New Insights into the Host–Pathogen Interaction of Mycoplasma gallisepticum and Avian Metapneumovirus in Tracheal Organ Cultures of Chicken

Respiratory pathogens are a health threat for poultry. Co-infections lead to the exacerbation of clinical symptoms and lesions. Mycoplasma gallisepticum (M. gallispeticum) and Avian Metapneumovirus (AMPV) are two avian respiratory pathogens that co-circulate worldwide. The knowledge about the host–pathogen interaction of M. gallispeticum and AMPV in the chicken respiratory tract is limited. We aimed to investigate how co-infections affect the pathogenesis of the respiratory disease and whether the order of invading pathogens leads to changes in host–pathogen interaction. We used chicken tracheal organ cultures (TOC) to investigate pathogen invasion and replication, lesion development, and selected innate immune responses, such as interferon (IFN) α, inducible nitric oxide synthase (iNOS) and IFNλ mRNA expression levels. We performed mono-inoculations (AMPV or M. gallispeticum) or dual-inoculations in two orders with a 24-h interval between the first and second pathogen. Dual-inoculations compared to mono-inoculations resulted in more severe host reactions. Pre-infection with AMPV followed by M. gallispeticum resulted in prolonged viral replication, more significant innate immune responses, and lesions (p < 0.05). AMPV as the secondary pathogen impaired the bacterial attachment process. Consequently, the M. gallispeticum replication was delayed, the innate immune response was less pronounced, and lesions appeared later. Our results suggest a competing process in co-infections and offer new insights in disease processes.

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Allosteric coupling between Mn2+ and dsDNA controls the catalytic efficiency and fidelity of cGAS

Nucleic Acids Research ◽

10.1093/nar/gkaa084 ◽

2020 ◽

Vol 48 (8) ◽

pp. 4435-4447 ◽

Cited By ~ 4

Author(s):

Richard M Hooy ◽

Guido Massaccesi ◽

Kimberly E Rousseau ◽

Michael A Chattergoon ◽

Jungsan Sohn

Keyword(s):

Immune Responses ◽

Catalytic Efficiency ◽

Genotoxic Stress ◽

Innate Immune ◽

Activation Mechanism ◽

Innate Immune Responses ◽

Allosteric Coupling ◽

Pathogen Invasion ◽

Length Dependent Activation ◽

Dsdna Binding

Abstract Cyclic-G/AMP (cGAMP) synthase (cGAS) triggers host innate immune responses against cytosolic double-stranded (ds)DNA arising from genotoxic stress and pathogen invasion. The canonical activation mechanism of cGAS entails dsDNA-binding and dimerization. Here, we report an unexpected activation mechanism of cGAS in which Mn2+ activates monomeric cGAS without dsDNA. Importantly, the Mn2+-mediated activation positively couples with dsDNA-dependent activation in a concerted manner. Moreover, the positive coupling between Mn2+ and dsDNA length-dependent activation requires the cognate ATP/GTP substrate pair, while negative-cooperativity suppresses Mn2+ utilization by either ATP or GTP alone. Additionally, while Mn2+ accelerates the overall catalytic activity, dsDNA length-dependent dimerization specifically accelerates the cyclization of cGAMP. Together, we demonstrate how the intrinsic allostery of cGAS efficiently yet precisely tunes its activity.

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Functional Roles of Syk in Macrophage-Mediated Inflammatory Responses

Mediators of Inflammation ◽

10.1155/2014/270302 ◽

2014 ◽

Vol 2014 ◽

pp. 1-12 ◽

Cited By ~ 71

Author(s):

Young-Su Yi ◽

Young-Jin Son ◽

Chongsuk Ryou ◽

Gi-Ho Sung ◽

Jong-Hoon Kim ◽

...

Keyword(s):

Immune Responses ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Innate Immune ◽

Innate Immune Responses ◽

Adaptive Immune Responses ◽

Functional Roles ◽

Pathogen Invasion ◽

Adaptive Immune ◽

Biological Responses

Inflammation is a series of complex biological responses to protect the host from pathogen invasion. Chronic inflammation is considered a major cause of diseases, such as various types of inflammatory/autoimmune diseases and cancers. Spleen tyrosine kinase (Syk) was initially found to be highly expressed in hematopoietic cells and has been known to play crucial roles in adaptive immune responses. However, recent studies have reported that Syk is also involved in other biological functions, especially in innate immune responses. Although Syk has been extensively studied in adaptive immune responses, numerous studies have recently presented evidence that Syk has critical functions in macrophage-mediated inflammatory responses and is closely related to innate immune response. This review describes the characteristics of Syk-mediated signaling pathways, summarizes the recent findings supporting the crucial roles of Syk in macrophage-mediated inflammatory responses and diseases, and discusses Syk-targeted drug development for the therapy of inflammatory diseases.

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Tropism of and Innate Immune Responses to the Novel Human Betacoronavirus Lineage C Virus in Human Ex Vivo Respiratory Organ Cultures

Journal of Virology ◽

10.1128/jvi.00009-13 ◽

2013 ◽

Vol 87 (12) ◽

pp. 6604-6614 ◽

Cited By ~ 110

Author(s):

R. W. Y. Chan ◽

M. C. W. Chan ◽

S. Agnihothram ◽

L. L. Y. Chan ◽

D. I. T. Kuok ◽

...

Keyword(s):

Immune Responses ◽

Ex Vivo ◽

Innate Immune ◽

The Novel ◽

Innate Immune Responses ◽

Organ Cultures ◽

Respiratory Organ

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Pathogen invasion changes the intestinal microbiota composition and induces innate immune responses in the zebrafish intestine

Fish & Shellfish Immunology ◽

10.1016/j.fsi.2017.09.075 ◽

2017 ◽

Vol 71 ◽

pp. 35-42 ◽

Cited By ~ 50

Author(s):

Hui-Ting Yang ◽

Song-Song Zou ◽

Li-Juan Zhai ◽

Yao Wang ◽

Fu-Miao Zhang ◽

...

Keyword(s):

Immune Responses ◽

Intestinal Microbiota ◽

Innate Immune ◽

Microbiota Composition ◽

Innate Immune Responses ◽

Pathogen Invasion

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PPP6C Negatively Regulates STING-Dependent Innate Immune Responses

mBio ◽

10.1128/mbio.01728-20 ◽

2020 ◽

Vol 11 (4) ◽

Author(s):

Guoxin Ni ◽

Zhe Ma ◽

Jason P. Wong ◽

Zhigang Zhang ◽

Emily Cousins ◽

...

Keyword(s):

Immune Responses ◽

Adaptor Protein ◽

Innate Immune ◽

Negative Regulator ◽

Host Cells ◽

Type I ◽

Innate Immune Responses ◽

Pathogen Invasion ◽

Major Player ◽

Sting Pathway

ABSTRACT Stimulator of interferon genes (STING) is an essential adaptor protein of the innate DNA-sensing signaling pathway, which recognizes genomic DNA from invading pathogens to establish antiviral responses in host cells. STING activity is tightly regulated by several posttranslational modifications, including phosphorylation. However, specifically how the phosphorylation status of STING is modulated by kinases and phosphatases remains to be fully elucidated. In this study, we identified protein phosphatase 6 catalytic subunit (PPP6C) as a binding partner of Kaposi’s sarcoma-associated herpesvirus (KSHV) open reading frame 48 (ORF48), which is a negative regulator of the cyclic GMP-AMP synthase (cGAS)-STING pathway. PPP6C depletion enhances double-stranded DNA (dsDNA)-induced and 5′ppp double-stranded RNA (dsRNA)-induced but not poly(I:C)-induced innate immune responses. PPP6C negatively regulates dsDNA-induced IRF3 activation but not NF-κB activation. Deficiency of PPP6C greatly inhibits the replication of herpes simplex virus 1 (HSV-1) and vesicular stomatitis virus (VSV) as well as the reactivation of KSHV, due to increased type I interferon production. We further demonstrated that PPP6C interacts with STING and that loss of PPP6C enhances STING phosphorylation. These data demonstrate the important role of PPP6C in regulating STING phosphorylation and activation, which provides an additional mechanism by which the host responds to viral infection. IMPORTANCE Cytosolic DNA, which usually comes from invading microbes, is a dangerous signal to the host. The cGAS-STING pathway is the major player that detects cytosolic DNA and then evokes the innate immune response. As an adaptor protein, STING plays a central role in controlling activation of the cGAS-STING pathway. Although transient activation of STING is essential to trigger the host defense during pathogen invasion, chronic STING activation has been shown to be associated with several autoinflammatory diseases. Here, we report that PPP6C negatively regulates the cGAS-STING pathway by removing STING phosphorylation, which is required for its activation. Dephosphorylation of STING by PPP6C helps prevent the sustained production of STING-dependent cytokines, which would otherwise lead to severe autoimmune disorders. This work provides additional mechanisms on the regulation of STING activity and might facilitate the development of novel therapeutics designed to prevent a variety of autoinflammatory disorders.

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Oral Immune Activation by Disgust and Disease-Related Pictures

Journal of Psychophysiology ◽

10.1027/0269-8803/a000143 ◽

2015 ◽

Vol 29 (3) ◽

pp. 119-129 ◽

Cited By ~ 4

Author(s):

Richard J. Stevenson ◽

Deborah Hodgson ◽

Megan J. Oaten ◽

Luba Sominsky ◽

Mehmet Mahmut ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Innate Immune Response ◽

Negative Control ◽

Innate Immune ◽

Innate Immune Responses ◽

Immune Markers ◽

Before And After ◽

Secondary Analyses ◽

Image Set

Abstract. Both disgust and disease-related images appear able to induce an innate immune response but it is unclear whether these effects are independent or rely upon a common shared factor (e.g., disgust or disease-related cognitions). In this study we directly compared these two inductions using specifically generated sets of images. One set was disease-related but evoked little disgust, while the other set was disgust evoking but with less disease-relatedness. These two image sets were then compared to a third set, a negative control condition. Using a wholly within-subject design, participants viewed one image set per week, and provided saliva samples, before and after each viewing occasion, which were later analyzed for innate immune markers. We found that both the disease related and disgust images, relative to the negative control images, were not able to generate an innate immune response. However, secondary analyses revealed innate immune responses in participants with greater propensity to feel disgust following exposure to disease-related and disgusting images. These findings suggest that disgust images relatively free of disease-related themes, and disease-related images relatively free of disgust may be suboptimal cues for generating an innate immune response. Not only may this explain why disgust propensity mediates these effects, it may also imply a common pathway.

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