scholarly journals The genome of self-complementary adeno-associated viral vectors increases Toll-like receptor 9–dependent innate immune responses in the liver

Blood ◽  
2011 ◽  
Vol 117 (24) ◽  
pp. 6459-6468 ◽  
Author(s):  
Ashley T. Martino ◽  
Masataka Suzuki ◽  
David M. Markusic ◽  
Irene Zolotukhin ◽  
Renee C. Ryals ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Immune Responses ◽  
Viral Vectors ◽  
Killer Cell ◽  
Primary Response ◽  
Innate Immune ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Capsid Sequence ◽  
Inducible Protein

AbstractAlthough adeno-associated viral (AAV) vectors have been successfully used in hepatic gene transfer for treatment of hemophilia and other diseases in animals, adaptive immune responses blocked long-term transgene expression in patients on administration of single-stranded AAV serotype-2 vector. More efficient vectors have been developed using alternate capsids and self-complimentary (sc) genomes. This study investigated their effects on the innate immune profile on hepatic gene transfer to mice. A mild and transient up-regulation of myeloid differentiation primary response gene (88), TLR9, TNF-α, monocyte chemotactic protein-1, IFN-γ inducible protein-10, and IFN-α/β expression in the liver was found after single-stranded AAV vector administration, regardless of the capsid sequence. In contrast, scAAV vectors induced higher increases of these transcripts, upregulated additional proinflammatory genes, and increased circulating IL-6. Neutrophil, macrophage, and natural killer cell liver infiltrates were substantially higher on injection of scAAV. Some but not all of these responses were Kupffer cell dependent. Independent of the capsid or expression cassette, scAAV vectors induced dose-dependent innate responses by signaling through TLR9. Increased innate responses to scAAV correlated with stronger adaptive immune responses against capsid (but not against the transgene product). However, these could be blunted by transient inhibition of TLR9.

scholarly journals RIG-I and MDA5 Protect Mice From Pichinde Virus Infection by Controlling Viral Replication and Regulating Immune Responses to the Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Morgan Brisse ◽  
Qinfeng Huang ◽  
Mizanur Rahman ◽  
Da Di ◽  
Yuying Liang ◽  
...  
Keyword(s):  
Virus Infection ◽  
Immune Responses ◽  
Innate Immune ◽  
Double Knockout ◽  
Adaptive Immune Responses ◽  
Pichinde Virus ◽  
Adaptive Immune ◽  
Control Virus ◽  
In The Wild ◽  
Sensor Proteins

RIG-I and MDA5 are major cytoplasmic innate-immune sensor proteins that recognize aberrant double-stranded RNAs generated during virus infection to activate type 1 interferon (IFN-I) and IFN-stimulated gene (ISG) expressions to control virus infection. The roles of RIG-I and MDA5 in controlling replication of Pichinde virus (PICV), a mammarenavirus, in mice have not been examined. Here, we showed that MDA5 single knockout (SKO) and RIG-I/MDA5 double knockout (DKO) mice are highly susceptible to PICV infection as evidenced by their significant reduction in body weights during the course of the infection, validating the important roles of these innate-immune sensor proteins in controlling PICV infection. Compared to the wildtype mice, SKO and DKO mice infected with PICV had significantly higher virus titers and lower IFN-I expressions early in the infection but appeared to exhibit a late and heightened level of adaptive immune responses to clear the infection. When a recombinant rPICV mutant virus (rPICV-NPmut) that lacks the ability to suppress IFN-I was used to infect mice, as expected, there were heightened levels of IFN-I and ISG expressions in the wild-type mice, whereas infected SKO and DKO mice showed delayed mouse growth kinetics and relatively low, delayed, and transient levels of innate and adaptive immune responses to this viral infection. Taken together, our data suggest that PICV infection triggers activation of immune sensors that include but might not be necessarily limited to RIG-I and MDA5 to stimulate effective innate and adaptive immune responses to control virus infection in mice.

scholarly journals Innate immunity and the pneumococcus

Microbiology ◽  
2006 ◽  
Vol 152 (2) ◽  
pp. 285-293 ◽  
Author(s):  
Gavin K. Paterson ◽  
Tim J. Mitchell
Keyword(s):  
Innate Immunity ◽  
Immune System ◽  
Streptococcus Pneumoniae ◽  
Immune Responses ◽  
Innate Immune System ◽  
Innate Immune ◽  
First Line ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Made In

The innate immune system provides a non-specific first line of defence against microbes and is crucial both in the development and effector stages of subsequent adaptive immune responses. Consistent with its importance, study of the innate immune system is a broad and fast-moving field. Here we provide an overview of the recent key advances made in this area with relation to the important pathogen Streptococcus pneumoniae (the pneumococcus).

scholarly journals Lessons from Bacillus Calmette-Guérin: Harnessing Trained Immunity for Vaccine Development

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2109
Author(s):  
Samuel T. Pasco ◽  
Juan Anguita
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Immune Responses ◽  
Vaccine Development ◽  
Vaccine Design ◽  
Innate Immune ◽  
Bacillus Calmette Guerin ◽  
Adaptive Immune Responses ◽  
Trained Immunity ◽  
Adaptive Immune ◽  
Potential Methods

Vaccine design traditionally focuses on inducing adaptive immune responses against a sole target pathogen. Considering that many microbes evade innate immune mechanisms to initiate infection, and in light of the discovery of epigenetically mediated innate immune training, the paradigm of vaccine design has the potential to change. The Bacillus Calmette-Guérin (BCG) vaccine induces some level of protection against Mycobacterium tuberculosis (Mtb) while stimulating trained immunity that correlates with lower mortality and increased protection against unrelated pathogens. This review will explore BCG-induced trained immunity, including the required pathways to establish this phenotype. Additionally, potential methods to improve or expand BCG trained immunity effects through alternative vaccine delivery and formulation methods will be discussed. Finally, advances in new anti-Mtb vaccines, other antimicrobial uses for BCG, and “innate memory-based vaccines” will be examined.

scholarly journals Mutations in a Highly Conserved Motif of nsp1β Protein Attenuate the Innate Immune Suppression Function of Porcine Reproductive and Respiratory Syndrome Virus

2016 ◽  
Vol 90 (7) ◽  
pp. 3584-3599 ◽  
Author(s):  
Yanhua Li ◽  
Duan-Liang Shyu ◽  
Pengcheng Shang ◽  
Jianfa Bai ◽  
Kang Ouyang ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Innate Immune ◽  
Respiratory Syndrome Virus ◽  
Adaptive Immune Responses ◽  
Virus Growth ◽  
Conserved Motif ◽  
Adaptive Immune ◽  
Infected Cells ◽  
Growth Ability

ABSTRACTPorcine reproductive and respiratory syndrome virus (PRRSV) nonstructural protein 1β (nsp1β) is a multifunctional viral protein, which is involved in suppressing the host innate immune response and activating a unique −2/−1 programmed ribosomal frameshifting (PRF) signal for the expression of frameshifting products. In this study, site-directed mutagenesis analysis showed that the R128A or R129A mutation introduced into a highly conserved motif (123GKYLQRRLQ131) reduced the ability of nsp1β to suppress interferon beta (IFN-β) activation and also impaired nsp1β's function as a PRF transactivator. Three recombinant viruses, vR128A, vR129A, and vRR129AA, carrying single or double mutations in the GKYLQRRLQ motif were characterized. In comparison to the wild-type (WT) virus, vR128A and vR129A showed slightly reduced growth abilities, while the vRR129AA mutant had a significantly reduced growth ability in infected cells. Consistent with the attenuated growth phenotypein vitro, pigs infected with nsp1β mutants had lower levels of viremia than did WT virus-infected pigs. Compared to the WT virus in infected cells, all three mutated viruses stimulated high levels of IFN-α expression and exhibited a reduced ability to suppress the mRNA expression of selected interferon-stimulated genes (ISGs). In pigs infected with nsp1β mutants, IFN-α production was increased in the lungs at early time points postinfection, which was correlated with increased innate NK cell function. Furthermore, the augmented innate response was consistent with the increased production of IFN-γ in pigs infected with mutated viruses. These data demonstrate that residues R128 and R129 are critical for nsp1β function and that modifying these key residues in the GKYLQRRLQ motif attenuates virus growth ability and improves the innate and adaptive immune responses in infected animals.IMPORTANCEPRRSV infection induces poor antiviral innate IFN and cytokine responses, which results in weak adaptive immunity. One of the strategies in next-generation vaccine construction is to manipulate viral proteins/genetic elements involved in antagonizing the host immune response. PRRSV nsp1β was identified to be a strong innate immune antagonist. In this study, two basic amino acids, R128 and R129, in a highly conserved GKYLQRRLQ motif were determined to be critical for nsp1β function. Mutations introduced into these two residues attenuated virus growth and improved the innate and adaptive immune responses of infected animals. Technologies developed in this study could be broadly applied to current commercial PRRSV modified live-virus (MLV) vaccines and other candidate vaccines.

scholarly journals Crosstalk between Dendritic Cells and Immune Modulatory Agents against Sepsis

Genes ◽  
2020 ◽  
Vol 11 (3) ◽  
pp. 323 ◽  
Author(s):  
Guoying Wang ◽  
Xianghui Li ◽  
Lei Zhang ◽  
Abualgasim Elgaili Abdalla ◽  
Tieshan Teng ◽  
...  
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Critical Role ◽  
Innate Immune ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Th2 Responses ◽  
Novel Strategy

Dendritic cells (DCs) play a critical role in the immune system which sense pathogens and present their antigens to prime the adaptive immune responses. As the progression of sepsis occurs, DCs are capable of orchestrating the aberrant innate immune response by sustaining the Th1/Th2 responses that are essential for host survival. Hence, an in-depth understanding of the characteristics of DCs would have a beneficial effect in overcoming the obstacle occurring in sepsis. This paper focuses on the role of DCs in the progression of sepsis and we also discuss the reverse sepsis-induced immunosuppression through manipulating the DC function. In addition, we highlight some potent immunotherapies that could be used as a novel strategy in the early treatment of sepsis.

scholarly journals Novel Concepts for HIV Vaccine Vector Design

mSphere ◽  
2017 ◽  
Vol 2 (6) ◽  
Author(s):  
Quazim A. Alayo ◽  
Nicholas M. Provine ◽  
Pablo Penaloza-MacMaster
Keyword(s):  
Immune Responses ◽  
Viral Vectors ◽  
Vaccine Development ◽  
Viral Vector ◽  
Intracellular Pathogens ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Recent Advances ◽  
Robust Adaptive ◽  
Selection Of

ABSTRACT The unprecedented challenges of developing effective vaccines against intracellular pathogens such as HIV, malaria, and tuberculosis have resulted in more rational approaches to vaccine development. Apart from the recent advances in the design and selection of improved epitopes and adjuvants, there are also ongoing efforts to optimize delivery platforms. The unprecedented challenges of developing effective vaccines against intracellular pathogens such as HIV, malaria, and tuberculosis have resulted in more rational approaches to vaccine development. Apart from the recent advances in the design and selection of improved epitopes and adjuvants, there are also ongoing efforts to optimize delivery platforms. Viral vectors are the best-characterized delivery tools because of their intrinsic adjuvant capability, unique cellular tropism, and ability to trigger robust adaptive immune responses. However, a known limitation of viral vectors is preexisting immunity, and ongoing efforts are aimed at developing novel vector platforms with lower seroprevalence. It is also becoming increasingly clear that different vectors, even those derived from phylogenetically similar viruses, can elicit substantially distinct immune responses, in terms of quantity, quality, and location, which can ultimately affect immune protection. This review provides a summary of the status of viral vector development for HIV vaccines, with a particular focus on novel viral vectors and the types of adaptive immune responses that they induce.

PRRs in pathogen recognition

2006 ◽  
Vol 1 (3) ◽  
pp. 299-313 ◽  
Author(s):  
Satoshi Uematsu ◽  
Shizuo Akira
Keyword(s):  
Pattern Recognition ◽  
Immune Responses ◽  
Pattern Recognition Receptors ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Pathogen Recognition ◽  
First Line ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Wide Range

AbstractThe innate immune system provides the first line of host defense against invading microorganisms before the development of adaptive immune responses. Innate immune responses are initiated by germline-encoded pattern recognition receptors (PRRs), which recognize specific structures of microorganisms. Toll-like receptors (TLRs) are pattern-recognition receptors that sense a wide range of microorganisms, including bacteria, fungi, protozoa and viruses. TLRs exist either on the cell surface or in the lysosome/endosome compartment and induce innate immune responses. Recently, cytoplasmic PRRs have been identified which detect pathogens that have invaded the cytosol. This review focuses on the pathogen recognition of PRRs in innate immunity.

scholarly journals Tweaking Innate Immunity: The Promise of Innate Immunologicals as Anti-Infectives

2006 ◽  
Vol 17 (5) ◽  
pp. 307-314 ◽  
Author(s):  
Kenneth L Rosenthal
Keyword(s):  
Innate Immunity ◽  
Immune System ◽  
Immune Responses ◽  
Innate Immune System ◽  
Immune Defense ◽  
Innate Immune ◽  
Parasitic Infections ◽  
Type I ◽  
Adaptive Immune Responses ◽  
Adaptive Immune

New and exciting insights into the importance of the innate immune system are revolutionizing our understanding of immune defense against infections, pathogenesis, and the treatment and prevention of infectious diseases. The innate immune system uses multiple families of germline-encoded pattern recognition receptors (PRRs) to detect infection and trigger a variety of antimicrobial defense mechanisms. PRRs are evolutionarily highly conserved and serve to detect infection by recognizing pathogen-associated molecular patterns that are unique to microorganisms and essential for their survival. Toll-like receptors (TLRs) are transmembrane signalling receptors that activate gene expression programs that result in the production of proinflammatory cytokines and chemokines, type I interferons and antimicrobial factors. Furthermore, TLR activation facilitates and guides activation of adaptive immune responses through the activation of dendritic cells. TLRs are localized on the cell surface and in endosomal/lysosomal compartments, where they detect bacterial and viral infections. In contrast, nucleotide-binding oligomerization domain proteins and RNA helicases are located in the cell cytoplasm, where they serve as intracellular PRRs to detect cytoplasmic infections, particularly viruses. Due to their ability to enhance innate immune responses, novel strategies to use ligands, synthetic agonists or antagonists of PRRs (also known as 'innate immunologicals') can be used as stand-alone agents to provide immediate protection or treatment against bacterial, viral or parasitic infections. Furthermore, the newly appreciated importance of innate immunity in initiating and shaping adaptive immune responses is contributing to our understanding of vaccine adjuvants and promises to lead to improved next-generation vaccines.

Graft-versus-host disease: regulation by microbe-associated molecules and innate immune receptors

Blood ◽  
2010 ◽  
Vol 115 (10) ◽  
pp. 1865-1872 ◽  
Author(s):  
Olaf Penack ◽  
Ernst Holler ◽  
Marcel R. M. van den Brink
Keyword(s):  
Immune Responses ◽  
Graft Versus Host Disease ◽  
Molecular Mechanisms ◽  
Innate Immune ◽  
Adaptive Immune Responses ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Adaptive Immune ◽  
Immune Receptors

Abstract Acute graft-versus-host disease (GVHD) remains the major obstacle to a more favorable therapeutic outcome of allogeneic hematopoietic stem cell transplantation (HSCT). GVHD is characterized by tissue damage in gut, liver, and skin, caused by donor T cells that are critical for antitumor and antimicrobial immunity after HSCT. One obstacle in combating GVHD used to be the lack of understanding the molecular mechanisms that are involved in the initiation phase of this syndrome. Recent research has demonstrated that interactions between microbial-associated molecules (pathogen-associated molecular patterns [PAMPs]) and innate immune receptors (pathogen recognition receptors [PRRs]), such as NOD-like receptors (NLRs) and Toll-like receptors (TLRs), control adaptive immune responses in inflammatory disorders. Polymorphisms of the genes encoding NOD2 and TLR4 are associated with a higher incidence of GVHD in HSC transplant recipients. Interestingly, NOD2 regulates GVHD through its inhibitory effect on antigen-presenting cell (APC) function. These insights identify important mechanisms regarding the induction of GVHD through the interplay of microbial molecules and innate immunity, thus opening a new area for future therapeutic approaches. This review covers current knowledge of the role of PAMPs and PRRs in the control of adaptive immune responses during inflammatory diseases, particularly GVHD.

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