Inhibition of type I interferon signaling abrogates early Mycobacterium bovis infection

Abstract Background Mycobacterium bovis (M. bovis) is the principal causative agent of bovine tuberculosis; however, it may also cause serious infection in human being. Type I IFN is a key factor in reducing viral multiplication and modulating host immune response against viral infection. However, the regulatory pathways of Type I IFN signaling during M. bovis infection are not yet fully explored. Here, we investigate the role of Type I IFN signaling in the pathogenesis of M. bovis infection in mice. Methods C57BL/6 mice were treated with IFNAR1-blocking antibody or Isotype control 24 h before M. bovis infection. After 21 and 84 days of infection, mice were sacrificed and the role of Type I IFN signaling in the pathogenesis of M. bovis was investigated. ELISA and qRT-PCR were performed to detect the expression of Type I IFNs and related genes. Lung lesions induced by M. bovis were assessed by histopathological examination. Viable bacterial count was determined by CFU assay. Results We observed an abundant expression of Type I IFNs in the serum and lung tissues of M. bovis infected mice. In vivo blockade of Type I IFN signaling reduced the recruitment of neutrophils to the lung tissue, mediated the activation of macrophages leading to an increased pro-inflammatory profile and regulated the inflammatory cytokine production. However, no impact was observed on T cell activation and recruitment in the early acute phase of infection. Additionally, blocking of type I IFN signaling reduced bacterial burden in the infected mice as compared to untreated infected mice. Conclusions Altogether, our results reveal that Type I IFN mediates a balance between M. bovis-mediated inflammatory reaction and host defense mechanism. Thus, modulating Type I IFN signaling could be exploited as a therapeutic strategy against a large repertoire of inflammatory disorders including tuberculosis.

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Inhibition of Type I Interferon Signaling Abrogates Early Mycobacterium bovis Infection

10.21203/rs.2.14196/v3 ◽

2019 ◽

Author(s):

Jie Wang ◽

Tariq Hussain ◽

Kai Zhang ◽

Yi Liao ◽

Jiao Yao ◽

...

Keyword(s):

Mycobacterium Bovis ◽

T Cell Activation ◽

Cell Activation ◽

Defense Mechanism ◽

Type I ◽

Type I Ifn ◽

Regulatory Pathways ◽

Type I Ifns

Abstract Background: Mycobacterium bovis (M. bovis) is the principal causative agent of bovine tuberculosis; however, it may also cause serious infection in human being. Type I IFN is a key factor in reducing viral multiplication and modulating host immune response against viral infection. However, the regulatory pathways of Type I IFN signaling during M. bovis infection are not yet fully explored. Here, we investigate the role of Type I IFN signaling in the pathogenesis of M. bovis infection in mice. Methods: C57BL/6 mice were treated with IFNAR1-blocking antibody or Isotype control 24 hour before M. bovis infection. After 21 and 84 days of infection, mice were sacrificed and the role of Type I IFN signaling in the pathogenesis of M. bovis was investigated. ELISA and qRT-PCR were performed to detect the expression of Type I IFNs and related genes. Lung lesions induced by M. bovis were assessed by histopathological examination.Viable bacterial count was determined by CFU assay. Results: We observed an abundant expression of Type I IFNs in the serum and lung tissues of M. bovis infected mice. In vivo blockade of Type I IFN signaling reduced the recruitment of neutrophils to the lung tissue, mediated the activation of macrophages leading to an increased pro-inflammatory profile and regulated the inflammatory cytokine production. However, no impact was observed on T cell activation and recruitment in the early acute phase of infection. Additionally, blocking of type I IFN signaling reduced bacterial burden in the infected mice as compared to untreated infected mice. Conclusions: Altogether, our results reveal that Type I IFN mediates a balance between M. bovis-mediated inflammatory reaction and host defense mechanism. Thus, modulating Type I IFN signaling could be exploited as a therapeutic strategy against a large repertoire of inflammatory disorders including tuberculosis.

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Inhibition of Type I Interferon Signaling Abrogates Early Mycobacterium bovis Infection

10.21203/rs.2.14196/v2 ◽

2019 ◽

Author(s):

Jie Wang ◽

Tariq Hussain ◽

Kai Zhang ◽

Yi Liao ◽

Jiao Yao ◽

...

Keyword(s):

Mycobacterium Bovis ◽

Defense Mechanism ◽

Histopathological Examination ◽

Bacterial Count ◽

Type I ◽

Type I Ifn ◽

Regulatory Pathways ◽

Type I Ifns

Abstract Background: Mycobacterium bovis (M. bovis) is the principal causative agent of bovine tuberculosis; however, it may also cause serious infection in human being. Type I IFN is a key factor in reducing viral multiplication and modulating host immune response against viral infection. However, the regulatory pathways of Type I IFN signaling during M. bovis infection are not yet fully explored. Here, we investigate the role of Type I IFN signaling in the pathogenesis of M. bovis infection in mice. Methods: C57BL/6 mice were treated with IFNAR1-blocking antibody or Isotype control 24 hour before M. bovis infection. After 21 and 84 days of infection, mice were sacrificed and role of Type I IFN signaling in the pathogenesis of M. bovis was investigated. ELISA and qRT-PCR was performed to detect the expression of Type I IFNs and related genes. M. bovis induced lung lesions were assessed by histopathological examination and viable bacterial count was determined by CFU assay. Results: We observed an abundant expression of Type I IFNs in the serum and lung tissues of M. bovis infected mice. In vivo blockade of Type I IFN signaling reduced the recruitment of neutrophils to the lung tissue, mediated the activation of macrophages leading to an increased pro-inflammatory profile and regulated the inflammatory cytokine production. However, no impact was observed on T cell recruitment and activation in the early acute phase of infection. Additionally, blocking of type I IFN signaling reduced bacterial burden in the infected mice as compared to untreated infected mice. Conclusions: Altogether, our results reveal that Type I IFN mediates a balance between M. bovis-mediated inflammatory reaction and host defense mechanism. Thus, modulating Type I IFN signaling could be exploited as a therapeutic strategy against a large repertoire of inflammatory disorders including tuberculosis.

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Inhibition of Type I Interferon Signaling abrogates Early Mycobacterium bovis Infection

10.21203/rs.2.14196/v1 ◽

2019 ◽

Author(s):

Jie Wang ◽

Tariq Hussain ◽

Kai Zhang ◽

Yi Liao ◽

Jiao Yao ◽

...

Keyword(s):

Mycobacterium Bovis ◽

Bacterial Count ◽

Immune Defense ◽

Type I ◽

Type I Ifn ◽

Human Beings ◽

Inflammatory Reactions ◽

Regulatory Pathways ◽

Type I Ifns

Abstract Background: Mycobacterium bovis (M. bovis) is the central causative agent of bovine tuberculosis; however, it also caused serious infection in human beings. Type I IFNs is a key factor in reducing viral multiplication and modulate host immune defense against viral infection. However, the regulatory pathways of type I IFN signaling during Mycobactrium bovis (M. bovis) infection are not yet fully explored. Here, we investigate the role of type I IFN signaling on the pathogenesis of M. bovis infection in mice. Methods: C57BL/6 mice were treated with IFNAR1-blocking antibody or Isotype control 24 hour before M. bovis infection. After 21 and 84 days of infection mice were sacrificed, for analysis of type I IFN signaling on the pathogenesis of M. bovis. qRT-PCR and ELISA was performed to detect the expression of type I IFNs and relative gene. M. bovis induced lung lesions and viable bacterial count was assessed by conducting histopathology and CFU assay. Results: We observed an abundant expression of type I IFNs in the blood serum and lung tissues of M. bovis infected mice. In vivo blockade of type I IFN signaling reduced the recruitment of neutrophils to the lung tissue, mediate the activation of macrophages toward a pro-inflammatory profile and regulate the inflammatory cytokine production; however, no impact on T cell recruitment and activation in the early acute phase of infection was observed. Additionally, blocking of type I IFN signaling reduces bacterial burden in infected mice than untreated infected mice. Conclusions: Altogether, our results reveal that type I IFN mediates a balance between infection-mediated inflammatory reactions and pathogen’s control mechanism of the host during M. bovis infection. Thus, modulating type I IFN signaling could be exploited as therapeutic strategies against a large repertoire of inflammatory disorders, including tuberculosis.

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Differential outcome of TRIF-mediated signaling in TLR4 and TLR3 induced DC maturation

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1510760112 ◽

2015 ◽

Vol 112 (45) ◽

pp. 13994-13999 ◽

Cited By ~ 32

Author(s):

Wei Hu ◽

Aakanksha Jain ◽

Yajing Gao ◽

Igor M. Dozmorov ◽

Rajakumar Mandraju ◽

...

Keyword(s):

Signaling Pathway ◽

T Cell Activation ◽

Cell Activation ◽

Molecular Mechanisms ◽

Type I ◽

Type I Ifn ◽

Important Distinction ◽

Type I Ifns ◽

Mitogen Activated Protein ◽

Dc Maturation

Recognition of pathogen-associated molecular patterns by Toll-like receptors (TLRs) on dendritic cells (DCs) leads to DC maturation, a process involving up-regulation of MHC and costimulatory molecules and secretion of proinflammatory cytokines. All TLRs except TLR3 achieve these outcomes by using the signaling adaptor myeloid differentiation factor 88. TLR4 and TLR3 can both use the Toll–IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF)-dependent signaling pathway leading to IFN regulatory factor 3 (IRF3) activation and induction of IFN-β and -α4. The TRIF signaling pathway, downstream of both of these TLRs, also leads to DC maturation, and it has been proposed that the type I IFNs act in cis to induce DC maturation and subsequent effects on adaptive immunity. The present study was designed to understand the molecular mechanisms of TRIF-mediated DC maturation. We have discovered that TLR4–TRIF-induced DC maturation was independent of both IRF3 and type I IFNs. In contrast, TLR3-mediated DC maturation was completely dependent on type I IFN feedback. We found that differential activation of mitogen-activated protein kinases by the TLR4– and TLR3–TRIF axes determined the type I IFN dependency for DC maturation. In addition, we found that the adjuvanticity of LPS to induce T-cell activation is completely independent of type I IFNs. The important distinction between the TRIF-mediated signaling pathways of TLR4 and TLR3 discovered here could have a major impact in the design of future adjuvants that target this pathway.

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cGAS/STING/TBK1/IRF3 Signaling Pathway Activates BMDCs Maturation Following Mycobacterium bovis Infection

International Journal of Molecular Sciences ◽

10.3390/ijms20040895 ◽

2019 ◽

Vol 20 (4) ◽

pp. 895 ◽

Cited By ~ 6

Author(s):

Qiang Li ◽

Chunfa Liu ◽

Ruichao Yue ◽

Saeed El-Ashram ◽

Jie Wang ◽

...

Keyword(s):

Dendritic Cells ◽

Signaling Pathway ◽

Mycobacterium Bovis ◽

New Drugs ◽

Type I Interferons ◽

Type I ◽

Type I Ifn ◽

Innate Immune Responses ◽

Dependent Signal

Cyclic GMP-AMP synthase (cGAS) is an important cytosolic DNA sensor that plays a crucial role in triggering STING-dependent signal and inducing type I interferons (IFNs). cGAS is important for intracellular bacterial recognition and innate immune responses. However, the regulating effect of the cGAS pathway for bone marrow-derived dendritic cells (BMDCs) during Mycobacterium bovis (M. bovis) infection is still unknown. We hypothesized that the maturation and activation of BMDCs were modulated by the cGAS/STING/TBK1/IRF3 signaling pathway. In this study, we found that M. bovis promoted phenotypic maturation and functional activation of BMDCs via the cGAS signaling pathway, with the type I IFN and its receptor (IFNAR) contributing. Additionally, we showed that the type I IFN pathway promoted CD4+ T cells’ proliferation with BMDC during M. bovis infection. Meanwhile, the related cytokines increased the expression involved in this signaling pathway. These data highlight the mechanism of the cGAS and type I IFN pathway in regulating the maturation and activation of BMDCs, emphasizing the important role of this signaling pathway and BMDCs against M. bovis. This study provides new insight into the interaction between cGAS and dendritic cells (DCs), which could be considered in the development of new drugs and vaccines against tuberculosis.

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Age-Associated Failure To Adjust Type I IFN Receptor Signaling Thresholds after T Cell Activation

The Journal of Immunology ◽

10.4049/jimmunol.1402389 ◽

2015 ◽

Vol 195 (3) ◽

pp. 865-874 ◽

Cited By ~ 21

Author(s):

Guangjin Li ◽

Jihang Ju ◽

Cornelia M. Weyand ◽

Jörg J. Goronzy

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Type I ◽

Receptor Signaling ◽

Type I Ifn ◽

Signaling Thresholds

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Acquired resistance to PD-L1 inhibition is associated with an enhanced type I IFN-stimulated secretory program in tumor cells

10.1101/2021.07.01.450417 ◽

2021 ◽

Author(s):

Yuhao Shi ◽

Melissa Dolan ◽

Michalis Mastri ◽

James W. Hill ◽

Adam Dommer ◽

...

Keyword(s):

T Cell Activation ◽

Cell Activation ◽

Immune Cell ◽

Ex Vivo ◽

Gene Knockout ◽

Acquired Resistance ◽

Mouse Tumor ◽

Type I ◽

Type I Ifn ◽

Signaling Crosstalk

Therapeutic inhibition of programmed cell death ligand (PD-L1) can reverse PD-1-mediated suppression of tumor-killing T-cells; however, many patients develop resistance. Acquired resistance may be derived from intracellular PD-L1 and interferon (IFN) signaling programs in the tumor that can have dual, sometimes opposing, influences on tumor immune responses. Here we show that PD-L1 inhibition induces a novel secretory program tightly controlled by IFN-signaling and specific to acquired, but not innate, resistance in tumors. A PD-L1 treatment-induced secretome (PTIS) was found to be enriched for several IFN-stimulated genes (ISGs) and then further enhanced by type I IFN stimulation (IFNα or IFNβ) in multiple mouse tumor models. Chronic inhibition or gene knockout of tumor PD-L1 in vitro could elicit similar type I IFN-enhanced secretory stimulation while resistant cells were able to suppress T cell activation and killing ex vivo. When reimplanted into mice, resistant tumors were more sensitive to IL-6 inhibition (a key PTIS component) and growth significantly reduced when type I IFN signaling was blocked. Together, these results show that prolonged PD-L1 inhibition can 'rewire' existing intracellular IFN:PD-L1 signaling crosstalk to drive secretory programs that help protect tumors from immune cell attack and represent a targetable vulnerability to overcome acquired resistance in patients.

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