[Show abstract][Hide abstract] ABSTRACT: 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.
Preview · Article · May 2012 · The Journal of Infectious Diseases
[Show abstract][Hide abstract] ABSTRACT: 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.
No preview · Article · Sep 2011 · Antiviral research
[Show abstract][Hide abstract] ABSTRACT: 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.
Full-text · Article · Feb 2011 · Journal of Reproductive Immunology
[Show abstract][Hide abstract] ABSTRACT: Natural Killer cells can distinguish between healthy and malignant cells and have the unique ability to lyse tumour cells without prior sensitization. Differences between murine and human NK cells complicate the translation of this knowledge into useful therapeutics. Humanized mouse models that support the development of human leukocytes are a promising avenue of research that aims to address this problem. Here we provide an in-depth phenotypic analysis of human NK cells in Balb/c Rag2(-/-)γ(c)(-/-) mice reconstituted with human hematopoietic stem cells. We have examined the development of NK cells in bone marrow, thymous, spleen, lymph node (LN) and liver. Interestingly, in naive reconstituted mice, NK cells were found in thymus and LN, but not in bone marrow. These NK cells expressed several inhibitory and activating receptors needed for malignant cell detection. Furthermore, we confirm that administration of recombinant human interleukin-15 (rhIL-15) or Ad-vector expressing hIL-15 is able to significantly enhance NK cell development and maturation, particularly in bone marrow and liver, in this model. Our results suggest that human NK cells developed in mice may have phenotypes and tissue distributions similar to those seen in human.
[Show abstract][Hide abstract] ABSTRACT: During activation, macrophages undergo physiological changes affecting their surface protein expression and cytokine production and have been subsequently categorized into M1 (classically-activated) and M2 (alternatively-activated) macrophages. It remains unclear which lymphocyte population provides the immune microenvironment to regulate macrophage polarization. In this study, we establish a functional and phenotypic profile of peritoneal macrophages from C57BL/6 wild-type mice. We also showed that Rag1(-/-) and Rag2(-/-)γc(-/-) mice have similar, exaggerated M1 characteristics in comparison to control mice, suggesting that NK and/or NK-T cells may not be essential in this process. By controlling for environmental factors, we determine that lymphocyte-derived cytokines, rather than inherent properties of macrophages themselves, are crucial for their regulation. Lastly, we report that macrophages from CD4(-/-) mice display an M1 profile, suggesting that CD4(+) T-cells play a dominant role over other lymphocyte populations in providing the cytokine environment for regulating macrophages towards an M2 profile under normal wild-type conditions.
No preview · Article · Oct 2010 · Cellular Immunology