Nicole G. Barra
McMaster University
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Featured researches published by Nicole G. Barra.
Obesity | 2010
Nicole G. Barra; Sarah Reid; Randy Mackenzie; Geoff H. Werstuck; Bernardo L. Trigatti; Carl D. Richards; Alison C. Holloway; Ali A. Ashkar
An alarming global rise in the prevalence of obesity and its contribution to the development of chronic diseases is a serious health concern. Recently, obesity has been described as a chronic low‐grade inflammatory condition, influenced by both adipose tissue and immune cells suggesting proinflammatory cytokines may play a role in its etiology. Here we examined the effects of interleukin‐15 (IL‐15) on adipose tissue and its association with obesity. Over expression of IL‐15 (IL‐15tg) was associated with lean body condition whereas lack of IL‐15 (IL‐15−/−) results in significant increase in weight gain without altering appetite. Interestingly, there were no differences in proinflammatory cytokines such as IL‐6 and tumor necrosis factor‐α (TNF‐α) in serum between the three strains of mice. In addition, there were significant numbers of natural killer (NK) cells in fat tissues from IL‐15tg and B6 compared to IL‐15−/− mice. IL‐15 treatment results in significant weight loss in IL‐15−/− knockout and diet‐induced obese mice independent of food intake. Fat pad cross‐sections show decreased pad size with over expression of IL‐15 is due to adipocyte shrinkage. IL‐15 induces weight loss without altering food consumption by affecting lipid deposition in adipocytes. Treatment of differentiated human adipocytes with recombinant human IL‐15 protein resulted in decreased lipid deposition. In addition, obese patients had significantly lower serum IL‐15 levels when compared to normal weight individuals. These results clearly suggest that IL‐15 may be involved in adipose tissue regulation and linked to obesity.
Journal of Experimental Medicine | 2014
Derek K. Chu; Rodrigo Jiménez-Saiz; Chris P. Verschoor; Tina D. Walker; Susanna Goncharova; Alba Llop-Guevara; Pamela Shen; Melissa E. Gordon; Nicole G. Barra; Jennifer Bassett; Joshua Kong; Ramzi Fattouh; Kathleen McCoy; Dawn M. E. Bowdish; Jonas Erjefält; Oliver Pabst; Alison A. Humbles; Roland Kolbeck; Susan Waserman; Manel Jordana
Eosinophil degranulation of peroxidase promotes DC activation and mobilization from the intestine to LNs to induce Th2 immunity and food allergy.
The Journal of Infectious Diseases | 2012
Mohamed Faizal Abdul-Careem; M. Firoz Mian; Geoffry Yue; Amy Gillgrass; Meghan J. Chenoweth; Nicole G. Barra; Marianne V. Chew; Tiffany Chan; Amal Al-Garawi; Manel Jordana; Ali A. Ashkar
Influenza viral infection results in excessive pulmonary inflammation that has been linked to the damage caused by immune responses and viral replication. The multifunctional cytokine interleukin (IL-15), influences the proliferation and maintenance of immune cells such as CD8(+) T cells and natural killer (NK) cells. Here we show that IL-15(-/-) mice are protected from lethal influenza infection. Irrespective of the mouse strains, the protection observed was linked to the lack of NK cells. Increased survival in the IL-15(-/-) or NK1.1(+) cell-depleted wild-type mice was associated with significantly lower lung lesions as well as decreased mononuclear cells and neutrophils in the airway lumen. Levels of interleukin 10 were significantly higher and levels of proinflammatory cytokines, including interleukin 6 and interleukin 12, were significantly lower in the bronchoalveolar lavage fluid from IL-15(-/-) and NK1.1(+) cell-depleted wild-type mice than in that from control mice. Our data suggest that NK cells significantly augment pulmonary inflammation, contributing to the pathogenesis of influenza infection.
Embo Molecular Medicine | 2015
Emmanuel Denou; Karine Lolmède; Lucile Garidou; Céline Pomié; Trevor C. Lau; Morgan D. Fullerton; Giulia Nigro; Alexia Zakaroff-Girard; Elodie Luche; Céline Garret; Matteo Serino; Jacques Amar; Joseph F. Cavallari; Brandyn D. Henriksbo; Nicole G. Barra; Kevin P. Foley; Joseph B. McPhee; Brittany M. Duggan; Hayley M. O'Neill; Amanda J. Lee; Philippe J. Sansonetti; Ali A. Ashkar; Waliul I. Khan; Michael G. Surette; Anne Bouloumié; Gregory R. Steinberg; Rémy Burcelin; Jonathan D. Schertzer
Pattern recognition receptors link metabolite and bacteria‐derived inflammation to insulin resistance during obesity. We demonstrate that NOD2 detection of bacterial cell wall peptidoglycan (PGN) regulates metabolic inflammation and insulin sensitivity. An obesity‐promoting high‐fat diet (HFD) increased NOD2 in hepatocytes and adipocytes, and NOD2−/− mice have increased adipose tissue and liver inflammation and exacerbated insulin resistance during a HFD. This effect is independent of altered adiposity or NOD2 in hematopoietic‐derived immune cells. Instead, increased metabolic inflammation and insulin resistance in NOD2−/− mice is associated with increased commensal bacterial translocation from the gut into adipose tissue and liver. An intact PGN‐NOD2 sensing system regulated gut mucosal bacterial colonization and a metabolic tissue dysbiosis that is a potential trigger for increased metabolic inflammation and insulin resistance. Gut dysbiosis in HFD‐fed NOD2−/− mice is an independent and transmissible factor that contributes to metabolic inflammation and insulin resistance when transferred to WT, germ‐free mice. These findings warrant scrutiny of bacterial component detection, dysbiosis, and protective immune responses in the links between inflammatory gut and metabolic diseases, including diabetes.
Journal of Reproductive Immunology | 2011
Tiffany Chan; Nicole G. Barra; Amanda J. Lee; Ali A. Ashkar
Herpes simplex virus type 2 (HSV-2) is becoming increasingly prevalent worldwide, despite the widespread use of antiviral drugs. Its ability to evade the immune system and establish a latent infection has made it difficult to develop an effective vaccine. Our understanding of the immune response against HSV-2 remains complex and involves a balance between innate signaling pathways and the adaptive immune response. Primary infection with HSV-2 induces toll-like receptor (TLR)-mediated Type I interferon (IFN) production, which establishes an antiviral state and activates multiple cell types, including natural killer cells and plasmacytoid dendritic cells. This innate response is not only crucial for controlling initial infection, but also for priming adaptive immune responses as well. Both humoral and cellular responses encompass adaptive immunity, although the former has been shown to be dispensable in response to HSV-2. Recently, numerous studies have attributed IFNγ producing CD4(+) T cells to be the key effector molecule responsible for clearing infection. It remains unclear whether regulatory T (Treg) cells are a source of aid or hindrance in the clearance of disease. Collectively, this review highlights the balance between innate and adaptive effector responses that contribute to the control and clearance of HSV-2 infection.
Journal of Immunology | 2012
Meghan J. Chenoweth; M. Firoz Mian; Nicole G. Barra; Tommy Alain; Nahum Sonenberg; Jonathan Bramson; Brian D. Lichty; Carl D. Richards; Averil Ma; Ali A. Ashkar
IL-15 plays many important roles within the immune system. IL-15 signals in lymphocytes via trans presentation, where accessory cells such as macrophages and dendritic cells present IL-15 bound to IL-15Rα in trans to NK cells and CD8+ memory T cells expressing IL-15/IL-2Rβ and common γ chain (γc). Previously, we showed that the prophylactic delivery of IL-15 to Rag2−/−γc−/− mice (mature T, B, and NK cell negative) afforded protection against a lethal HSV-2 challenge and metastasis of B16/F10 melanoma cells. In this study, we demonstrated that in vivo delivery of an adenoviral construct optimized for the secretion of human IL-15 to Rag2−/−γc−/− mice resulted in significant increases in spleen size and cell number, leading us to hypothesize that IL-15 signals differently in myeloid immune cells compared with lymphocytes, for which IL-15/IL-2Rβ and γc expression are essential. Furthermore, treatment with IL-15 induced RANTES production by Rag2−/−γc−/− bone marrow cells, but the presence of γc did not increase bone marrow cell sensitivity to IL-15. This IL-15–mediated RANTES production by Rag2−/−γc−/− bone marrow cells occurred independently of the IL-15/IL-2Rβ and Jak/STAT pathways and instead required IL-15Rα signaling as well as activation of JNK and NF-κB. Importantly, we also showed that the trans presentation of IL-15 by IL-15Rα boosts IL-15–mediated IFN-γ production by NK cells but reduces IL-15–mediated RANTES production by Rag2−/−γc−/− myeloid bone marrow cells. Our data clearly show that IL-15 signaling in NK cells is different from that of myeloid immune cells. Additional insights into IL-15 biology may lead to novel therapies aimed at bolstering targeted immune responses against cancer and infectious disease.
Diabetes, Obesity and Metabolism | 2012
Nicole G. Barra; Marianne V. Chew; Alison C. Holloway; Ali A. Ashkar
The prevalence of metabolic diseases associated with obesity, such as type 2 diabetes, continues to rise along with obesity rates. Recently, obesity has been described as an inflammatory condition, suggesting a link between the dysregulation in proinflammatory cytokine production and the aetiology of these metabolic diseases. While known as an immunomodulatory cytokine, Interleukin‐15 (IL‐15) has been shown to have effects on adipose tissue and induce weight loss in diet‐induced obese mice. As weight loss improves glucose homeostasis, the goal of this study was to determine whether IL‐15 impacts glucose regulation in a mouse model of diet‐induced obesity. Our data demonstrate that IL‐15 treatment significantly improves insulin sensitivity and glucose and insulin responses to an oral glucose challenge compared to obese counterparts and/or lean controls. These results show that IL‐15 may be a novel therapeutic target for the treatment of obesity and its associated abnormal glucose regulation.
Antiviral Research | 2011
Mohamed Faizal Abdul-Careem; M. Firoz Mian; Amy Gillgrass; Meghan J. Chenoweth; Nicole G. Barra; Tiffany Chan; Amal Al-Garawi; Marianne V. Chew; Geoffry Yue; Nico van Roojen; Zhou Xing; Ali A. Ashkar
Fimbriae H protein (FimH) is a novel TLR4 ligand that has been shown to stimulate the innate immune system and elicits protective responses against bacterial and viral infections. Here, we evaluated the protective role of local delivery of FimH against influenza A infection in a mouse model. We show that intranasal delivery of FimH prior to lethal challenge with influenza A virus, resulted in decreased morbidity and mortality in wild-type, but not TLR4(-/-), mice. Importantly, FimH was able to reduce the early viral burden in the lung leading to minimal cell infiltration into the airway lumen and reduced pulmonary pathology following infection in wild type mice compared to TLR4(-/-) mice. Local delivery of FimH to C57BL/6, not TLR4(-/-), mice in a prophylactic manner increased the IL-12 and RANTES responses as well as neutrophil recruitment into the airway lumen. These effects correlate to the course of influenza infection. The FimH-mediated antiviral response against influenza virus appears to be partially dependent on alveolar macrophages. The antiviral effects are likely mediated by the innate mediators (TNF-α, IL-12 or RANTES) and/or by activation of a feedback inhibition loop to curtail the pulmonary inflammation possibly be the potential mechanisms involved in FimH-mediated protection. FimH thus holds promise to be a possible prophylactic mean of control against influenza viral infection.
PLOS ONE | 2012
Nicole G. Barra; Marianne V. Chew; Sarah Reid; Ali A. Ashkar
Obesity is a chronic inflammatory condition characterized by activation and infiltration of proinflammatory immune cells and a dysregulated production of proinflammatory cytokines. While known as a key regulator of immune natural killer (NK) cell function and development, we have recently demonstrated that reduced expression of the cytokine Interleukin-15 (IL-15) is closely linked with increased body weight and adiposity in mice and humans. Previously, we and others have shown that obese individuals have lower circulating levels of IL-15 and NK cells. Lean IL-15 overexpressing (IL-15 tg) mice had an accumulation in adipose NK cells compared to wildtype and NK cell deficient obese IL-15−/− mice. Since IL-15 induces weight loss in IL-15−/− and diet induced obese mice and has effects on various lymphocytes, the aim of this paper was to determine if lymphocytes, particularly NK cells, play a role in IL-15 mediated weight loss. Acute IL-15 treatment resulted in an increased accumulation of NK, NKT, and CD3+ T cells in adipose tissue of B6 mice. Mice depleted of NK and NKT cells had similar weight loss comparable to controls treated with IL-15. Finally, IL-15 treatment induces significant weight loss in lymphocyte deficient RAG2−/−γc−/− mice independent of food intake. Fat pad cross-sections show decreased pad size with cytokine treatment is due to adipocyte shrinkage. These results clearly suggest that IL-15 mediates weight loss independent of lymphocytes.
Mucosal Immunology | 2014
Mangalakumari Jeyanathan; Sarah McCormick; Rocky Lai; Sam Afkhami; Christopher R. Shaler; Carly Horvath; Daniela Damjanovic; Anna Zganiacz; Nicole G. Barra; Ali A. Ashkar; Manel Jordana; Naoko Aoki; Zhou Xing
Interaction of mycobacteria with the host leads to retarded expression of T helper cell type 1 (Th1) immunity in the lung. However, the immune mechanisms remain poorly understood. Using in vivo and in vitro models of Mycobacterium tuberculosis (M. tb) infection, we find the immunoadaptor DAP12 (DNAX-activating protein of 12 kDa) in antigen-presenting cells (APCs) to be critically involved in this process. Upon infection of APCs, DAP12 is required for IRAK-M (interleukin-1 receptor-associated kinase M) expression, which in turn induces interleukin-10 (IL-10) and an immune-suppressed phenotype of APCs, thus leading to suppressed Th1 cell activation. Lack of DAP12 reduces APC IL-10 production and increases their Th1 cell-activating capability, resulting in expedited Th1 responses and enhanced protection. On the other hand, adoptively transferred DAP12-competent APCs suppress Th1 cell activation within DAP12-deficient hosts, and blockade of IL-10 aborts the ability of DAP12-competent APCs to suppress Th1 activation. Our study identifies the DAP12/IRAK-M/IL-10 to be a novel molecular pathway in APCs exploited by mycobacterial pathogens, allowing infection a foothold in the lung.