ORCID Profile
0000-0002-9259-7873
Current Organisation
James Cook University
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Publisher: Public Library of Science (PLoS)
Date: 25-07-2007
Publisher: Wiley
Date: 23-03-2021
DOI: 10.1002/AME2.12159
Abstract: Tuberculosis (TB) is one of the deadliest infectious diseases in the world. The metabolic disease type 2 diabetes (T2D) significantly increases the risk of developing active TB. Effective new TB vaccine candidates and novel therapeutic interventions are required to meet the challenges of global TB eradication. Recent evidence suggests that the microbiota plays a significant role in how the host responds to infection, injury and neoplastic changes. Animal models that closely reflect human physiology are crucial in assessing new treatments and to decipher the underlying immunological defects responsible for increased TB susceptibility in comorbid patients. In this study, using a diet‐induced murine T2D model that reflects the etiopathogenesis of clinical T2D and increased TB susceptibility, we investigated how the intestinal microbiota may impact the development of T2D, and how the gut microbial composition changes following a very low‐dose aerosol infection with Mycobacterium tuberculosis ( Mtb ). Our data revealed a substantial intestinal microbiota dysbiosis in T2D mice compared to non‐diabetic animals. The observed differences were comparable to previous clinical reports in TB patients, in which it was shown that Mtb infection causes rapid loss of microbial ersity. Furthermore, ersity index and principle component analyses demonstrated distinct clustering of Mtb ‐infected non‐diabetic mice vs. Mtb ‐infected T2D mice. Our findings support a broad applicability of T2D mice as a tractable small animal model for studying distinct immune parameters, microbiota and the immune‐metabolome of TB/T2D comorbidity. This model may also enable answers to be found to critical outstanding questions about targeted interventions of the gut microbiota and the gut‐lung axis.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 06-03-2020
Abstract: We provide an empirical model to evaluate and rank data obtained from preclinical tuberculosis vaccine studies.
Publisher: Elsevier BV
Date: 02-2014
DOI: 10.1016/J.MIB.2013.12.004
Abstract: Salmonella enterica subsp. enterica includes several very important human serovars including Typhi, Paratyphi, Typhimurium and Enteritidis. These bacteria cause a significant global burden of disease, typically classified into enteric fever, gastroenteritis and, more recently, invasive non-typhoidal salmonellosis (iNTS). Vaccines have been developed for one of these serovars, S. Typhi and the recent increase in iNTS cases has resulted in a push to develop new vaccines that will inhibit disease by S. Typhimurium and S. Enteritidis, the most common iNTS S. enterica serovars. The development of new human vaccines has been informed by studies in the murine model of typhoid fever based on S. Typhimurium infections of very 'sensitive' (Nr -1(S)) mice, which has some obvious deficiencies, not the least that antibodies protect humans against S. Typhi infection but are only weakly protective in 'sensitive' mice infected with S. Typhimurium. S. Typhimurium also lacks Vi, the target of protective antibodies in typhoid fever. Notwithstanding these deficiencies, the murine model has identified a very complex series of innate and adaptive immune responses to infection that might be exploited to develop new vaccines. Equally, advances in understanding the pathogenesis of infection, through pathogenomics and more sophisticated animal models will likely contribute to the development of novel immunogens.
Publisher: Korean Society of Epidemiology
Date: 07-04-2021
Abstract: India has a higher tuberculosis (TB) burden than any other country, accounting for an estimated one-fourth of the global burden. Drug-resistant tuberculosis (DR-TB) presents a major public health problem in India. Patients with DR-TB often require profound changes in their drug regimens, which are invariably linked to poor treatment adherence and sub-optimal treatment outcomes compared to drug-sensitive TB. The challenge of addressing DR-TB is critical for India, as India contributes over 27% of global DR-TB cases. In recent decades, India has been proactive in its battle against TB, even implementing a revised National Strategic Plan to eliminate TB by 2025. However, to achieve this ambitious goal, the country will need to take a multifaceted approach with respect to its management of DR-TB. Despite concerted efforts made by the National TB Elimination Program, India faces substantial challenges with regard to DR-TB care, especially in peripheral and resource-limited endemic zones. This article describes some of the major challenges associated with mitigating the growing DR-TB epidemic in India and their implications.
Publisher: Elsevier BV
Date: 2015
Publisher: American Society for Microbiology
Date: 16-12-2020
DOI: 10.1128/AAC.01422-20
Abstract: Comorbid type 2 diabetes poses a great challenge to the global control of tuberculosis. Here, we assessed the efficacy of metformin (MET), an antidiabetic drug, in mice infected with a very low dose of Mycobacterium tuberculosis . In contrast to diabetic mice, infected nondiabetic mice that received the same therapeutic concentration of MET presented with significantly higher disease burden. This warrants further studies to investigate the disparate efficacy of MET against tuberculosis in diabetic and nondiabetic in iduals.
Publisher: Wiley
Date: 2020
DOI: 10.1002/CTI2.1158
Publisher: American Society for Clinical Investigation
Date: 25-04-2016
DOI: 10.1172/JCI84978
Publisher: Elsevier BV
Date: 04-2018
DOI: 10.1016/J.CELREP.2018.03.097
Abstract: Inflammasomes promote immunity to microbial pathogens by regulating the function of IL-1-family cytokines such as IL-18 and IL-1β. However, the roles for inflammasomes during parasitic helminth infections remain unclear. We demonstrate that mice and humans infected with gastrointestinal nematodes display increased IL-18 secretion, which in Trichuris-infected or worm antigen-treated mice and in macrophages co-cultured with Trichuris antigens or exosome-like vesicles was dependent on the NLRP3 inflammasome. NLRP3-deficient mice displayed reduced pro-inflammatory type 1 cytokine responses and augmented protective type 2 immunity, which was reversed by IL-18 administration. NLRP3-dependent suppression of immunity partially required CD4
Publisher: Akademiai Kiado Zrt.
Date: 09-2013
Publisher: American Society for Microbiology
Date: 30-12-2016
Abstract: Mycobacterium bovis Bacille Calmette-Guérin (BCG) is the only licensed vaccine against tuberculosis (TB), yet its moderate efficacy against pulmonary TB calls for improved vaccination strategies. Mucosal BCG vaccination generates superior protection against TB in animal models however, the mechanisms of protection remain elusive. Tissue-resident memory T (T RM ) cells have been implicated in protective immune responses against viral infections, but the role of T RM cells following mycobacterial infection is unknown. Using a mouse model of TB, we compared protection and lung cellular infiltrates of parenteral and mucosal BCG vaccination. Adoptive transfer and gene expression analyses of lung airway cells were performed to determine the protective capacities and phenotypes of different memory T cell subsets. In comparison to subcutaneous vaccination, intratracheal and intranasal BCG vaccination generated T effector memory and T RM cells in the lung, as defined by surface marker phenotype. Adoptive mucosal transfer of these airway-resident memory T cells into naive mice mediated protection against TB. Whereas airway-resident memory CD4 + T cells displayed a mixture of effector and regulatory phenotype, airway-resident memory CD8 + T cells displayed prototypical T RM features. Our data demonstrate a key role for mucosal vaccination-induced airway-resident T cells in the host defense against pulmonary TB. These results have direct implications for the design of refined vaccination strategies. IMPORTANCE BCG remains the only licensed vaccine against TB. Parenterally administered BCG has variable efficacy against pulmonary TB, and thus, improved prevention strategies and a more refined understanding of correlates of vaccine protection are required. Induction of memory T cells has been shown to be essential for protective TB vaccines. Mimicking the natural infection route by mucosal vaccination has been known to generate superior protection against TB in animal models however, the mechanisms of protection have remained elusive. Here we performed an in-depth analysis to dissect the immunological mechanisms associated with superior mucosal protection in the mouse model of TB. We found that mucosal, and not subcutaneous, BCG vaccination generates lung-resident memory T cell populations that confer protection against pulmonary TB. We establish a comprehensive phenotypic characterization of these populations, providing a framework for future vaccine development.
Publisher: Springer Science and Business Media LLC
Date: 08-01-2012
DOI: 10.1038/NI.2195
Abstract: Memory T cells exert antigen-independent effector functions, but how these responses are regulated is unclear. We discovered an in vivo link between flagellin-induced NLRC4 inflammasome activation in splenic dendritic cells (DCs) and host protective interferon-γ (IFN-γ) secretion by noncognate memory CD8(+) T cells, which could be activated by Salmonella enterica serovar Typhimurium, Yersinia pseudotuberculosis and Pseudomonas aeruginosa. We show that CD8α(+) DCs were particularly efficient at sensing bacterial flagellin through NLRC4 inflammasomes. Although this activation released interleukin 18 (IL-18) and IL-1β, only IL-18 was required for IFN-γ production by memory CD8(+) T cells. Conversely, only the release of IL-1β, but not IL-18, depended on priming signals mediated by Toll-like receptors. These findings provide a comprehensive mechanistic framework for the regulation of noncognate memory T cell responses during bacterial immunity.
Publisher: Proceedings of the National Academy of Sciences
Date: 10-08-2020
Abstract: Tuberculosis (TB) susceptibility and disease are significantly exacerbated in people with type 2 diabetes. The underlying mechanisms are incompletely understood, and it is not known if new TB vaccine candidates will be safe and provide protection in the context of diabetes. Using a long-term diet-induced murine model of type 2 diabetes, we demonstrate that increased susceptibility to TB is caused by impaired mycobacterial recognition and killing in the diabetic lung. Importantly, we show that mucosal vaccination of diabetic mice with Bacillus Calmette–Guérin (BCG) strains expressing the ESX-1 secretion system from Mycobacterium tuberculosis can overcome this defect and provide superior immunity against TB. Our data warrant a consideration of ESX-1–containing BCG strains as effective TB vaccines in older in iduals and diabetics.
Publisher: Akademiai Kiado Zrt.
Date: 09-2013
Publisher: Frontiers Media SA
Date: 11-06-2018
Publisher: American Society for Microbiology
Date: 12-2014
DOI: 10.1128/IAI.02192-14
Abstract: The rational design of vaccines requires an understanding of the contributions of in idual immune cell subsets to immunity. With this understanding, targeted vaccine delivery approaches and adjuvants can be developed to maximize vaccine efficiency and to minimize side effects (S. H. E. Kaufmann et al., Immunity 33:555–577, 2010 T. Ben-Yedidia and R. Arnon, Hum. Vaccines 1:95–101, 2005). We have addressed the contributions of different immune cell subsets and their ability to contribute to the control and clearance of the facultative intracellular pathogen Salmonella enterica serovar Typhimurium ( S . Typhimurium) in a murine model. Using a systematic and reproducible model of experimental attenuated S . Typhimurium infection, we show that distinct lymphocyte deficiencies lead to one of four different infection outcomes: clearance, chronic infection, early death, or late death. Our study demonstrates a high level of functional redundancy in the ability of different lymphocyte subsets to provide interferon gamma (IFN-γ), a critical cytokine in Salmonella immunity. Whereas early control of the infection was entirely dependent on IFN-γ but not on any particular lymphocyte subset, clearance of the infection critically required CD4 + T cells but appeared to be independent of IFN-γ. These data reinforce the idea of a bimodal immune response against Salmonella : an early T cell-independent but IFN-γ-dependent phase and a late T cell-dependent phase that may be IFN-γ independent.
Publisher: Elsevier BV
Date: 11-2016
Publisher: Public Library of Science (PLoS)
Date: 25-10-2021
DOI: 10.1371/JOURNAL.PPAT.1010004
Abstract: While Salmonella enterica is seen as an archetypal facultative intracellular bacterial pathogen where protection is mediated by CD4 + T cells, identifying circulating protective cells has proved very difficult, inhibiting steps to identify key antigen specificities. Exploiting a mouse model of vaccination, we show that the spleens of C57BL/6 mice vaccinated with live-attenuated Salmonella serovar Typhimurium ( S . Typhimurium) strains carried a pool of IFN-γ + CD4 + T cells that could adoptively transfer protection, but only transiently. Circulating Salmonella -reactive CD4 + T cells expressed the liver-homing chemokine receptor CXCR6, accumulated over time in the liver and assumed phenotypic characteristics associated with tissue-associated T cells. Liver memory CD4 + T cells showed TCR selection bias and their accumulation in the liver could be inhibited by blocking CXCL16. These data showed that the circulation of CD4 + T cells mediating immunity to Salmonella is limited to a brief window after which Salmonella -specific CD4 + T cells migrate to peripheral tissues. Our observations highlight the importance of triggering tissue-specific immunity against systemic infections.
Publisher: Oxford University Press (OUP)
Date: 12-2021
Abstract: The pulmonary immune system plays a vital role in protecting the delicate structures of gaseous exchange against invasion from bacterial pathogens. With antimicrobial resistance becoming an increasing concern, finding novel strategies to develop vaccines against bacterial lung diseases remains a top priority. In order to do so, a continued expansion of our understanding of the pulmonary immune response is warranted. While some aspects are well characterized, emerging paradigms such as the importance of innate cells and inducible immune structures in mediating protection provide avenues of potential to rethink our approach to vaccine development. In this review, we aim to provide a broad overview of both the innate and adaptive immune mechanisms in place to protect the pulmonary tissue from invading bacterial organisms. We use specific ex les from several infection models and human studies to depict the varying functions of the pulmonary immune system that may be manipulated in future vaccine development. Particular emphasis has been placed on emerging themes that are less reviewed and underappreciated in vaccine development studies.
Publisher: Elsevier BV
Date: 08-2019
DOI: 10.1016/J.IMMUNI.2019.06.002
Abstract: Interactions with the microbiota influence many aspects of immunity, including immune cell development, differentiation, and function. Here, we examined the impact of the microbiota on CD8
Publisher: Elsevier BV
Date: 03-2019
DOI: 10.1016/J.TUBE.2019.02.005
Abstract: Diabetes is one of the major co-morbidities contributing to the high global burden of tuberculosis (TB). The increased susceptibility of in iduals with type 2 diabetes (T2D) to TB is multifactorial and may influence the efficacy of vaccines. This study was undertaken to determine the early immune responses that occur following infection with Mycobacterium bovis Bacille Calmette-Guérin (BCG) in a diet-induced murine model of T2D. The phagocytic capabilities of alveolar (AM) and resident peritoneal macrophages (RPM) were assessed using ex vivo assays. Compared to macrophages from non-diabetic mice, macrophages from diabetic animals showed decreased BCG uptake and killing and inflammatory cytokine production (TNF-α, MCP-1, IL-6, IL-1β). In vivo susceptibility to BCG was determined following intravenous infection and diabetic mice showed a trend towards increased mortality, higher bacterial burden in the lung, liver and spleen and increased inflammatory lesions compared to controls. Differences between tissue cytokines were observed as early as one day post-infection and by days 14 and 35, lung and liver TNF-α and IFN-γ levels were decreased in diabetic mice compared to controls. These results suggest that early dysregulated immune responses may influence the susceptibility of T2D mice to BCG infection.
Publisher: Elsevier BV
Date: 12-2021
DOI: 10.1016/J.VACCINE.2021.08.030
Abstract: Tuberculosis (TB) is the leading infectious cause of death globally. The only licensed TB vaccine, Bacille Calmette-Guérin (BCG), has low efficacy against TB in adults and is not recommended in people with impaired immunity. The incorporation of the Mycobacterium tuberculosis (Mtb) secretion system ESX-1 into BCG improves immunogenicity and protection against TB in animal models, which is associated with the secretion of the ESX-1-dependent protein ESAT-6. However, the resulting strain, BCG::ESX1
Publisher: American Society for Microbiology
Date: 15-12-2021
DOI: 10.1128/CMR.00348-20
Abstract: About half of the world’s population and 80% of the world’s bio ersity can be found in the tropics. Many diseases are specific to the tropics, with at least 41 diseases caused by endemic bacteria, viruses, parasites, and fungi. Such diseases are of increasing concern, as the geographic range of tropical diseases is expanding due to climate change, urbanization, change in agricultural practices, deforestation, and loss of bio ersity.
Publisher: Public Library of Science (PLoS)
Date: 08-07-2016
Publisher: Frontiers Media SA
Date: 09-07-2018
Publisher: Cold Spring Harbor Laboratory
Date: 13-04-2019
DOI: 10.1101/606392
Abstract: Alternatively activated macrophages are essential effector cells during type 2 immunity and tissue repair following helminth infections. We previously showed that Ym1, an alternative activation marker, can drive innate IL-1R-dependent neutrophil recruitment during infection with the lung-migrating nematode, Nippostrongylus brasiliensis suggesting a potential role for the inflammasome in the IL-1-mediated innate response to infection. While inflammasome proteins such as NLRP3 have important pro-inflammatory functions in macrophages, their role during type 2 responses and repair are less defined. We therefore infected Nlrp3 −/− mice with N. brasiliensis . Unexpectedly, compared to WT mice, infected Nlrp3 −/− mice had increased neutrophilia and eosinophilia, correlating with enhanced worm killing but at the expense of increased tissue damage and delayed lung repair. Transcriptional profiling showed that infected Nlrp3 −/− mice exhibited elevated type 2 gene expression compared to WT mice. Notably, inflammasome activation was not evident early post-infection with N. brasiliensis and in contrast to Nlrp3 −/− mice, anti-helminth responses were unaffected in caspase-1/11 deficient or WT mice treated with the NLRP3-specific inhibitor MCC950. Together these data suggest that NLRP3 can constrain lung neutrophilia and helminth killing and negatively regulate type 2 immune responses in an inflammasome-independent manner.
Publisher: American Chemical Society (ACS)
Date: 09-11-2020
Publisher: Frontiers Media SA
Date: 21-03-2019
Publisher: Public Library of Science (PLoS)
Date: 14-05-2014
Publisher: Elsevier BV
Date: 04-2009
Abstract: Sago starch is an important dietary carbohydrate in lowland Papua New Guinea (PNG). An investigation was conducted to determine whether microbes play a role in its preservation using traditional methods. In 12 stored sago s les collected from PNG villages, lactic acid bacteria (LAB) were present (> or = 3.6 x 10(4)cfu/g) and pH ranged from 6.8 to 4.2. Acetic and propionic acids were detected in all s les, while butyric, lactic and valeric acids were present in six or more. In freshly prepared sago, held in sealed containers in the laboratory at 30 degrees C, spontaneous fermentation by endogenous microflora of sago starch was observed. This was evident by increasing concentrations of acetic, butyric and lactic acids over 4 weeks, and pH reducing from 4.9 to 3.1: both LAB and yeasts were involved. Survival of potential bacterial pathogens was monitored by seeding sago starch with approximately 10(4)/g of selected organisms. Numbers of Bacillus cereus, Listeria monocytogenes and Staphylococcus aureus fell to < 30/g within 7 days. Salmonella sp. was present only in low numbers after 7 days ( 10(2)/g). Fermentation appeared to increase the storability and safety of the product.
Publisher: Public Library of Science (PLoS)
Date: 21-12-2012
Publisher: The American Association of Immunologists
Date: 03-2010
Abstract: Given the central role of intestinal dendritic cells (DCs) in the regulation of gut immune responses, it is not surprising that several bacterial pathogens have evolved strategies to prevent or bypass recognition by DCs. In this article, we will review recent findings on the interaction between intestinal DCs and prototypical bacterial pathogens, such as Salmonella, Yersinia, or Helicobacter. We will discuss the different approaches with which these pathogens seek to evade DC recognition and subsequent T cell activation. These erse strategies span to include mounting irrelevant immune responses, inhibition of Ag presentation by DCs, and stretch as far as to manipulate the Th1/Th2 balance of CD4+ T cells in the bacteria’s favor.
Publisher: Proceedings of the National Academy of Sciences
Date: 23-01-2013
Abstract: IFN-γ is critical for immunity against infections with intracellular pathogens, such as Salmonella enterica . However, which of the many cell types capable of producing IFN-γ controls Salmonella infections remains unclear. Using a mouse model of systemic Salmonella infection, we observed that only a lack of all lymphocytes or CD90 (Thy1) + cells, but not the absence of T cells, Retinoic acid-related orphan receptor (ROR)-γt–dependent lymphocytes, (NK)1.1 + cells, natural killer T (NKT), and/or B cells alone, replicated the highly susceptible phenotype of IFN-γ–deficient mice to Salmonella infection. A combination of antibody depletions and adoptive transfer experiments revealed that early protective IFN-γ was provided by Thy1-expressing natural killer (NK) cells and that these cells improved antibacterial immunity through the provision of IFN-γ. Further analysis of NK cells producing IFN-γ in response to Salmonella indicated that less mature NK cells were more efficient at mediating antibacterial effector function than terminally differentiated NK cells. Inspired by recent reports of Thy1 + NK cells contributing to immune memory, we analyzed their role in secondary protection against otherwise lethal WT Salmonella infections. Notably, we observed that a newly generated Salmonella vaccine strain not only conferred superior protection compared with conventional regimens but that this enhanced efficiency of recall immunity was afforded by incorporating CD4 − CD8 − Thy1 + cells into the secondary response. Taken together, these findings demonstrate that Thy1-expressing NK cells play an important role in antibacterial immunity.
Start Date: 2017
End Date: 2020
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2018
End Date: 2021
Funder: National Health and Medical Research Council
View Funded Activity