by Rhiannon B. Werder, Jason P. Lynch, Jennifer C

Slides:

Advertisements

Similar presentations

Sejal Saglani, MD, Stephen Lui, PhD, Nicola Ullmann, MD, Gaynor A

Advertisements

Glucagon-like peptide 1 receptor signaling attenuates respiratory syncytial virus– induced type 2 responses and immunopathology Melissa H. Bloodworth,

Frank Kirstein, PhD, Natalie E

Volume 15, Issue 1, Pages (January 2014)

Early-life chlamydial lung infection enhances allergic airways disease through age- dependent differences in immunopathology Jay C. Horvat, PhD, Malcolm.

Fig. 3 TLR8 signaling induces CXCL4 and IFN-α secretion by SSc PDCs.

Aeroallergen-induced IL-33 predisposes to respiratory virus–induced asthma by dampening antiviral immunity Jason P. Lynch, PhD, Rhiannon B. Werder, B.

Frank Kirstein, PhD, Natalie E

Inhibition of house dust mite–induced allergic airways disease by antagonism of microRNA-145 is comparable to glucocorticoid treatment Adam Collison,

FIP200 deficiency alters mitochondria activation and ROS production in T cells. FIP200 deficiency alters mitochondria activation and ROS production in.

Neutrophil antifungal response in CCR2-depleted mice is rescued by adoptive transfer of CCR2+ monocytes or by treatment with recombinant IFNs. Neutrophil.

Toll-like receptor 7 gene deficiency and early-life Pneumovirus infection interact to predispose toward the development of asthma-like pathology in mice

IL-2–inducible T-cell kinase modulates TH2-mediated allergic airway inflammation by suppressing IFN-γ in naive CD4+ T cells Arun K. Kannan, MS, Nisebita.

Dysfunctional antifungal neutrophils have impaired expression of IFN-inducible genes. Dysfunctional antifungal neutrophils have impaired expression of.

CCR2+ monocytes are a relevant source of type I IFN in response to Af.

Core 2 O-glycan synthesis is stimulated by IL-15 signaling.

Arp2/3-mediated formation of nuclear actin networks is essential for CD4+ T cell effector functions. Arp2/3-mediated formation of nuclear actin networks.

Nonredundant antigen presentation by CD1c+ DCs infected with HIV and influenza virus. Nonredundant antigen presentation by CD1c+ DCs infected with HIV.

Donor and recipient BAL T cells are phenotypically and functionally memory T cells. Donor and recipient BAL T cells are phenotypically and functionally.

Differential expression of TRM markers by donor- and recipient-derived T cells with time. Differential expression of TRM markers by donor- and recipient-derived.

T-bethi MP cells produce IFN-γ in response to IL-12.

Fig. 6 In utero injection of inflammatory cytokines or adoptive transfer of activated T cells leads to pregnancy loss. In utero injection of inflammatory.

Murine gingival MSCs and skin MSCs produce and secrete IL-1RA–EV

Fig. 2 AcPGP induces IL-8 and G-CSF release from human bronchial epithelial cells. AcPGP induces IL-8 and G-CSF release from human bronchial epithelial.

Fig. 4. PVSRIPO infection of DCs is sublethal, is marginally productive, and induces sustained proinflammatory cytokine production. PVSRIPO infection of.

Fig. 5 A competent Fc is required for the antitumor immune response.

Fig. 8 Combining M7824 with radiation or chemotherapy enhances antitumor efficacy. Combining M7824 with radiation or chemotherapy enhances antitumor efficacy.

Fig. 5. In vivo characterization of adipogenesis by CT.

Fig. 2 IT1t prevents TLR7-mediated inflammation in pDCs.

Slc7a5 deficiency stimulates osteoclastogenesis in vitro.

Fig. 1. CAR4 and CAR8 cells demonstrate in vitro and in vivo antileukemic efficacy. CAR4 and CAR8 cells demonstrate in vitro and in vivo antileukemic efficacy.

Fig. 6 IT1t controls induced and spontaneous inflammation in vitro in cells from patients with SLE. IT1t controls induced and spontaneous inflammation.

Fig. 4 Administration of BMS to mice inhibits autoimmune-relevant pharmacodynamic endpoints driven by IL-12 and IFNα. Administration of BMS

Fig. 4 Rational therapeutic modulation of the tumor microenvironment sensitizes tumors to ICB. Rational therapeutic modulation of the tumor microenvironment.

Fig. 3 BMS blocks functional responses in primary immune cells driven by IL-23 and IL-12. BMS blocks functional responses in primary immune.

Fig. 7 BMS reduces the elevated expression of type I IFN–regulated genes both ex vivo in blood from patients with lupus and in a phase 1 study of.

BMS blocks functional responses in primary immune cells driven by IFNα

Fig. 5 Treatment with BMS (PO BID) protects from wasting and colitis in two SCID mouse models. Treatment with BMS (PO BID) protects from.

Fig. 6 RUNX/CBFB interaction inhibitor, Ro5-3335, significantly decreases mouse neurofibroma growth in vivo. RUNX/CBFB interaction inhibitor, Ro5-3335,

Aeroallergen-induced IL-33 predisposes to respiratory virus–induced asthma by dampening antiviral immunity Jason P. Lynch, PhD, Rhiannon B. Werder, B.

Fig. 1 A time-course RNA-seq analysis reveals prominent IRF8 expression in the spinal cord during the recovery phase after SCI. A time-course RNA-seq analysis.

Fig. 3 Local Maraba treatment of TNBC tumors provides long-term systemic protection. Local Maraba treatment of TNBC tumors provides long-term systemic.

Fig. 2 Adult LPL−/− mice that received neonatal rGM-CSF therapy are protected from pneumococcal infection. Adult LPL−/− mice that received neonatal rGM-CSF.

Fig. 1. The HCN channel blocker ivabradine (IVA) is analgesic in a mouse model of type 1 diabetes. The HCN channel blocker ivabradine (IVA) is analgesic.

Neutrophil antifungal response in CCR2-depleted mice is rescued by adoptive transfer of CCR2+ monocytes or by treatment with recombinant IFNs. Neutrophil.

Fig. 2 NDR2-deficient mice are more vulnerable to RNA viral infection.

Plasmacytoid dendritic cells promote systemic sclerosis with a key role for TLR8 by Marie Dominique Ah Kioon, Claudio Tripodo, David Fernandez, Kyriakos.

Fig. 3. Human liver tissue seed graft function.

by Jianghong Zhong, Tatjana Scholz, Anthony C. Y

Targeting p53-dependent stem cell loss for intestinal chemoprotection

Fig. 2 Neonatal ZIKV infection induces seizures in young mice and increases susceptibility to chemically induced seizures in adult mice. Neonatal ZIKV.

Fig. 4 IP6K1-mediated polyP production by platelets plays a critical role in LPS-induced NPA formation. IP6K1-mediated polyP production by platelets plays.

Fig. 5 Increased myometrial cell contractility in response to fetal T cells from preterm infants. Increased myometrial cell contractility in response to.

Fig. 6 Antitumor effect on tumor growth and pulmonary metastasis of CSSD-9 in vivo. Antitumor effect on tumor growth and pulmonary metastasis of CSSD-9.

An extracellular matrix fragment drives epithelial remodeling and airway hyperresponsiveness by Dhiren F. Patel, Teresa Peiró, Amelia Shoemark, Samia Akthar,

IFN treatment of human midgestation villous explants induces syncytial knot formation. IFN treatment of human midgestation villous explants induces syncytial.

Fig. 3 Characterization of SGN responses to optogenetic stimulation.

IL-33 is not critical for initiation of allergic airways disease phenotype. IL-33 is not critical for initiation of allergic airways disease phenotype.

Fig. 2 BX795 is nontoxic to HCE cells at therapeutic concentration.

Fig. 7 BEL immune response.

Fig. 6. Combinatorial VCPI and OV M1 treatment is efficacious in vivo and ex vivo. Combinatorial VCPI and OV M1 treatment is efficacious in vivo and ex.

Fig. 2. Mechanism of PD-L1 down-regulation in NOD HSPCs.

Circadian gene expression in ILC3s is associated with rhythmic cytokine expression. Circadian gene expression in ILC3s is associated with rhythmic cytokine.

Fig. 6 Methionine oxidation catalyzed by viperin increases the stability and function of RNA helicase RIG-I. Methionine oxidation catalyzed by viperin.

Meningeal γδ T cells are biased toward IL-17 production.

Fig. 1 Generation and characterization of MeV-based vaccine candidates for Lassa virus. Generation and characterization of MeV-based vaccine candidates.

In vivo function of MeTro sealants using rat incision model of lungs

In response to allergen, T cells and ILCs are equally important sources of IL-13. In response to allergen, T cells and ILCs are equally important sources.

T cell–derived IL-13 is essential for the inception of AHR.

Cxxc1-deficient TH17 cells exhibit a Treg cell–like expression profile

Presentation transcript:

PGD2/DP2 receptor activation promotes severe viral bronchiolitis by suppressing IFN-λ production by Rhiannon B. Werder, Jason P. Lynch, Jennifer C. Simpson, Vivian Zhang, Nick H. Hodge, Matthew Poh, Elizabeth Forbes-Blom, Christina Kulis, Mark L. Smythe, John W. Upham, Kirsten Spann, Mark L. Everard, and Simon Phipps Sci Transl Med Volume 10(440):eaao0052 May 9, 2018 Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

Fig. 1 Severe bronchiolitis induced by PVM/CRE coexposure promotes PGD2. Severe bronchiolitis induced by PVM/CRE coexposure promotes PGD2. (A) Study design. Neonatal mice were infected with PVM [1 plaque-forming unit (PFU)] at 7 days old and/or exposed to CRE 3 days later. End points were assessed 2 hours later at 5, 7, or 10 dpi. To induce asthma-like pathology, mice were reinfected with PVM and exposed to CRE as shown, and end points were assessed at 66 dpi. h-PGDS expression in (B) peribronchial leukocytes or in (C and D) AECs (arrows indicate positive AECs), analyzed by two-way analysis of variance (ANOVA). (E) Neonates were infected with PVM and/or treated with low-dose exogenous IL-33. h-PGDS in AECs was assessed at 7 dpi. (F) PGD2 in the lung. Data are presented as mean ± SEM or as box-and-whisker plots to show quartiles (boxes) and range (whiskers) and are representative of two experiments (n = 5 to 8 mice per group per experiment), analyzed by one-way ANOVA. *P < 0.05, **P < 0.01, and ***P < 0.001 compared with vehicle-treated mice. #P < 0.05 and ###P < 0.001 compared with PVM/CRE mice. Rhiannon B. Werder et al., Sci Transl Med 2018;10:eaao0052 Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

Fig. 2 RSV infection promotes PGD2. RSV infection promotes PGD2. Pediatric human bronchial epithelial cells isolated from healthy children were uninfected (UI) or infected with RSV (MOI, 1). (A) h-PGDS (red) and nuclei (blue) in uninfected (left) or 48 hours after RSV infection (right) in hAECs. (B) h-PGDS expression was quantified as a percentage of hAECs. (C) PGD2 was detected in cell supernatants. Box-and-whisker plots show quartiles (boxes) and range (whiskers), and data are representative of three experiments (n = 4 individual hAEC samples per group in duplicate), analyzed by one-way ANOVA. (D) Details of bronchiolitis patients. (E) Nasal swabs were collected from healthy infants or those admitted to the hospital with RSV bronchiolitis, and PGD2 was measured. n = 7 to 14 infants per group, analyzed by Mann-Whitney test. *P < 0.05, **P < 0.01, and ***P < 0.001. Rhiannon B. Werder et al., Sci Transl Med 2018;10:eaao0052 Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

Fig. 3 DP2 antagonism promotes antiviral immunity in PVM/CRE mice. DP2 antagonism promotes antiviral immunity in PVM/CRE mice. (A) Study design. Mice were inoculated at 7 days old with PVM and then exposed to CRE 3 dpi (intranasal). Some mice were treated daily with a DP2 antagonist (AM156) from 3 to 9 dpi (oral gavage). End points were assessed at 5, 7, and 10 dpi. (B) Weight gain. (C) Viral load in AECs detected by immunohistochemistry, or (D) whole-lung viral copies assessed by quantitative polymerase chain reaction (qPCR). (E) IFN-α, IFN-λ (IL-28A/B), and IFN-γ expression in bronchoalveolar lavage fluid (BALF) and IL-12p40 expression in lung were assessed at 5 dpi (top) and 7 dpi (bottom). (F) Interferon regulatory factor 7 (Irf7) gene and (G) Caspase-3 (Casp3) gene expression in whole lung was assessed by qPCR. (H) Mice were inoculated with PVM ± CRE and treated daily with AM156. Some mice were treated with anti–IL-28A (intraperitoneally) at 4 dpi. (I) Viral load in AECs or (J) viral copies. (K) Irf7 and (L) Casp3 expression. Data are presented as mean ± SEM or as box-and-whisker plots to show quartiles (boxes) and range (whiskers) and are representative of two experiments (n = 5 to 10 mice per group), analyzed by one-way or two-way ANOVA. *P < 0.05, **P < 0.01, and ***P < 0.001 compared with PVM-alone mice or as indicated. #P < 0.05 and ###P < 0.001 compared with PVM/CRE mice. Dashed lines represent uninfected controls. Rhiannon B. Werder et al., Sci Transl Med 2018;10:eaao0052 Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

Fig. 4 DP2 antagonism ameliorates type 2 inflammation in PVM/CRE mice. DP2 antagonism ameliorates type 2 inflammation in PVM/CRE mice. Mice were treated as per Fig. 3A. (A) ILC2s in the lung. (B) Eosinophils in the BALF. (C) PGD2 expression in the lung and (D) IL-33 expression in the BALF. ILC2s were isolated from PVM/CRE mice and cultured with PGD2 ± DP2 antagonist (AM156) or IFN-λ. (E) IL-5 and (F) IL-13 expression was measured in the supernatant. (G) Airway smooth muscle (ASM) mass in vivo expressed as √area/perimeter of the basement membrane (Pbm). (H) ASM cells were isolated and cultured from neonatal mice and stimulated, and proliferation was measured using V450 dye dilution. Data are presented as mean ± SEM. (I) ASM cells were stimulated with PGD2, DP1-specific, or DP2-specific agonists, and proliferation was measured. (J) PVM/CRE-infected mice were treated with the DP2 antagonist as per Fig. 3A and then exposed to PVM and CRE in later life (as per Fig. 1A) to induce asthma-like pathologies. Eosinophils in the BALF. (K) Muc5a expression as a percentage of AECs. (L) ASM mass. (M) Airway resistance (Rn) in response to increasing doses of methacholine (MCh). Data are presented as mean ± SEM or as box-and-whisker plots to show quartiles (boxes) and range (whiskers) and are representative of two experiments (n = 4 to 8 mice per group or four to five replicates in vitro), analyzed by Mann-Whitney test or one-way or two-way ANOVA. *P < 0.05, **P < 0.01, and ***P < 0.001. Dashed lines represent uninfected controls. Rhiannon B. Werder et al., Sci Transl Med 2018;10:eaao0052 Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

Fig. 5 DP2 but not DP1 antagonism prevents severe bronchiolitis in PVM/CRE mice. DP2 but not DP1 antagonism prevents severe bronchiolitis in PVM/CRE mice. (A) Study design. Mice were inoculated at 7 days old with PVM and then exposed to CRE 3 dpi (intranasal). Some mice were treated daily from 3 dpi with a DP2 antagonist (AM156), a DP1 antagonist (MK-0524), or both antagonists from 3 to 9 dpi (oral gavage). End points were assessed at 5, 7, and 10 dpi. (B) Viral load in AECs detected by immunohistochemistry or (C) whole-lung viral copies assessed by qPCR. (D) IFN-λ (IL-28A/B) expression in the BALF at 7 dpi. (E) Irf7 and (F) Casp3 gene expression in whole lung assessed by qPCR. (G) Eosinophils in the BALF at 10 dpi. (H) ILC2s in the lung at 10 dpi. (I) ASM mass expressed as √area/perimeter of the basement membrane at 10 dpi (Pbm). Data are presented as mean ± SEM or as box-and-whisker plots to show quartiles (boxes) and range (whiskers) and are representative of two experiments (n = 4 to 8 mice per group), analyzed by one-way or two-way ANOVA. *P < 0.05, **P < 0.01, and ***P < 0.001. Dashed lines represent uninfected controls. Rhiannon B. Werder et al., Sci Transl Med 2018;10:eaao0052 Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

Fig. 6 DP1 activation promotes IFN-λ to limit viral load and type 2 inflammation. DP1 activation promotes IFN-λ to limit viral load and type 2 inflammation. (A) Study design. All mice were inoculated at 7 days old with PVM. PVM/CRE-coexposed mice were exposed to CRE at 3 dpi and received no other treatment. Mice that received PGD2, a DP1 agonist (BW245C), or a DP2 agonist [15(R)-15-methyl-PGD2] were treated daily from 3 to 9 dpi. End points were assessed at 5, 7, and 10 dpi. (B) Viral load in AECs detected by immunohistochemistry or (C) whole-lung viral copies assessed by qPCR. (D) IFN-λ (IL-28A/B) expression in the BALF at 5 and 7 dpi. (E) Irf7 gene and (F) Casp3 gene expression in whole lung assessed by qPCR. (G) Cleaved caspase-3 expression (green) and nuclei (blue). (H) ILC2s in the lung at 10 dpi. (I) Eosinophils in the BALF at 10 dpi. (J) ASM mass expressed as √area/perimeter of the basement membrane at 10 dpi. (K) ILC2s were cultured with IL-33 ± DP1 agonist (BW245C). ILC2 proliferation was measured by dilution of carboxyfluorescein diacetate succinimidyl ester (CFSE). (L) IL-5 and (M) IL-13 secretion measured in the supernatant. Box-and-whisker plots show quartiles (boxes) and range (whiskers), and data are representative of two experiments (n = 4 to 8 mice per group or five replicates in vitro), analyzed by one-way or two-way ANOVA. *P < 0.05, **P < 0.01, and ***P < 0.001 compared to PVM-alone mice or as indicated. Dashed lines represent uninfected controls. Rhiannon B. Werder et al., Sci Transl Med 2018;10:eaao0052 Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

Fig. 7 DP2 antagonism or DP1 activation of AECs promotes IFN-λ expression to alleviate viral burden. DP2 antagonism or DP1 activation of AECs promotes IFN-λ expression to alleviate viral burden. (A) hAECs were preincubated with 50 nM DP2 antagonist (AM156) before infection with RSV (MOI, 1). Viral copies were assessed by qPCR at 24 and 48 hours after infection. (B) IL28A gene expression and (C) IFN-λ (IL-28A) protein expression. (D) IRF7 and (E) CASP3 gene expression. (F) hAECs or mouse AECs (mAECs) were infected with RSV or PVM (MOI, 1), respectively. Cells were preincubated with 100 nM DP1 agonist (BW245C). Viral copies were assessed by qPCR at 24 and 48 hours after RSV infection. (G) PVM viral copies and (H) G protein expression in mAECs differentiated at the air-liquid interface. (I) IL28A gene expression in hAECs (left) and mAECs (right). (J) IFN-λ (hIL-28A or mIL-28A/B) protein expression. (K) IRF7 gene expression. (L) CASP3 gene expression. Box-and-whisker plots show quartiles (boxes) and range (whiskers), and data are representative of three experiments (n = 6 individual patients or mice in duplicate), analyzed by Wilcoxon or Mann-Whitney test. *P < 0.05, **P < 0.01, and ***P < 0.001. Dashed lines represent uninfected controls. Rhiannon B. Werder et al., Sci Transl Med 2018;10:eaao0052 Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

Fig. 8 DP1 activation of AECs promotes IFN-λ expression. DP1 activation of AECs promotes IFN-λ expression. (A) hAECs were preincubated with anti–IL-28A before infection (MOI, 1) ± DP1 agonist. Viral copies and (B) IRF7 gene and (C) CASP3 gene expression were assessed by qPCR at 48 hours. (D) hAECs were treated with polyI:C ± DP1 agonist. IL28A gene expression, (E) IFN-λ (IL-28A) protein expression, and (F) IRF7 and (G) CASP3 gene expression. Box-and-whisker plots show quartiles (boxes) and range (whiskers), and data are representative of three experiments (n = 6 individual patients per mice in duplicate), analyzed by Wilcoxon or Mann-Whitney test. *P < 0.05. Dashed lines represent uninfected controls. Rhiannon B. Werder et al., Sci Transl Med 2018;10:eaao0052 Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works