Activation and evasion of innate immune signaling pathways by Yersinia pestis

Mapping Intimacies ◽

10.32469/10355/57356 ◽

2016 ◽

Author(s):

◽

Miqdad Onali Dhariwala

Keyword(s):

Immune System ◽

Immune Responses ◽

Yersinia Pestis ◽

Immune Cells ◽

Bacterial Pathogen ◽

The Body ◽

Type I ◽

Type I Ifn ◽

Virus Infections ◽

Immune Signaling

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Yersinia pestis is a bacterial pathogen that causes the disease plague in mammals. The disease is rapidly lethal and infected individuals can succumb to the disease in as less as three days post-infection. This suggests that the immune system completely fails at restricting bacterial growth and eliminating the bacteria from the body. We therefore used Y. pestis to study its interactions with the mammalian immune system to gain a deeper understanding of the pathogens strategy to overcome immune responses. We identified that Y. pestis activates Toll-like receptor 7 (TLR7), traditionally considered a mammalian sensor of virus infections. We further demonstrate that this bacterium activates TLR7 to promote mammalian immune cells to produce the type I interferon (IFN), interferon beta, a cytokine released by cells of the immune system in response to infection. In this work we demonstrate that TLR7 and type I IFN are vital for Y. pestis to cause plague. Moreover, we show that this bacterium triggers a previously unknown immune signaling pathway in mammalian immune cells. Since we showed that TLR7 and type I IFN are required for this pathogen to cause plague we can potentially use this information to better design therapeutic strategies that potentiate immune responses. Such strategies can help us move away from the extensive use of antibiotics and circumvent the emerging problem of antibiotic resistance.

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Innate immune responses elicited by Sin Nombre virus or type I IFN agonists protect hamsters from lethal Andes virus infections

Journal of General Virology ◽

10.1099/jgv.0.001131 ◽

2018 ◽

Vol 99 (10) ◽

pp. 1359-1366 ◽

Cited By ~ 3

Author(s):

Rebecca L. Brocato ◽

Victoria Wahl ◽

Christopher D. Hammerbeck ◽

Matthew D. Josleyn ◽

Anita K. McElroy ◽

...

Keyword(s):

Immune Responses ◽

Innate Immune ◽

Sin Nombre Virus ◽

Type I ◽

Type I Ifn ◽

Innate Immune Responses ◽

Virus Infections ◽

Andes Virus

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Herpes simplex virus 1 targets IRF7 via ICP0 to limit type I IFN induction

Scientific Reports ◽

10.1038/s41598-020-77725-4 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

David Shahnazaryan ◽

Rana Khalil ◽

Claire Wynne ◽

Caroline A. Jefferies ◽

Joan Ní Gabhann-Dromgoole ◽

...

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Immune Responses ◽

Tear Film ◽

Cell Protein ◽

Type I ◽

Type I Ifn ◽

Herpes Simplex Virus 1 ◽

Simplex Virus ◽

Hsv 1

AbstractHerpes simplex keratitis (HSK), caused by herpes simplex virus type 1 (HSV-1) infection, is the commonest cause of infectious blindness in the developed world. Following infection the virus is initially suspended in the tear film, where it encounters a multi-pronged immune response comprising enzymes, complement, immunoglobulins and crucially, a range of anti-viral and pro-inflammatory cytokines. However, given that HSV-1 can overcome innate immune responses to establish lifelong latency throughout a susceptible individual’s lifetime, there is significant interest in understanding the mechanisms employed by HSV-1 to downregulate the anti-viral type I interferon (IFN) mediated immune responses. This study aimed to investigate the interactions between infected cell protein (ICP)0 and key elements of the IFN pathway to identify possible novel targets that contribute to viral immune evasion. Reporter gene assays demonstrated the ability of ICP0 to inhibit type I IFN activity downstream of pathogen recognition receptors (PRRs) which are known to be involved in host antiviral defences. Further experiments identified interferon regulatory factor (IRF)7, a driver of type I IFN, as a potential target for ICP0. These findings increase our understanding of the pathogenesis of HSK and suggest IRF7 as a potential therapeutic target.

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The immune response of T cells and therapeutic targets related to regulating the levels of T helper cells after ischaemic stroke

Journal of Neuroinflammation ◽

10.1186/s12974-020-02057-z ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Tian-Yu Lei ◽

Ying-Ze Ye ◽

Xi-Qun Zhu ◽

Daniel Smerin ◽

Li-Juan Gu ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Immune System ◽

Immune Responses ◽

Ischaemic Stroke ◽

Immune Cells ◽

Tissue Injury ◽

Recovery Period ◽

Vital Functions ◽

Anti Inflammatory

AbstractThrough considerable effort in research and clinical studies, the immune system has been identified as a participant in the onset and progression of brain injury after ischaemic stroke. Due to the involvement of all types of immune cells, the roles of the immune system in stroke pathology and associated effects are complicated. Past research concentrated on the functions of monocytes and neutrophils in the pathogenesis of ischaemic stroke and tried to demonstrate the mechanisms of tissue injury and protection involving these immune cells. Within the past several years, an increasing number of studies have elucidated the vital functions of T cells in the innate and adaptive immune responses in both the acute and chronic phases of ischaemic stroke. Recently, the phenotypes of T cells with proinflammatory or anti-inflammatory function have been demonstrated in detail. T cells with distinctive phenotypes can also influence cerebral inflammation through various pathways, such as regulating the immune response, interacting with brain-resident immune cells and modulating neurogenesis and angiogenesis during different phases following stroke. In view of the limited treatment options available following stroke other than tissue plasminogen activator therapy, understanding the function of immune responses, especially T cell responses, in the post-stroke recovery period can provide a new therapeutic direction. Here, we discuss the different functions and temporal evolution of T cells with different phenotypes during the acute and chronic phases of ischaemic stroke. We suggest that modulating the balance between the proinflammatory and anti-inflammatory functions of T cells with distinct phenotypes may become a potential therapeutic approach that reduces the mortality and improves the functional outcomes and prognosis of patients suffering from ischaemic stroke.

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Role of the Innate Immunity Signaling Pathway in the Pathogenesis of Sjögren’s Syndrome

International Journal of Molecular Sciences ◽

10.3390/ijms22063090 ◽

2021 ◽

Vol 22 (6) ◽

pp. 3090

Author(s):

Toshimasa Shimizu ◽

Hideki Nakamura ◽

Atsushi Kawakami

Keyword(s):

Immune Responses ◽

Sjögren's Syndrome ◽

Sjogren’S Syndrome ◽

Sjogren's Syndrome ◽

Innate Immune ◽

Type I ◽

Type I Ifn ◽

Adaptive Immune ◽

Sjögren‘S Syndrome

Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by chronic inflammation of the salivary and lacrimal glands and extra-glandular lesions. Adaptive immune response including T- and B-cell activation contributes to the development of SS. However, its pathogenesis has not yet been elucidated. In addition, several patients with SS present with the type I interferon (IFN) signature, which is the upregulation of the IFN-stimulated genes induced by type I IFN. Thus, innate immune responses including type I IFN activity are associated with SS pathogenesis. Recent studies have revealed the presence of activation pattern recognition receptors (PRRs) including Toll-like receptors, RNA sensor retinoic acid-inducible gene I and melanoma differentiation-associated gene 5, and inflammasomes in infiltrating and epithelial cells of the salivary glands among patients with SS. In addition, the activation of PRRs via the downstream pathway such as the type I IFN signature and nuclear factor kappa B can directly cause organ inflammation, and it is correlated with the activation of adaptive immune responses. Therefore, this study assessed the role of the innate immune signal pathway in the development of inflammation and immune abnormalities in SS.

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Epigenetic therapy activates type I interferon signaling in murine ovarian cancer to reduce immunosuppression and tumor burden

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1712514114 ◽

2017 ◽

Vol 114 (51) ◽

pp. E10981-E10990 ◽

Cited By ~ 82

Author(s):

Meredith L. Stone ◽

Katherine B. Chiappinelli ◽

Huili Li ◽

Lauren M. Murphy ◽

Meghan E. Travers ◽

...

Keyword(s):

Ovarian Cancer ◽

Tumor Microenvironment ◽

Immune Cells ◽

Immune Checkpoint ◽

Histone Deacetylase Inhibitors ◽

Unmet Need ◽

Tumor Burden ◽

Epigenetic Therapy ◽

Type I ◽

Type I Ifn

Ovarian cancer is the most lethal of all gynecological cancers, and there is an urgent unmet need to develop new therapies. Epithelial ovarian cancer (EOC) is characterized by an immune suppressive microenvironment, and response of ovarian cancers to immune therapies has thus far been disappointing. We now find, in a mouse model of EOC, that clinically relevant doses of DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi, respectively) reduce the immune suppressive microenvironment through type I IFN signaling and improve response to immune checkpoint therapy. These data indicate that the type I IFN response is required for effective in vivo antitumorigenic actions of the DNMTi 5-azacytidine (AZA). Through type I IFN signaling, AZA increases the numbers of CD45+ immune cells and the percentage of active CD8+ T and natural killer (NK) cells in the tumor microenvironment, while reducing tumor burden and extending survival. AZA also increases viral defense gene expression in both tumor and immune cells, and reduces the percentage of macrophages and myeloid-derived suppressor cells in the tumor microenvironment. The addition of an HDACi to AZA enhances the modulation of the immune microenvironment, specifically increasing T and NK cell activation and reducing macrophages over AZA treatment alone, while further increasing the survival of the mice. Finally, a triple combination of DNMTi/HDACi plus the immune checkpoint inhibitor α-PD-1 provides the best antitumor effect and longest overall survival, and may be an attractive candidate for future clinical trials in ovarian cancer.

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Type I Interferon Inhibition and Dendritic Cell Activation during Gammaherpesvirus Respiratory Infection

Journal of Virology ◽

10.1128/jvi.00360-07 ◽

2007 ◽

Vol 81 (18) ◽

pp. 9778-9789 ◽

Cited By ~ 24

Author(s):

Janet L. Weslow-Schmidt ◽

Nancy A. Jewell ◽

Sara E. Mertz ◽

J. Pedro Simas ◽

Joan E. Durbin ◽

...

Keyword(s):

Dendritic Cells ◽

Dendritic Cell ◽

Cell Activation ◽

Type I Interferon ◽

Plasmacytoid Dendritic Cells ◽

The Body ◽

Type I ◽

Type I Ifn ◽

Dendritic Cell Activation ◽

Murine Gammaherpesvirus

ABSTRACT The respiratory tract is a major mucosal site for microorganism entry into the body, and type I interferon (IFN) and dendritic cells constitute a first line of defense against viral infections. We have analyzed the interaction between a model DNA virus, plasmacytoid dendritic cells, and type I IFN during lung infection of mice. Our data show that murine gammaherpesvirus 68 (γHV68) inhibits type I IFN secretion by dendritic cells and that plasmacytoid dendritic cells are necessary for conventional dendritic cell maturation in response to γHV68. Following γHV68 intranasal inoculation, the local and systemic IFN-α/β response is below detectable levels, and plasmacytoid dendritic cells are activated and recruited into the lung with a tissue distribution that differs from that of conventional dendritic cells. Our results suggest that plasmacytoid dendritic cells and type I IFN have important but independent roles during the early response to a respiratory γHV68 infection. γHV68 infection inhibits type I IFN production by dendritic cells and is a poor inducer of IFN-α/β in vivo, which may serve as an immune evasion strategy.

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The opportunistic intracellular bacterial pathogen Rhodococcus equi elicits type I interferons by engaging cytosolic DNA sensing in macrophages

10.1101/2021.03.28.437424 ◽

2021 ◽

Author(s):

Krystal J Vail ◽

Bibiana Petri da Silveira ◽

Samantha L Bell ◽

Angela I Bordin ◽

Noah D Cohen ◽

...

Keyword(s):

Bacterial Pathogen ◽

Opportunistic Pathogen ◽

Rhodococcus Equi ◽

Type I Interferons ◽

Type I ◽

Type I Ifn ◽

Dna Sensing ◽

Interferon Stimulated Genes ◽

Galectin 3 ◽

Dna Release

Rhodococcus equi is a major cause of foal pneumonia and an opportunistic pathogen in immunocompromised humans. While alveolar macrophages constitute the primary replicative niche for R. equi, little is known about how intracellular R. equi is sensed by macrophages. Here, we discovered that that in addition to previously characterized pro-inflammatory cytokines (e.g., Tnfa, Il6, Il1b), macrophages infected with R. equi induce a robust type I IFN response, including Ifnb and interferon-stimulated genes (ISGs), similar to the evolutionarily related pathogen, Mycobacterium tuberculosis. Follow up studies using a combination of mammalian and bacterial genetics, demonstrated that induction of this type I IFN expression program is largely dependent on the cGAS/STING/TBK1 axis of the cytosolic DNA surveillance pathway, suggesting that R. equi perturbs the phagosomal membrane and causes DNA release into the cytosol following phagocytosis. Consistent with this we found that a population of ~12% of R. equi phagosomes recruited the galectin-3, -8 and -9 danger receptors. Interesting, neither phagosomal damage nor induction of type I IFN required the R. equi's virulence-associated plasmid. Importantly, R. equi infection of both mice and foals stimulated ISG expression, in organs (mice) and circulating monocytes (foals). By demonstrating that R. equi activates cytosolic DNA sensing in macrophages and elicits type I IFN responses in animal models, our work provides novel insights into how R. equi engages the innate immune system and furthers our understanding how this zoonotic pathogen causes inflammation and disease.

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Regulatory Immune Cells in Idiopathic Pulmonary Fibrosis: Friends or Foes?

Frontiers in Immunology ◽

10.3389/fimmu.2021.663203 ◽

2021 ◽

Vol 12 ◽

Author(s):

Chiel van Geffen ◽

Astrid Deißler ◽

Markus Quante ◽

Harald Renz ◽

Dominik Hartl ◽

...

Keyword(s):

Immune System ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Immune Responses ◽

Immune Cells ◽

Current Knowledge ◽

Suppressor Cells ◽

Interstitial Lung Diseases ◽

Stromal Stem Cells

The immune system is receiving increasing attention for interstitial lung diseases, as knowledge on its role in fibrosis development and response to therapies is expanding. Uncontrolled immune responses and unbalanced injury-inflammation-repair processes drive the initiation and progression of idiopathic pulmonary fibrosis. The regulatory immune system plays important roles in controlling pathogenic immune responses, regulating inflammation and modulating the transition of inflammation to fibrosis. This review aims to summarize and critically discuss the current knowledge on the potential role of regulatory immune cells, including mesenchymal stromal/stem cells, regulatory T cells, regulatory B cells, macrophages, dendritic cells and myeloid-derived suppressor cells in idiopathic pulmonary fibrosis. Furthermore, we review the emerging role of regulatory immune cells in anti-fibrotic therapy and lung transplantation. A comprehensive understanding of immune regulation could pave the way towards new therapeutic or preventive approaches in idiopathic pulmonary fibrosis.

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Physical plasma and leukocytes – immune or reactive?

Biological Chemistry ◽

10.1515/hsz-2018-0224 ◽

2018 ◽

Vol 400 (1) ◽

pp. 63-75 ◽

Cited By ~ 10

Author(s):

Sander Bekeschus ◽

Christian Seebauer ◽

Kristian Wende ◽

Anke Schmidt

Keyword(s):

Wound Healing ◽

Immune System ◽

Plasma Treatment ◽

Immune Cells ◽

The Body ◽

Adaptive Immune ◽

Adaptive Immune Cells ◽

Physical Plasma

AbstractLeukocytes are professionals in recognizing and removing pathogenic or unwanted material. They are present in virtually all tissues, and highly motile to enter or leave specific sites throughout the body. Less than a decade ago, physical plasmas entered the field of medicine to deliver their delicate mix of reactive species and other physical agents for mainly dermatological or oncological therapy. Plasma treatment thus affects leukocytes via direct or indirect means: immune cells are either present in tissues during treatment, or infiltrate or exfiltrate plasma-treated areas. The immune system is crucial for human health and resolution of many types of diseases. It is therefore vital to study the response of leukocytes after plasma treatmentin vitroandin vivo. This review gathers together the major themes in the plasma treatment of innate and adaptive immune cells, and puts these into the context of wound healing and oncology, the two major topics in plasma medicine.

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