Viral Vaccines and CTL Response

Immune induction by successful vaccine formulations seems to involve stimulation of both humoral and cellular arms of immunity. Nevertheless, CD8+ CTLs are of critical relevance in the context of intracellular infection and tumor for many reasons. The task of exerting antipathogen activity by CD8+ T cells, which principally function to control and eradicate intracellular pathogens, is enabled by constitutive expression of MHC class-I molecules on all tissue types. CTL induction offers hope for vaccines against pathogens that are resistant to neutralizing activity. This review discusses the mechanism of immune induction by some successful vaccines and based on the accrued evidence suggests ideas for improved design of CTL-inducing vaccines

Viral Vaccines and CTL Response

Immune induction by successful vaccine formulations seems to involve stimulation of both humoral and cellular arms of immunity. Nevertheless, CD8+ CTLs are of critical relevance in the context of intracellular infection and tumor for many reasons. The task of exerting antipathogen activity by CD8+ T cells, which principally function to control and eradicate intracellular pathogens, is enabled by constitutive expression of MHC class-I molecules on all tissue types. CTL induction offers hope for vaccines against pathogens that are resistant to neutralizing activity. This review discusses the mechanism of immune induction by some successful vaccines and based on the accrued evidence suggests ideas for improved design of CTL-inducing vaccines

Dynamically linking influenza virus infection kinetics, lung injury, inflammation, and disease severity

Influenza viruses cause a significant amount of morbidity and mortality. Understanding host immune control efficacy and how different factors influence lung injury and disease severity are critical. We established and validated dynamical connections between viral loads, infected cells, CD

The Multifaceted Contribution of Natural Killer Cells During Herpes Simplex Type-1 Viral Infection.

Natural killer (NK) cells are non-specific killer cells of the innate immune system that eliminate target cells based on discrimination between self and non-self. Activation is carefully regulated through integration of signals received through both activating and inhibitory receptors. During the course of a herpes simplex virus type-1 (HSV-1) infection, NK cells can influence host susceptibility to infection with severe infections occurring in individuals with genetic defects in the NK cell response. In response to HSV infection, NK cells are recruited to the inflammatory tissue where ensuing reciprocal interactions with accessory cells and proinflammatory cytokines induce NK cell activation, cytolytic activity, and cytokine production, contributing to innate immune response and ultimately influencing the adaptive immune response. The objective of this study was to elucidate the multiple roles of NK cells during the numerous steps in anti-HSV immune induction. Accordingly, we have demonstrated that NK cells are novel helpers that assist and influence an anti-HSV immune response via the secretion of cytokines that enhance HSV-specific CD8+ T cell effector function and cytokine production. Taken together, data from this study presented the critical importance of NK cells in mounting an essential and efficient anti-HSV immunity. The key findings of our study were: 1. In the absence of NK cells, dendritic cells have decreased capacity to prime HSV-specific T cells. 2. HSV infected NK cells can be directly activated via toll-like receptor (TLR) in a MyD88-dependent mechanism; however, interaction with HSV infected dendritic cells yields optimal NK cell activation and function (CD69 and IFNγ). 3. TRAIL-expressing NK cells eliminate antigen-bearing immature dermal DCs (CD11c+CD8α-DR5+), that migrate to draining lymphoid organs, to facilitate antigen transfer to lymphoid resident CD8α+ DC for T cell cross priming. 4. \u27Helpless\u27 CD8+ T cell function, generated in the absence of CD4+ T cells, can be partially restored to wild-type levels by NK cell supplementation. 5. Treatment of NK cells with anti-CD69 antibody results in a heightened NK activated state and augments the adaptive immune response, without increasing NK cell numbers. These findings may contribute to the potential revelation of avenues to manipulate NK cells for anti-viral therapies

Natural Killer Cells Adjudicate Every Stage of Anti-Viral Immune Response

The definition of Natural Killer (NK) cells has undergone dramatic modification with the advance of immunological research tools. NK cells can no longer be classified only as indiscriminate killer innate immune cells. NK cells are now known to form functional relationships with accessory cells to shape and promote the adaptive immune response. Recently, antigen specific and cytokine induced memory NK cells have been demonstrated to exhibit the characteristic phases of an adaptive immune cell, including extended persistence and robust function in response to reexposure. New findings in basic NK immunobiology indicate that the role of NK cells is underappreciated and these cells may potentially be manipulated for the development of anti-viral therapies

Natural Killer Cells as Novel Helpers in Anti-Herpes Simplex Virus Immune Response▿

Innate defenses help to eliminate infection, but some of them also play a major role in shaping the magnitude and efficacy of the adaptive immune response. With regard to influencing subsequent adaptive immunity, NK cells aided by dendritic cells may be the most relevant components of the innate reaction to herpes simplex virus (HSV) infection. We confirm that mice lacking or depleted of NK cells are susceptible to HSV-induced lesions. The quantity and quality of CD8+ cytotoxic T lymphocytes generated in the absence of NK cells were diminished, thereby contributing to susceptibility to HSV-induced encephalitis. We demonstrate a novel helper role for NK cells, in that NK cells compensate for the loss of CD4 helper T cells and NK cell supplementation enhances the function of wild type anti-HSV CD8 T cells. In addition, NK cells were able to partially rescue the dysfunctional CD8+ T cells generated in the absence of CD4 T helper cells, thereby performing a novel rescue function. Hence, NK cells may well be exploited for enhancing and rescuing the T-cell response in situations where the CD4 helper response is affected

Dynamic Pneumococcal Genetic Adaptations Support Bacterial Growth and Inflammation during Coinfection with Influenza

Streptococcus pneumoniae (pneumococcus) is one of the primary bacterial pathogens that complicates influenza virus infections. These bacterial coinfections increase influenza-associated morbidity and mortality through a number of immunological and viral-mediated mechanisms, but the specific bacterial genes that contribute to postinfluenza pathogenicity are not known. Here, we used genome-wide transposon mutagenesis (Tn-Seq) to reveal bacterial genes that confer improved fitness in influenza virus-infected hosts. The majority of the 32 genes identified are involved in bacterial metabolism, including nucleotide biosynthesis, amino acid biosynthesis, protein translation, and membrane transport. We generated mutants with single-gene deletions (SGD) of five of the genes identified, SPD1414, SPD2047 (cbiO1), SPD0058 (purD), SPD1098, and SPD0822 (proB), to investigate their effects on in vivo fitness, disease severity, and host immune responses. The growth of the SGD mutants was slightly attenuated in vitro and in vivo, but each still grew to high titers in the lungs of mock- and influenza virus-infected hosts. Despite high bacterial loads, mortality was significantly reduced or delayed with all SGD mutants. Time-dependent reductions in pulmonary neutrophils, inflammatory macrophages, and select proinflammatory cytokines and chemokines were also observed. Immunohistochemical staining further revealed altered neutrophil distribution with reduced degeneration in the lungs of influenza virus-SGD mutant-coinfected animals. These studies demonstrate a critical role for specific bacterial genes and for bacterial metabolism in driving virulence and modulating immune function during influenza-associated bacterial pneumonia.Open access articleThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]