Progress on Poxvirus E3 Ubiquitin Ligases and Adaptor Proteins

Poxviruses have evolved a variety of innate immunity evasion mechanisms, some of which involve poxvirus-encoded E3 ubiquitin ligases and adaptor proteins. Based on their functional domains and ubiquitin transfer mechanisms, these poxvirus-encoded E3 ubiquitin ligases and adaptor proteins can be divided into five categories: PRANC, ANK/BC, BBK, P28/RING, and MARCH proteins. Although the substrates of many poxvirus E3 ubiquitin ligases remain to be discovered, most of the identified substrates are components of the innate immune system. In this review, we discuss the current research progress on poxvirus-encoded E3 ubiquitin ligases and adaptor proteins to provide mechanistic insights into the interplay between these viruses and their hosts.

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Innate immunity and the pneumococcus

Microbiology ◽

10.1099/mic.0.28551-0 ◽

2006 ◽

Vol 152 (2) ◽

pp. 285-293 ◽

Cited By ~ 52

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).

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P0022INNATE IMMUNE RESPONSES ELICITED BY TOLL-LIKE RECEPTORS ARE POSSIBLY INVOLVED IN THE PATHOGENESIS OF NEPHROTIC SYNDROME

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0022 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Eriko Tanaka ◽

Ichiro Hada ◽

Naoaki Mikami ◽

Kunimasa Yan

Keyword(s):

Innate Immunity ◽

Nephrotic Syndrome ◽

Immune System ◽

Innate Immune System ◽

Expression Profiles ◽

Kidney Tissue ◽

Innate Immune ◽

Rna Expression ◽

Toll Like Receptors ◽

Tissue Samples

Abstract Background and Aims Pathogenesis of idiopathic nephrotic syndrome (INS) is yet to be fully elucidated. Immunological disorders are reported to be involved in the etiology of INS. Due to the efficacy of immunosuppressant agents such as calcineurin inhibitor and rituximab in treating nephrotic syndrome, aberrant activation of the acquired immune system through T and B cells are considered to be the underlying pathogenic mechanisms of INS. Nevertheless, there is a possibility that the innate immune system plays a key role in INS pathogenesis. This study aims to investigate the involvement of innate immunity in INS pathogenesis by examining the expressions of toll-like receptors (TLRs). Method Kidney tissue samples from two INS patients were collected at two points of time: the first biopsy was performed during nephrosis and the second during remission. Total RNA was extracted from the kidney tissue samples, and RNA-sequencing was performed to investigate RNA expression profiles. The differences between RNA expression profiles of TLRs and molecules related to TLR pathways in the tissue samples collected during nephrosis and remission were analyzed. Results There was a significant decrease in RNA expression of TLR9 and TLR10 during remission compared to nephrosis: fold change in each patient was -2.12 and -2.12 for TLR9, and -2.51 and -2.09 for TLR10. RNA expression of TLR8 also decreased: fold change in each patient was -1.19 and -1.75. There were no significant changes in the RNA expression profiles of TLR1, 2, 3, 4, 5, 6, and 7. In addition, there were no differences in the RNA expression profiles of MYD88, IRAK family, and TRAF family molecules that are associated with TLR pathways. However, RNA expressions of IL6, IL1B, IL12B, and TNF, as well as the cytokines controlled by TLR8 and TLR9 pathways, which were activated during nephrosis, disappeared or decreased during remission. Conclusion The involvement of the innate immune system in the pathogenesis of nephrotic syndrome has been suggested in some reports. Based on the fact that the onset or recurrence of nephrosis is triggered by non-specific viral infection, it is highly possible that innate immunity is involved in the pathogenesis of nephrotic syndrome. TLRs play a key role in innate immunity as they elicit the innate immune system after detecting pathogens, induce inflammatory cytokine production, and trigger signaling pathways that activate lymphocytes via maturation of dendritic cells. Specifically, TLR8, 9, and 10 mediate pathways of the first immune response to viral infections. Our study reveals that TLRs play a pivotal role in innate immunity associated with renal tissue during the onset of nephrosis.

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Still Enigmatic: Innate Immunity in the Ctenophore Mnemiopsis leidyi

Integrative and Comparative Biology ◽

10.1093/icb/icz116 ◽

2019 ◽

Vol 59 (4) ◽

pp. 811-818 ◽

Cited By ~ 4

Author(s):

Nikki Traylor-Knowles ◽

Lauren E Vandepas ◽

William E Browne

Keyword(s):

Innate Immunity ◽

Immune System ◽

Innate Immune System ◽

Defense Mechanism ◽

Innate Immune ◽

Phylogenetic Position ◽

Mnemiopsis Leidyi ◽

Immunity Genes ◽

Review Current

Abstract Innate immunity is an ancient physiological response critical for protecting metazoans from invading pathogens. It is the primary pathogen defense mechanism among invertebrates. While innate immunity has been studied extensively in diverse invertebrate taxa, including mollusks, crustaceans, and cnidarians, this system has not been well characterized in ctenophores. The ctenophores comprise an exclusively marine, non-bilaterian lineage that diverged early during metazoan diversification. The phylogenetic position of ctenophore lineage suggests that characterization of the ctenophore innate immune system will reveal important features associated with the early evolution of the metazoan innate immune system. Here, we review current understanding of the ctenophore immune repertoire and identify innate immunity genes recovered from three ctenophore species. We also isolate and characterize Mnemiopsis leidyi cells that display macrophage-like behavior when challenged with bacteria. Our results indicate that ctenophores possess cells capable of phagocytosing microbes and that two distantly related ctenophores, M. leidyi and Hormiphora californiensis, possess many candidate innate immunity proteins.

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A Critical Role for Innate Immunity In Allogeneic Hematopoietic Cell Rejection Via the TLR4/TRIF Pathway

Blood ◽

10.1182/blood.v116.21.77.77 ◽

2010 ◽

Vol 116 (21) ◽

pp. 77-77

Author(s):

Hong Xu ◽

Jun Yan ◽

Ziqiang Zhu ◽

Yiming Huang ◽

Yujie Wen ◽

...

Keyword(s):

Bone Marrow ◽

Innate Immunity ◽

T Cells ◽

Immune System ◽

T Cell ◽

Innate Immune System ◽

Critical Role ◽

Innate Immune ◽

Wild Type

Abstract Abstract 77 Adaptive immunity, especially T cells, has long been believed to be the dominant immune barrier in allogeneic transplantation. Targeting host T cells significantly reduces conditioning for bone marrow cell (BMC) engraftment. Innate immunity has been recently shown to pose a significant barrier in solid organ transplantation, but has not been addressed in bone marrow transplantation (BMT). Using T cell deficient (TCR-β/δ−/−) or T and B cell deficient (Rag−/−) mice, we found that allogeneic BMC rejection occurred early before the time required for T cell activation and was T- and B-cell independent, suggesting an effector role for innate immune cells in BMC rejection. Therefore, we hypothesized that by controlling both innate and adaptive immunity, the donor BMC would have a window of advantage to engraft. Survival of BMC in vivo was significantly improved by depleting recipient macrophages and/or NK cells, but not neutrophils. Moreover, depletion of macrophages and NK cells in combination with co-stimulatory blockade with anti-CD154 and rapamycin as a novel form of conditioning resulted in 100% allogeneic engraftment without any irradiation and T cell depletion. Donor chimerism remained stable and durable up to 6 months. Moreover, specific Vβ5½ and Vβ11 clonal deletion was detected in host CD4+ T cells in chimeras, indicating central tolerance to donor alloantigens. Whether and how the innate immune system recognizes or responds to allogeneic BMCs remains unknown. Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. The signaling function of TLR depends on intracellular adaptors. The adaptor MyD88 transmits signals emanating from all TLR, except TLR3 while TRIF specifically mediates TLR3 and TLR4 signaling via type 1 IFN. To further determine the innate signaling pathways in allogeneic BMC rejection, B6 background (H2b) MyD88−/− and TRIF−/− mice were conditioned with anti-CD154/rapamycin plus 100 cGy total body irradiation and transplanted with 15 × 106 BALB/c (H2d) BMC. Only 33.3% of MyD88−/− recipients engrafted at 1 month, resembling outcomes for wild-type B6 mice. In contrast, 100% of TRIF−/− mice engrafted. The level of donor chimerism in TRIF−/− mice was 5.1 ± 0.6% at one month, significantly higher than in MyD88−/− and wild-type B6 controls (P < 0.005). To determine the mechanism of innate signaling in BMC rejection, we examined whether TRIF linked TLR3 or TLR4 is the key pattern recognition receptor involved in BMC recognition. To this end, TLR3−/− and TLR4−/− mice were transplanted with BALB/c BMC with same conditioning. None of the TLR3−/− mice engrafted. In contrast, engraftment was achieved in 100% of TLR4−/− mice up to 6 months follow up. Taken together, these results suggest that rejection of allogeneic BMC is uniquely dependent on the TLR4/TRIF signaling pathway. Thus, our results clearly demonstrate a previously unappreciated role for innate immunity in allogeneic BMC rejection. Our current findings are distinct from prior reports demonstrating a critical role of MyD88 in rejection of allogeneic skin grafts and lung, and may reflect unique features related to BMC. The findings of the role of innate immunity in BMC rejection would lead to revolutionary changes in our understanding and management of BMT. This would be informative in design of more specific innate immune targeted conditioning proposals in BMT to avoid the toxicity. Disclosures: Bozulic: Regenerex LLC: Employment. Ildstad:Regenerex LLC: Equity Ownership.

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Interaction of Antibiotics with Innate Host Defense Factors against Salmonella enterica Serotype Newport

mSphere ◽

10.1128/msphere.00410-17 ◽

2017 ◽

Vol 2 (6) ◽

Cited By ~ 15

Author(s):

George Sakoulas ◽

Monika Kumaraswamy ◽

Armin Kousha ◽

Victor Nizet

Keyword(s):

Innate Immunity ◽

Immune System ◽

Innate Immune System ◽

Salmonella Enterica ◽

Clinical Performance ◽

Innate Immune ◽

Content Type ◽

Antimicrobial Assay

ABSTRACT It is becoming increasingly understood that the current paradigms of in vitro antimicrobial susceptibility testing may have significant shortcomings in predicting activity in vivo. This study evaluated the activity of several antibiotics alone and in combination against clinical isolates of Salmonella enterica serotype Newport (meningitis case) utilizing both conventional and physiological media. In addition, the interactions of these antibiotics with components of the innate immune system were evaluated. Azithromycin, which has performed quite well clinically despite high MICs in conventional media, was shown to be more active in physiological media and to enhance innate immune system killing. Alternatively, chloramphenicol did not show enhanced immune system killing, paralleling its inferior clinical performance to other antibiotics that have been used to treat Salmonella meningitis. These findings are important additions to the building understanding of current in vitro antimicrobial assay limitations that hopefully will amount to future improvements in these assays to better predict clinical efficacy and activity in vivo. This study examines the pharmacodynamics of antimicrobials that are used to treat Salmonella with each other and with key components of the innate immune system. Antimicrobial synergy was assessed using time-kill and checkerboard assays. Antimicrobial interactions with innate immunity were studied by employing cathelicidin LL-37, whole-blood, and neutrophil killing assays. Ceftriaxone and ciprofloxacin were found to be synergistic in vitro against Salmonella enterica serotype Newport. Ceftriaxone, ciprofloxacin, and azithromycin each demonstrated synergy with the human cathelicidin defense peptide LL-37 in killing Salmonella. Exposure of Salmonella to sub-MICs of ceftriaxone resulted in enhanced susceptibility to LL-37, whole blood, and neutrophil killing. The activity of antibiotics in vivo against Salmonella may be underestimated in bacteriologic media lacking components of innate immunity. The pharmacodynamic interactions of antibiotics used to treat Salmonella with each other and with components of innate immunity warrant further study in light of recent findings showing in vivo selection of antimicrobial resistance by single agents in this pathogen. IMPORTANCE It is becoming increasingly understood that the current paradigms of in vitro antimicrobial susceptibility testing may have significant shortcomings in predicting activity in vivo. This study evaluated the activity of several antibiotics alone and in combination against clinical isolates of Salmonella enterica serotype Newport (meningitis case) utilizing both conventional and physiological media. In addition, the interactions of these antibiotics with components of the innate immune system were evaluated. Azithromycin, which has performed quite well clinically despite high MICs in conventional media, was shown to be more active in physiological media and to enhance innate immune system killing. Alternatively, chloramphenicol did not show enhanced immune system killing, paralleling its inferior clinical performance to other antibiotics that have been used to treat Salmonella meningitis. These findings are important additions to the building understanding of current in vitro antimicrobial assay limitations that hopefully will amount to future improvements in these assays to better predict clinical efficacy and activity in vivo.

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Toll-like receptors and hypertension

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00194.2014 ◽

2014 ◽

Vol 307 (5) ◽

pp. R501-R504 ◽

Cited By ~ 27

Author(s):

Madhu V. Singh ◽

François M. Abboud

Keyword(s):

Immune System ◽

Innate Immune System ◽

Expression Patterns ◽

Adaptor Proteins ◽

Nuclear Factor Κb ◽

Innate Immune ◽

Toll Like Receptors ◽

Cardiovascular Damage ◽

Inflammatory Processes ◽

Molecular Patterns

Hypertension and associated inflammatory processes that accelerate cardiovascular damage are regulated by the innate immune system. Toll-like receptors (TLR) are major components of the innate immune system that recognize endogenous damage-associated molecular patterns to activate prominent inflammatory signaling including activation of nuclear factor-κB (NF-κB). However, the role of TLR in the etiology of hypertension is not well understood. TLR signaling is dependent on adaptor proteins that, along with the TLR expression patterns, confer specificity of the inflammatory response and its pathological targets. Here we review the conceptual framework of how TLR and their adaptor proteins may differentially affect hypertension and cardiac hypertrophy by different stimuli.

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Clinical Immunology and Innate Immunity

10.2310/anes.2225 ◽

2019 ◽

Author(s):

Lung-Yi Lee ◽

David P Foley

Keyword(s):

Innate Immunity ◽

Immune System ◽

Innate Immune System ◽

Innate Immune ◽

Solid Organ ◽

Daily Lives ◽

Organ Rejection ◽

Vein Thrombosis ◽

Molecular Pattern ◽

Clinical Scenarios

Our body encounters a multitude of microorganisms in our daily lives. Due to surveillance of our robust immune system, these microbial encounters remain largely benign and only become pathologic at times. The majority of these pathogens are cleared rapidly by our innate immune system. The innate immune system is our body’s first line of defense that mounts a nonspecific response against pathogens. In this review, a contemporary summary of this complex system and its relevance to disease processes that are commonly seen in the surgical setting are presented, including components and activation of innate immunity, and relevant clinical scenarios. This review contains 10 figures, 11 tables, and 32 references. Keywords: Innate immunity, humoral immunity, phagocytosis, neutrophils, macrophages, pathogen-associated molecular pattern, damage-associated molecular pattern, wound healing, sepsis, SIRS, deep vein thrombosis, solid-organ rejection

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Innate Immunity Is Responsible for Early Allorejection of Donor Bone Marrow Cells.

Blood ◽

10.1182/blood.v114.22.3523.3523 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3523-3523

Author(s):

Hong Xu ◽

Jun Yan ◽

Ziqiang Zhu ◽

Lala-Rukh Hussain ◽

Yiming Huang ◽

...

Keyword(s):

Bone Marrow ◽

Innate Immunity ◽

Immune System ◽

T Cell ◽

Innate Immune System ◽

Immune Cell ◽

Marrow Cell ◽

Donor Cell ◽

Innate Immune ◽

Kinetics Of

Abstract Abstract 3523 Poster Board III-460 Adaptive immunity, especially T cells, has long been believed to be the dominant immune response in allogeneic transplantation. However, innate immunity has been recently shown to pose a significant barrier to the induction of tolerance to solid organ transplants. The role of the innate immune system in bone marrow cell alloreactivity has not been addressed. The innate immune system provides the first line of defense in the removal of pathogens because of the delay in generation of adaptive immune responses. Our present findings show that innate immunity is a significant first line barrier in bone marrow cell (BMC) rejection. To determine the effect of innate immune cell populations on rejection of donor BMCs, T cell deficient mice (TCR β/δ−/−) were used as BMC recipients in in vivo cytotoxicity assays (Figure A). TCRβ/δ−/− mice have normal innate immune cell populations but do not initiate adaptive cell-mediated cytotoxic or humoral responses. 20 × 106 CFSE labeled donor (high CFSE fluorescence intensity) and recipient control splenocytes (low CFSE fluorescence intensity) were injected into TCRβ/δ−/− and wildtype control B6 recipient mice. Donor cell survival was compared over time. Donor BALB/c splenocytes were eliminated in wildtype B6, with rejection complete by day 3. The kinetics of elimination of donor cells in TCRβ/δ−/− mice was similar to that for wildtype B6 controls, with donor cells eliminated by day 3. These results indicate that early rejection of the splenocytes in wildtype mice was T cell-independent. The acute rejection of BMC in wildtype B6 recipients occurred within 3 days, which is prior to the time required for T cell activation. Thus the effectors mediating BMC rejection would be the innate immune cells: macrophages, neutrophils, or NK cells. To rule out potential involvement of natural Abs in the cytotoxicity we observed in the TCRβ/δ−/− mice, Rag−/− mice were used as recipients (Figure B). Rag−/− mice do not produce mature T cells or B cells. 20 × 106 CFSE labeled donor (high CFSE intensity) and recipient control BM cells (low CFSE intensity) were injected into Rag−/−mice. Rag−/− and wildtype B6 control mice exhibited similar kinetics of donor cell cytolysis. The rapid elimination of allogeneic cells from immunocompetent mice is comparable with that observed in T cell- (TCRβ/δ−/−) or T and B cell- (Rag−/−) deficient mice indicates that allogeneic cells are subject to T cell-independent rejection at the early time period after cell infusion (≤ 3 days). As the kinetics of cytotoxicity were similar in experiments using either splenocytes or BMCs as target cells in our later experiments, our data suggest that the innate immune system is responsible for early allorejection of donor BMC at the early inductive period for adaptive immunity. These findings may have significant impact on the development of immune-based nonmyeloablative conditioning strategies and show for the first time that a dominant factor in BMC rejection is contributed by innate immune responses. Disclosures: Bozulic: Regenerex: Employment. Ildstad:Regenerex: Equity Ownership.

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Stress Hyperglycemia, Insulin Treatment, and Innate Immune Cells

International Journal of Endocrinology ◽

10.1155/2014/486403 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 41

Author(s):

Fangming Xiu ◽

Mile Stanojcic ◽

Li Diao ◽

Marc G. Jeschke

Keyword(s):

Insulin Resistance ◽

Innate Immunity ◽

Immune System ◽

Critical Illness ◽

Immune Cells ◽

Innate Immune System ◽

Insulin Treatment ◽

Innate Immune ◽

Morbidity And Mortality ◽

Innate Immune Cells

Hyperglycemia (HG) and insulin resistance are the hallmarks of a profoundly altered metabolism in critical illness resulting from the release of cortisol, catecholamines, and cytokines, as well as glucagon and growth hormone. Recent studies have proposed a fundamental role of the immune system towards the development of insulin resistance in traumatic patients. A comprehensive review of published literatures on the effects of hyperglycemia and insulin on innate immunity in critical illness was conducted. This review explored the interaction between the innate immune system and trauma-induced hypermetabolism, while providing greater insight into unraveling the relationship between innate immune cells and hyperglycemia. Critical illness substantially disturbs glucose metabolism resulting in a state of hyperglycemia. Alterations in glucose and insulin regulation affect the immune function of cellular components comprising the innate immunity system. Innate immune system dysfunction via hyperglycemia is associated with a higher morbidity and mortality in critical illness. Along with others, we hypothesize that reduction in morbidity and mortality observed in patients receiving insulin treatment is partially due to its effect on the attenuation of the immune response. However, there still remains substantial controversy regarding moderate versus intensive insulin treatment. Future studies need to determine the integrated effects of HG and insulin on the regulation of innate immunity in order to provide more effective insulin treatment regimen for these patients.

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

Canadian Journal of Infectious Diseases and Medical Microbiology ◽

10.1155/2006/195957 ◽

2006 ◽

Vol 17 (5) ◽

pp. 307-314 ◽

Cited By ~ 8

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.

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