranasal route with a prime-boost regimen. Isolated HIV-specific CD8 T-cells displayed polyfunctional cytokine and degranulation profiles. Mice boosted via intravaginal route induced recall responses from the distal lung mucosa and developed heightened HIV-specific CD8 T-cell responses in the vaginal mucosa. These findings demonstrate the potential utility of recombinant influenza viruses as vaccines for mucosal immunity against HIV-1 infection.
Publisher: Elsevier BV
Date: 05-2017
DOI: 10.1016/J.VIRUSRES.2017.04.002
Abstract: Influenza A vaccine efficacy in the elderly is generally poor and so identification of novel molecular adjuvants to improve immunogenicity is important to reduce the overall burden of disease. Short non-coding RNAs, known as microRNAs (miRNAs) are known to regulate gene expression and have the potential to influence immune responses. One such miRNA, miR-155, has been shown to modulate T and B cell development and function. We incorporated miR-155 into the influenza A virus (IAV) genome creating a self-adjuvanting 'live vaccine' with the ability to modify immunogenicity. Infection of mice with a recombinant influenza virus encoding miR-155 in the NS gene segment altered epitope-specific expansion of influenza-specific CD8
Publisher: Proceedings of the National Academy of Sciences
Date: 03-2004
Abstract: Much of the CD8 + T cell response in H2 b mice with influenza pneumonia is directed at the nucleoprotein 366-374 (NP 366 ) and acid polymerase 224-233 (PA 224 ) peptides presented by the H2D b MHC class I glycoprotein. These D b NP 366 - and D b PA 224 -specific T cell populations are readily analyzed by staining with tetrameric complexes of MHC + peptide (tetramers) or by cytokine production subsequent to in vitro stimulation with the cognate peptides. The D b PA 224 -specific CD8 + effector T cells make more tumor necrosis factor (TNF) α than the comparable CD8 + D b NP 366 + set, a difference reflected in the greater sensitivity of the CD8 + D b PA 224 + population to TNF receptor (TNFR) 2-mediated apoptosis under conditions of in vitro culture. Freshly isolated CD8 + D b NP 366 + and CD8 + D b PA 224 + T cells from influenza-infected TNFR2 -/- mice produce higher levels of IFN-γ and TNF-α after in vitro stimulation with peptide, although the avidity of the T cell receptor-epitope interaction does not change. Increased numbers of both CD8 + D b PA 224 + and CD8 + D b NP 366 + T cells were recovered from the lungs (but not the spleens) of secondarily challenged TNFR2 -/- mice, a pattern that correlates with the profiles of TNFR expression in the TNFR2 +/+ controls. Thus, it seems that TNFR2-mediated editing of influenza-specific CD8 + T cells functions to limit the numbers of effectors that have localized to the site of pathology in the lung but does not modify the size of the less activated responder T cell populations in the spleen. Therefore, the massive difference in magnitude for the secondary, although not the primary, response to these D b NP 366 and D b PA 224 epitopes cannot be considered to reflect differential TNFR2-mediated T cell editing.
Publisher: Elsevier BV
Date: 03-2005
DOI: 10.1016/J.VACCINE.2004.10.030
Abstract: Despite decades of work, an effective HIV vaccine remains elusive. In an effort to elicit protective immunity, investigators have sought to define vaccines able to elicit durable HIV-specific B-cell and T-cell activities. Additionally, vaccines are sought which can induce antibodies of a variety of isotypes, as each isotype possesses unique attributes in terms of opsonization, Fc receptor binding capacity, complement fixation and location. One prominent new vaccine strategy, applied to numerous distinct antigenic systems is the prime boost-regimen, with DNA, vaccinia virus (VV), and/or purified recombinant protein. To examine the durability, location and isotype distribution of responses induced by prime-boost regimens, we tested successive immunizations with DNA, VV and protein (D-V-P), comparing three forms of protein inoculations: (i) purified protein administered intramuscularly with complete Freunds adjuvant, (ii) purified protein administered intranasally, and (iii) purified protein conjugated to oxidized mannan, administered intranasally. We found that all three protocols elicited serum antibodies of multiple isotypes, with serum IgA being most prominent among mice immunized with mannan-conjugated protein. All D-V-P protocols, regardless of protein form or route, also elicited antibody responses at mucosal surfaces. In bronchoalveolar lavage, a tendency toward IgA production was again most prominent in mice boosted with the protein-mannan conjugate. Both B-cell and T-cell responses were sustained for more than 1 year post-immunization following each form of vaccination. Contemporaneous with long-lasting serum and mucosal antibodies were antibody forming cells in the bone marrow of primed animals. Results highlight the D-V-P vaccination strategy as a promising approach for attaining durable, multi-isotype B-cell and T-cell activities toward HIV.
Publisher: Springer Science and Business Media LLC
Date: 07-2009
Publisher: Wiley
Date: 12-01-2012
DOI: 10.1096/FJ.11-193466
Publisher: Public Library of Science (PLoS)
Date: 05-03-2012
Publisher: Elsevier BV
Date: 2012
DOI: 10.1016/J.TIPS.2011.09.001
Abstract: Influenza A viral infections claim millions of lives worldwide and continue to impose a major burden on healthcare systems. Current pharmacological strategies to control influenza A virus-induced lung disease are problematic owing to antiviral resistance and the requirement for strain-specific vaccination. The production of reactive oxygen species (ROS), particularly superoxide, is an important host defence mechanism for killing invading pathogens. However, excessive superoxide may be detrimental following influenza A virus infection. Indeed, suppression of superoxide production by targeting the primary enzymatic source of superoxide in mammalian inflammatory cells, NADPH oxidase 2 (Nox2), markedly alleviates influenza A virus-induced lung injury and virus replication, irrespective of the infecting strain. Therefore, we propose that Nox2 oxidase inhibitors, in combination with current therapeutics (i.e. antivirals and vaccines), could be useful for suppression of influenza A virus-induced lung disease.
Publisher: Wiley
Date: 15-10-2015
DOI: 10.1002/RMV.1846
Publisher: Proceedings of the National Academy of Sciences
Date: 29-05-2003
Abstract: Influenza virus-specific CD8 + T cells generally recognize peptides derived from conserved, internal proteins that are not subject to antibody-mediated selection pressure. Prior exposure to any one influenza A virus (H1N1) can prime for a secondary CD8 + T cell response to a serologically different influenza A virus (H3N2). The protection afforded by this recall of established CD8 + T cell memory, although limited, is not negligible. Key characteristics of primary and secondary influenza-specific host responses are probed here with recombinant viruses expressing modified nucleoprotein (NP) and acid polymerase (PA) genes. Point mutations were introduced into the epitopes derived from the NP and PA such that they no longer bound the presenting H2D b MHC class I glycoprotein, and reassortant H1N1 and H3N2 viruses were made by reverse genetics. Conventional (C57BL/6J, H2 b , and Ig + / + ) and Ig - / - (μMT) mice were more susceptible to challenge with the single NP [HKx31 influenza A virus (HK)-NP] and PA (HK-PA) mutants, but unlike the Ig - / - mice, Ig + / + mice were surprisingly resistant to the HK-NP/-PA double mutant. This virus was found to promote an enhanced IgG response resulting, perhaps, from the delayed elimination of antigen-presenting cells. Antigen persistence also could explain the increase in size of the minor K b PB1 703 CD8 + T cell population in mice infected with the mutant viruses. The extent of such compensation was always partial, giving the impression that any virus-specific CD8 + T cell response operates within constrained limits. It seems that the relationship between protective humoral and cellular immunity is neither simple nor readily predicted.
Publisher: American Thoracic Society
Date: 2013
Publisher: Future Medicine Ltd
Date: 10-2014
DOI: 10.2217/FVL.14.69
Publisher: Elsevier BV
Date: 02-2007
Publisher: Public Library of Science (PLoS)
Date: 16-09-2010
Publisher: Springer Science and Business Media LLC
Date: 10-2009
Publisher: Elsevier BV
Date: 11-2018
DOI: 10.1038/S41385-018-0065-9
Abstract: The lung is the primary site of infection with the major human pathogen, Mycobacterium tuberculosis. Effective vaccines against M. tuberculosis must stimulate memory T cells to provide early protection in the lung. Recently, tissue-resident memory T cells (T
Publisher: Future Medicine Ltd
Date: 03-2010
DOI: 10.2217/FVL.10.3
Abstract: Seasonal influenza virus infection is a leading cause of illness and mortality in young children and the elderly each year. Current influenza vaccines generate protective antibody responses however, these must be given annually to provide protection against serologically distinct viruses. By contrast, CD8 + T cells are capable of recognizing conserved antigenic determinants within the influenza virion and, as such, may provide protection against a number of variant strains of the virus. CD8 + T cells play a critical key role in controlling and resolving influenza virus infections via the production of cytokines and cytolytic mediators. This article focuses on the induction of the influenza-specific CD8 + T-cell response and how these cells acquire and maintain effector function after induction. Moreover, we discuss how cytotoxic T-lymphocyte function correlates with protection following vaccination.
Publisher: Wiley
Date: 03-2010
Abstract: TCR repertoire ersity is important for the protective efficacy of CD8(+) T cells, limiting viral escape and cross-reactivity between unrelated epitopes. The exact mechanism for selection of restricted versus erse TCR repertoires is far from clear, although one thought is that the epitopes resembling self-peptides might select a limited array of TCR due to the deletion of autoreactive TCR. The molecule Aire promotes the expression of tissue-specific Ag on thymic medullary epithelial cells and the deletion of autoreactive cells, and in the absence of Aire autoreactive cells persist. However, the contribution of Aire-dependent peptides to the selection of the Ag-specific TCR repertoire remains unknown. In this study, we dissect restricted (D(b)NP(366)%(+)CD8(+)) and erse (D(b)PA(224)%(+)CD8(+), K(d)NP(147)%(+)CD8(+)) TCR repertoires responding to three influenza-derived peptides in Aire-deficient mice on both B6 and BALB/c backgrounds. Our study shows that the number, qualitative characteristics and TCR repertoires of all influenza-specific, D(b)NP(366)%(+)CD8(+), D(b)PA(224)%(+)CD8(+) and K(d)NP(147)%(+)CD8(+) T cells are not significantly altered in the absence of Aire. This provides the first demonstration that the selection of an Ag-specific T-cell repertoire is not significantly perturbed in the absence of Aire.
Publisher: Elsevier BV
Date: 10-2008
DOI: 10.1016/J.VACCINE.2008.07.102
Abstract: We report here on the use of a Sindbis virus-based DNA-launch RNA replicon vector (pSIN-HA) that expresses influenza hemagglutinin (HA) as an immunogen. Immunization of mice with pSIN-HA generated anti-HA antibody and CTL responses and resulted in lower lung viral titers after influenza challenge when compared to controls. Importantly, immunization with a low dose of pSIN-HA mediated significantly reduced lung viral titers following challenge at 43 weeks after the final immunization. In contrast, immunization with a non-replicon DNA vector expressing HA failed to mediate reduced lung viral titer at the same dose. This demonstrated the dose-sparing capacity of the SIN vector system and its ability to stimulate long-term memory responses, properties that are highly desirable in any vaccine formulation.
Publisher: Springer Science and Business Media LLC
Date: 19-10-2018
DOI: 10.1038/S41598-018-33605-6
Abstract: Current prophylactic and therapeutic strategies targeting human influenza viruses include vaccines and antivirals. Given variable rates of vaccine efficacy and antiviral resistance, alternative strategies are urgently required to improve disease outcomes. Here we describe the use of HiSeq deep sequencing to analyze host gene expression in primary human alveolar epithelial type II cells infected with highly pathogenic avian influenza H5N1 virus. At 24 hours post-infection, 623 host genes were significantly upregulated, including the cell adhesion molecule CEACAM1 . H5N1 virus infection stimulated significantly higher CEACAM1 protein expression when compared to influenza A PR8 (H1N1) virus, suggesting a key role for CEACAM1 in influenza virus pathogenicity. Furthermore, silencing of endogenous CEACAM1 resulted in reduced levels of proinflammatory cytokine/chemokine production, as well as reduced levels of virus replication following H5N1 infection. Our study provides evidence for the involvement of CEACAM1 in a clinically relevant model of H5N1 infection and may assist in the development of host-oriented antiviral strategies.
Publisher: The American Association of Immunologists
Date: 02-2007
DOI: 10.4049/JIMMUNOL.178.3.1285
Abstract: Influenza A virus infection of C57BL/6 (B6) mice is characterized by prominent CD8+ T cell responses to H2Db complexed with peptides from the viral nucleoprotein (NP366, ASNENMETM) and acid polymerase (PA224, SSLENFRAYV). An in vivo cytotoxicity assay that depends on the adoptive transfer of peptide-pulsed, syngeneic targets was used in this study to quantitate the cytotoxic potential of DbNP366- and DbPA224-specific acute and memory CD8+ T cells following primary or secondary virus challenge. Both T cell populations displayed equivalent levels of in vivo effector function when comparable numbers were transferred into naive B6 hosts. Cytotoxic activity following primary infection clearly correlated with the frequency of tetramer-stained CD8+ T cells. This relationship looked, however, to be less direct following secondary exposure, partly because the numbers of CD8+DbNP366+ T cells were greatly in excess. However, calculating the in vivo E:T ratios indicated that in vivo lysis, like many other biological functions, is threshold dependent. Furthermore, the capacity to eliminate peptide-pulsed targets was independent of the differentiation state (i.e., primary or secondary effectors) and was comparable for the two T cell specificities that were analyzed. These experiments provide insights that may be of value for adoptive immunotherapy, where careful consideration of both the activation state and the number of effector cells is required.
Publisher: American Society for Microbiology
Date: 04-2013
DOI: 10.1128/JVI.01342-12
Abstract: Hendra virus is a highly pathogenic zoonotic paramyxovirus in the genus Henipavirus . Thirty-nine outbreaks of Hendra virus have been reported since its initial identification in Queensland, Australia, resulting in seven human infections and four fatalities. Little is known about cellular host factors impacting Hendra virus replication. In this work, we demonstrate that Hendra virus makes use of a microRNA (miRNA) designated miR-146a, an NF-κB-responsive miRNA upregulated by several innate immune ligands, to favor its replication. miR-146a is elevated in the blood of ferrets and horses infected with Hendra virus and is upregulated by Hendra virus in human cells in vitro . Blocking miR-146a reduces Hendra virus replication in vitro , suggesting a role for this miRNA in Hendra virus replication. In silico analysis of miR-146a targets identified ring finger protein (RNF)11, a member of the A20 ubiquitin editing complex that negatively regulates NF-κB activity, as a novel component of Hendra virus replication. RNA interference-mediated silencing of RNF11 promotes Hendra virus replication in vitro , suggesting that increased NF-κB activity aids Hendra virus replication. Furthermore, overexpression of the IκB superrepressor inhibits Hendra virus replication. These studies are the first to demonstrate a host miRNA response to Hendra virus infection and suggest an important role for host miRNAs in Hendra virus disease.
Publisher: Elsevier BV
Date: 04-2018
DOI: 10.1016/J.VACCINE.2018.03.037
Abstract: Tuberculosis (TB) infection affects a quarter of the global population resulting in a large burden of TB disease and mortality. The long-term control of TB requires vaccines with greater efficacy and durability than the current Mycobacterium bovis Bacille Calmette-Guérin (BCG). Pulmonary immunization may increase and prolong immunity at the site of Mycobacterium tuberculosis infection. We have investigated recombinant influenza A viruses (rIAVs) expressing the p25 CD4
Publisher: Public Library of Science (PLoS)
Date: 17-11-2016
Publisher: Bentham Science Publishers Ltd.
Date: 04-2005
Abstract: A central obstacle to the design of a global HIV vaccine is viral ersity. Antigenic differences in envelope proteins result in distinct HIV serotypes, operationally defined such that antibodies raised against envelope molecules from one serotype will not bind envelope molecules from a different serotype. The existence of serotypes has presented a similar challenge to vaccine development against other pathogens. In such cases, antigenic ersity has been addressed by vaccine design. For ex le, the poliovirus vaccine includes three serotypes of poliovirus, and Pneumovax presents a cocktail of 23 pneumococcal variants to the immune system. It is likely that a successful vaccine for HIV must also comprise a cocktail of antigens. Here, data relevant to the development of cocktail vaccines, designed to harness erse, envelope-specific B-cell and T-cell responses, are reviewed.
Publisher: Public Library of Science (PLoS)
Date: 03-02-2011
Publisher: Elsevier BV
Date: 06-2004
Publisher: Elsevier BV
Date: 11-2009
DOI: 10.1016/J.VACCINE.2009.08.079
Abstract: Understanding CD8+ T cell responses generated by live virus vectors is critical for the rational design of next generation HIV CTL-based vaccines. We used recombinant influenza viruses expressing the HIV Env(311-320) peptide in the neuraminidase stalk to study response magnitude, cytokine production and repertoire ersity for the elicited CD8+ D(d)Env(311) CTL set. The insertion of the CD8+ D(d)Env(311) epitope into the NA stalk resulted in a decrease in viral fitness that was reflected in lower lung viral titres. While not affecting the magnitude of endogenous primary influenza-specific responses, the introduction of the D(d)Env(311) CD8+ T cell epitope altered the hierarchy of responses following secondary challenge. The CD8+ K(d)NP(147) response increased 9-fold in the spleen following secondary infection whereas the CD8+ D(d)Env(311) response increased 15-fold in the spleen. Moreover, this study is the first to describe narrowing of CD8+ TCR repertoire ersity in the context of an evolving secondary immune response against influenza A virus. Analysis of Vbeta bias for CD8+ D(d)Env(311) T cell responses showed a narrowing of CD8+ Vbeta8.1/8.2 D(d)Env(311) TCR repertoire ersity. This work further emphasizes the importance of understanding vaccine-induced CD8+ T cell responses.
Publisher: Microbiology Society
Date: 09-2014
Abstract: Difficulties associated with efficient delivery and targeting of miRNAs to cells is h ering the real world application of miRNA technology. This study utilized an influenza A-based delivery system to express miR-155 in order to knockdown SOCS1 mRNA. Using qPCR and dual luciferase technology we show that miR-155 delivery resulted in a significant increase in cellular miR-155 which facilitated a downregulation of SOCS1 gene expression and a functional increase in IL-6 and IFN-β cytokines.
Publisher: Wiley
Date: 09-01-2007
Abstract: Influenza A viruses that circulate normally in the human population cause a debilitating, though generally transient, illness that is sometimes fatal, particularly in the elderly. Severe complications arising from pandemic influenza or the highly pathogenic avian H5N1 viruses are often associated with rapid, massive inflammatory cell infiltration, acute respiratory distress, reactive hemophagocytosis and multiple organ involvement. Histological and pathological indicators strongly suggest a key role for an excessive host response in mediating at least some of this pathology. Here, we review the current literature on how various effector arms of the immune system can act deleteriously to initiate or exacerbate pathological damage in this viral pneumonia. Generally, the same immunological factors mediating tissue damage during the anti-influenza immune response are also critical for efficient elimination of virus, thereby posing a significant challenge in the design of harmless yet effective therapeutic strategies for tackling influenza virus.
Publisher: American Society for Microbiology
Date: 15-04-2013
DOI: 10.1128/JVI.02645-12
Abstract: There is an urgent need for a human immunodeficiency virus (HIV) vaccine that induces robust mucosal immunity. CD8 + cytotoxic T lymphocytes (CTLs) apply substantial antiviral pressure, but CTLs to in idual epitopes select for immune escape variants in both HIV in humans and SIV in macaques. Inducing multiple simian immunodeficiency virus (SIV)-specific CTLs may assist in controlling viremia. We vaccinated 10 Mane-A1 * 08401 + female pigtail macaques with recombinant influenza viruses expressing three Mane-A1 * 08401 -restricted SIV-specific CTL epitopes and subsequently challenged the animals, along with five controls, intravaginally with SIV mac251 . Seroconversion to the influenza virus vector resulted and small, but detectable, SIV-specific CTL responses were induced. There was a boost in CTL responses after challenge but no protection from high-level viremia or CD4 depletion was observed. All three CTL epitopes underwent a coordinated pattern of immune escape during early SIV infection. CTL escape was more rapid in the vaccinees than in the controls at the more dominant CTL epitopes. Although CTL escape can incur a “fitness” cost to the virus, a putative compensatory mutation 20 amino acids upstream from an immunodominant Gag CTL epitope also evolved soon after the primary CTL escape mutation. We conclude that vaccines based only on CTL epitopes will likely be undermined by rapid evolution of both CTL escape and compensatory mutations. More potent and possibly broader immune responses may be required to protect pigtail macaques from SIV.
Publisher: American Society for Microbiology
Date: 08-2009
DOI: 10.1128/JVI.00470-09
Abstract: There is an urgent need for human immunodeficiency virus (HIV) vaccines that induce robust mucosal immunity. Influenza A viruses (both H1N1 and H3N2) were engineered to express simian immunodeficiency virus (SIV) CD8 T-cell epitopes and evaluated following administration to the respiratory tracts of 11 pigtail macaques. Influenza virus was readily detected from respiratory tract secretions, although the infections were asymptomatic. Animals seroconverted to influenza virus and generated CD8 and CD4 T-cell responses to influenza virus proteins. SIV-specific CD8 T-cell responses bearing the mucosal homing marker β7 integrin were induced by vaccination of naïve animals. Further, SIV-specific CD8 T-cell responses could be boosted by recombinant influenza virus-SIV vaccination of animals with already-established SIV infection. Sequential vaccination with influenza virus-SIV recombinants of different subtypes (H1N1 followed by H3N2 or vice versa) produced only a limited boost in immunity, probably reflecting T-cell immunity to conserved internal proteins of influenza A virus. SIV challenge of macaques vaccinated with an influenza virus expressing a single SIV CD8 T cell resulted in a large anamnestic recall CD8 T-cell response, but immune escape rapidly ensued and there was no impact on chronic SIV viremia. Although our results suggest that influenza virus-HIV vaccines hold promise for the induction of mucosal immunity to HIV, broader antigen cover will be needed to limit cytotoxic T-lymphocyte escape.
Publisher: Springer Science and Business Media LLC
Date: 08-2018
DOI: 10.1038/S41598-018-29944-Z
Abstract: Low pathogenicity avian influenza viruses (LPAIVs) are generally asymptomatic in their natural avian hosts. LPAIVs can evolve into highly pathogenic forms, which can affect avian and human populations with devastating consequences. The switch to highly pathogenic avian influenza virus (HPAIV) from LPAIV precursors requires the acquisition of multiple basic amino acids in the haemagglutinin cleavage site (HACS) motif. Through reverse genetics of an H5N1 HPAIV, and experimental infection of chickens, we determined that viruses containing five or more basic amino acids in the HACS motif were preferentially selected over those with three to four basic amino acids, leading to rapid replacement with virus types containing extended HACS motifs. Conversely, viruses harbouring low pathogenicity motifs containing two basic amino acids did not readily evolve to extended forms, suggesting that a single insertion of a basic amino acid into the cleavage site motif of low-pathogenic viruses may lead to escalating selection for extended motifs. Our results may explain why mid-length forms are rarely detected in nature. The stability of the short motif suggests that pathogenicity switching may require specific conditions of intense selection pressure (such as with high host density) to boost selection of the initial mid-length HACS forms.
Publisher: Elsevier BV
Date: 11-2013
DOI: 10.1038/MI.2013.1
Abstract: We have established that mucosal immunization can generate high-avidity human immunodeficiency virus (HIV)-specific CD8(+) T cells compared with systemic immunization, and interleukin (IL)-13 is detrimental to the functional avidity of these T cells. We have now constructed two unique recombinant HIV-1 vaccines that co-express soluble or membrane-bound forms of the IL-13 receptor α2 (IL-13Rα2), which can "transiently" block IL-13 activity at the vaccination site causing wild-type animals to behave similar to an IL-13 KO animal. Following intranasal/intramuscular prime-boost immunization, these IL-13Rα2-adjuvanted vaccines have shown to induce (i) enhanced HIV-specific CD8(+) T cells with higher functional avidity, with broader cytokine/chemokine profiles and greater protective immunity using a surrogate mucosal HIV-1 challenge, and also (ii) excellent multifunctional mucosal CD8(+) T-cell responses, in the lung, genito-rectal nodes (GN), and Peyer's patch (PP). Data revealed that intranasal delivery of these IL-13Rα2-adjuvanted HIV vaccines recruited large numbers of unique antigen-presenting cell subsets to the lung mucosae, ultimately promoting the induction of high-avidity CD8(+) T cells. We believe our novel IL-13R cytokine trap vaccine strategy offers great promise for not only HIV-1, but also as a platform technology against range of chronic infections that require strong sustained high-avidity mucosal/systemic immunity for protection.
Publisher: Wiley
Date: 23-12-2015
Abstract: Tuberculosis remains a global health problem, in part due to failure of the currently available vaccine, BCG, to protect adults against pulmonary forms of the disease. We explored the impact of pulmonary delivery of recombinant influenza A viruses (rIAVs) on the induction of Mycobacterium tuberculosis (M. tuberculosis)-specific CD4(+) and CD8(+) T-cell responses and the resultant protection against M. tuberculosis infection in C57BL/6 mice. Intranasal infection with rIAVs expressing a CD4(+) T-cell epitope from the Ag85B protein (PR8.p25) or CD8(+) T-cell epitope from the TB10.4 protein (PR8.TB10.4) generated strong T-cell responses to the M. tuberculosis-specific epitopes in the lung that persisted long after the rIAVs were cleared. Infection with PR8.p25 conferred protection against subsequent M. tuberculosis challenge in the lung, and this was associated with increased levels of poly-functional CD4(+) T cells at the time of challenge. By contrast, infection with PR8.TB10.4 did not induce protection despite the presence of IFN-γ-producing M. tuberculosis-specific CD8(+) T cells in the lung at the time of challenge and during infection. Therefore, the induction of pulmonary M. tuberculosis epitope-specific CD4(+), but not CD8(+) T cells, is essential for protection against acute M. tuberculosis infection in the lung.
Publisher: Elsevier BV
Date: 11-2008
DOI: 10.1016/J.PHARMTHERA.2008.08.007
Abstract: Antigen-specific CD8+ T cells play an important role in virus clearance. Here we review the current understanding of influenza virus-specific CD8+ T cell immunity in experimental mouse models and humans. The characteristics and nature of CD8+ T cell killing are discussed, as is the selection and maintenance of the influenza-specific effector and memory repertoires. Consideration is given to vaccine strategies and to the effects of ageing. Understanding the complexities of CD8+ T cell mediated immunity and memory has the potential for improving vaccine design, particularly to combat pandemics caused by newly emerging influenza viruses.
Publisher: Frontiers Media SA
Date: 2011
Abstract: Sialic acids (SA) usually linked to galactose (Gal) in an α2,6- or α2,3-configuration are considered the main cell receptors for influenza viruses, in particular for their hemagglutinins (HA). The typing of influenza virus HA receptor selectivity is relevant for understanding the transmissibility of avian and swine viruses to the human population. In this study we developed a simple and inexpensive gel-capture assay (GCA) of the influenza virus HA receptor-binding selectivity. Its principle is the binding of soluble influenza virus to pentasaccharide analogs, representatives of receptors of human and avian influenza viruses, immobilized on a gel resin. The human and avian analogs consisted of a sialyllactose-N-tetraose c (LSTc) [Neu5Ac(α2,6)Gal(β1-3)GlcNAc(β1-3)Gal(β1-4)Glc] and a sialyllactose-N-tetraose a (LSTa) [Neu5Ac(α2,3)Gal(β1-3)GlcNAc(β1-3)Gal(β1-4)Glc], respectively. Following equilibration, the unbound virus is washed away and the bound one is assayed via HA by densitometry as a function of the analog concentration. Using GCA, the receptor selectivity of three influenza viruses of different HA subtype was investigated. The results showed that the egg-adapted A/California/07/2009 (H1N1) virus exhibited an avian α2,3-linked LSTa selectivity, however, it retained the ability to bind to the α2,6-linked LSTc human receptor analog. Influenza B virus B/Florida/4/2006 showed α2,6-linked LSTc selectivity and a poor α2,3-linked LSTa avidity. The H3N2 virus A/Wisconsin/15/2009 displayed almost comparable avidity for both receptor analogs with a marginally greater α2,3-linked LSTa avidity. The described assay protocol provides a simple and rapid method for the characterization of influenza virus HA receptor binding selectivity.
Publisher: American Society for Microbiology
Date: 04-2005
DOI: 10.1128/JVI.79.7.4329-4339.2005
Abstract: The extent to which CD8 + T cells specific for other antigens expand to compensate for the mutational loss of the prominent D b NP 366 and D b PA 224 epitopes has been investigated using H1N1 and H3N2 influenza A viruses modified by reverse genetics. Significantly increased numbers of CD8 + K b PB1 703 + , CD8 + K b NS2 114 + , and CD8 + D b PB1-F2 62 + T cells were found in the spleen and in the inflammatory population recovered by bronchoalveolar lavage from mice that were first given the −NP−PA H1N1 virus intraperitoneally and then challenged intranasally with the homologous H3N2 virus. The effect was less consistent when this prime-boost protocol was reversed. Also, though the quality of the response measured by cytokine staining showed some evidence of modification when these minor CD8 + -T-cell populations were forced to play a more prominent part, the effects were relatively small and no consistent pattern emerged. The magnitude of the enhanced clonal expansion following secondary challenge suggested that the prime-boost with the −NP−PA viruses gave a response overall that was little different in magnitude from that following comparable exposure to the unmanipulated viruses. This was indeed shown to be the case when the total response was measured by ELISPOT analysis with virus-infected cells as stimulators. More surprisingly, the same effect was seen following primary challenge, though in idual analysis of the CD8 + K b PB1 703 + , CD8 + K b NS2 114 + , and CD8 + D b PB1-F2 62 + sets gave no indication of compensatory expansion. A possible explanation is that novel, as yet undetected epitopes emerge following primary exposure to the −NP−PA deletion viruses. These findings have implications for both natural infections and vaccines.
Publisher: The American Association of Immunologists
Date: 07-2013
Abstract: In iduals infected with mycobacteria are likely to experience episodes of concurrent infections with unrelated respiratory pathogens, including the seasonal or pandemic circulating influenza A virus strains. We analyzed the impact of influenza A virus and mycobacterial respiratory coinfection on the development of CD8 T cell responses to each pathogen. Coinfected mice exhibited reduced frequency and numbers of CD8 T cells specific to Mycobacterium bovis bacille Calmette-Guérin (BCG) in the lungs, and the IFN-γ CD8 T cell response to BCG-encoded OVA was decreased in the lungs of coinfected mice, when compared with mice infected with BCG alone. Moreover, after 2 wk of infection, mice coinfected with both pathogens showed a significant increase in the number of mycobacteria present in the lung compared with mice infected with BCG only. Following adoptive transfer into coinfected mice, transgenic CD8 T cells specific for OVA257–264 failed to proliferate as extensively in the mediastinal lymph nodes as in mice infected only with BCG-OVA. Also noted was a reduction in the proliferation of BCG-specific CD4 transgenic T cells in mice coinfected with influenza compared with mice infected with BCG alone. Furthermore, phenotypic analysis of CD11c+ dendritic cells from mediastinal lymph nodes of the infected mice showed that coinfection was associated with decreased surface expression of MHC class II and class I. Thus, concurrent pulmonary infection with influenza A virus is associated with decreased MHC expression on dendritic cells, reduced activation of BCG-specific CD4 and CD8 T cells, and impaired clearance of mycobacteria.
Publisher: Proceedings of the National Academy of Sciences
Date: 05-06-2007
Abstract: The rapid recall of influenza virus-specific CD8 + T cell effector function is protective, although our understanding of T cell memory remains incomplete. Recent debate has focused particularly on the CD62L lymph node homing receptor. The present analysis shows that although functional memory can be established from both CD62L hi and CD62L lo CD8 + T cell subsets soon after initial encounter between naïve precursors and antigen, the optimal precursors are CD8 + CD44 hi CD25 lo immune lymphocytes isolated from draining lymph nodes on day 3.5 after influenza virus infection. Analysis of primed T cells at different times after challenge indicates that the capacity to transfer memory is diminished at the peak of the primary cytotoxic T lymphocyte response, challenging speculations that the transition to memory first requires full differentiation to effector status. It seems that location rather than CD62Lhi/lo phenotype may be the more profitable focus for further dissection of the early establishment of T cell memory.
No related organisations have been discovered for John Stambas.
Start Date: 10-2012
End Date: 12-2012
Amount: $520,000.00
Funder: Australian Research Council
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