Live attenuated pertussis vaccine BPZE1 induces a broad antibody response in humans

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Abstract

BACKGROUND. The live attenuated BPZE1 vaccine candidate induces protection against B. pertussis and prevents nasal colonization in animal models. Here we report on the responses in humans receiving a single intranasal administration of BPZE1. METHODS. We performed multiple assays to dissect the immune responses induced in humans (n=12) receiving BPZE1, with particular emphasis on the magnitude and characteristics of the antibody responses. Such responses were benchmarked to adolescents (n=12) receiving the complete vaccination program of the currently used acellular pertussis vaccine (aPV). Using immunoproteomics analysis, novel immunogenic B. pertussis antigens were identified. RESULTS. All BPZE1 vaccinees showed robust B. pertussis-specific antibody responses with regard to significant increase in one or more of the parameters IgG, IgA and memory B cells to B. pertussis antigens. BPZE1-specific T cells showed a Th1 phenotype and the IgG exclusively consisted of IgG1 and IgG3. In contrast, all aPV vaccinees showed a Th2-biased response. Immunoproteomics profiling revealed that BPZE1 elicited broader and different antibody specificities to B. pertussis antigens as compared to the aPV that primarily induced antibodies to the vaccine antigens. Moreover, BPZE1 was superior at inducing opsonizing antibodies that stimulated reactive oxygen species (ROS) production in neutrophils and enhanced bactericidal function, which was in line with that antibodies against adenylate cyclase toxin were only elicited by BPZE1. CONCLUSIONS. The breadth of the antibodies, the Th1-type cellular response and killing mechanisms elicited by BPZE1 may hold prospects of improving vaccine efficacy and protection against B. pertussis transmission. TRIAL REGISTRATION. ClinicalTrials.gov NCT02453048, NCT00870350 FUNDING. ILiAD Biotechnologies, Swedish Research Council (Vetenskapsrådet), Swedish Heart-lung Foundation.

Authors

Ang Lin, Danijela Apostolovic, Maja Jahnmatz, Frank Liang, Sebastian Ols, Teghesti Tecleab, Chenyan Wu, Marianne van Hage, Ken Solovay, Keith Rubin, Camille Locht, Rigmor Thorstensson, Marcel Thalen, Karin Loré

Transcription factor c-Maf is a checkpoint that programs macrophages in lung cancer

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Abstract

Macrophages have been linked to tumor initiation, progression, metastasis and treatment resistance. However, the transcriptional regulation of macrophages driving the pro-tumor function remains elusive. Here, we demonstrate that the transcription factor c-Maf is a critical controller for immunosuppressive macrophage polarization and function in cancer. c-Maf controls many M2-related genes and has direct binding sites within a conservative non-coding sequence of csf-1r gene and promotes M2-like macrophage-mediated T cell suppression and tumor progression. c-Maf also serves as a metabolic checkpoint regulating TCA cycle and UDP-GlcNAc biosynthesis thus promoting M2-like macrophage polarization and activation. Additionally, c-Maf is highly expressed in tumor-associated macrophages (TAM) and regulates TAM immunosuppressive function. Deletion of c-Maf specifically in myeloid cells results in reduced tumor burden with enhanced antitumor T cell immunity. Inhibition of c-Maf partly overcomes resistance to anti-PD-1 therapy in a subcutaneous LLC tumor model. Similarly, c-Maf is expressed in human M2 and tumor-infiltrating macrophages/monocytes as well as circulating monocytes of human non-small cell lung carcinoma (NSCLC) patients and critically regulates its immunosuppressive activity. Natural compound β-glucan downregulates c-Maf expression on macrophages leading to enhanced antitumor immunity in mice. These findings establish a paradigm for immunosuppressive macrophage polarization and transcriptional regulation by c-Maf and suggest that c-Maf is a potential target for effective tumor immunotherapy.

Authors

Min Liu, Zan Tong, Chuanlin Ding, Fengling Luo, Shouzhen Wu, Caijun Wu, Sabrin Albeituni, Liqing He, Xiaoling Hu, David Tieri, Eric C. Rouchka, Michito Hamada, Satoru Takahashi, Andrew A. Gibb, Goetz Kloecker, Huang-Ge Zhang, Michael Bousamra, Bradford G. Hill, Xiang Zhang, Jun Yan

Visceral adipose NLRP3 impairs cognition in obesity via IL1R1 on Cx3cr1⁺ cells

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Abstract

Induction of the inflammasome protein cryopyrin (NLRP3) in visceral adipose tissue (VAT) promotes release of the pro-inflammatory cytokine interleukin-1β (IL1β) in obesity. While this mechanism contributes to peripheral metabolic dysfunction, effects on the brain remain unexplored. These studies investigated whether visceral adipose NLRP3 impairs cognition by activating microglial interleukin-1 receptor 1 (IL1R1). After observing protection against obesity-induced neuroinflammation and cognitive impairment in NLRP3KO mice, we transplanted VAT from obese WT or NLRP3KO donors into lean recipients. Transplantation of VAT from a WT donor (TRANSWT) increased hippocampal IL1β and impaired cognition, but VAT transplants from comparably obese NLRP3KO donors (TRANSKO) had no effect. Visceral adipose NLRP3 was required for deficits in long-term potentiation (LTP) in transplant recipients, and LTP impairment in TRANSWT mice was IL1-dependent. Flow cytometric and gene expression analyses revealed that VAT transplantation recapitulated the effects of obesity on microglial activation and IL1β gene expression, and visualization of hippocampal microglia revealed similar effects in vivo. Inducible ablation of IL1R1 in CX3CR1-expressing cells eliminated cognitive impairment in mice with dietary obesity and in transplant recipients and restored immunoquiescence in hippocampal microglia. These results indicate that visceral adipose NLRP3 impairs memory via IL1-mediated microglial activation, and suggest that NLRP3-IL1β signaling may underlie correlations between visceral adiposity and cognitive impairment in humans.

Authors

De-Huang Guo, Masaki Yamamoto, Caterina M. Hernandez, Hesam Khodadadi, Babak Baban, Alexis M. Stranahan

Capsular glycan recognition provides antibody-mediated immunity against tuberculosis

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Abstract

A better understanding of all immune components involved in protecting against M. tuberculosis infection is urgently needed to inform strategies for novel immunotherapy and tuberculosis (TB) vaccine development. While cell-mediated immunity is critical, increasing evidence supports that antibodies also have a protective role against TB. Yet, knowledge of protective antigens is limited. Analyzing sera from 97 US immigrants at various states of M. tuberculosis infection, we showed protective in vitro and in vivo efficacy of polyclonal IgG to the M. tuberculosis capsular polysaccharide arabinomannan (AM). Using recently developed glycan arrays, we established that anti-AM IgG induced in natural infection is highly heterogeneous in its binding specificity and differs in both its reactivity to oligosaccharide motifs within AM and its functions between BCG vaccination and/or controlled (latent) versus uncontrolled (TB) M. tuberculosis infection. We showed that anti-AM IgG from asymptomatic but not diseased individuals was protective, and provided data suggesting a potential role of IgG2 and specific AM oligosaccharides. Filling a gap in the current knowledge of protective antigens in humans, our data support the key role of the M. tuberculosis surface glycan AM and suggest the importance of targeting specific glycan epitopes within AM in antibody-mediated immunity against TB.

Authors

Tingting Chen, Caroline Blanc, Yanyan Liu, Elise Ishida, Sarah Singer, Jiayong Xu, Maju Joe, Elizabeth R. Jenny-Avital, John Chan, Todd L. Lowary, Jacqueline M. Achkar

Microbiota dependent production of butyrate is required for the bone anabolic activity of PTH

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Abstract

PTH is a critical regulator of skeletal development that promotes both bone formation and bone resorption. Using microbiota depletion by wide-spectrum antibiotics and germ-free (GF) female mice we showed that the microbiota was required for PTH to stimulate bone formation and increase bone mass. Microbiota depletion lowered butyrate levels, a metabolite responsible for gut-bone communication, while reestablishment of physiologic levels of butyrate restored PTH-induced anabolism. The permissive activity of butyrate was mediated by GPR43 signaling in dendritic cells (DCs) and by GPR43-independent signaling in T cells. Butyrate was required for PTH to increase the number of bone marrow (BM) regulatory T cells (Tregs). Tregs stimulated production of the osteogenic Wnt ligand Wnt10b by BM CD8+ T cells, which activated Wnt dependent bone formation. Together, these data highlight the role that butyrate produced by gut luminal microbiota plays in triggering regulatory pathways which are critical for the anabolic action of PTH in bone.

Authors

Jau-Yi Li, Mingcan Yu, Subhashis Pal, Abdul Malik Tyagi, Hamid Dar, Jonathan Adams, M. Neale Weitzmann, Rheinallt M. Jones, Roberto Pacifici

Inhibiting the coregulator CoREST impairs Foxp3⁺ Treg function and promotes antitumor immunity

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Abstract

Foxp3+ T-regulatory (Treg) cells are key to immune homeostasis, but the contributions of various large, multiprotein complexes that regulate gene expression remain unexplored. We analyzed the role in Tregs of the evolutionarily conserved CoREST complex consisting of a scaffolding protein, Rcor1 or Rcor2, plus Hdac1 or Hdac2 and Lsd1 enzymes. Rcor1, Rcor2 and Lsd1 were physically associated with Foxp3, and mice with conditional deletion of Rcor1 in Foxp3+ Tregs had decreased proportions of Tregs in peripheral lymphoid tissues, and increased Treg expression of IL-2 and IFN-γ compared to WT cells. Mice with conditional deletion of the gene encoding Rcor1 in their Tregs had reduced suppression of homeostatic proliferation, inability to maintain long-term allograft survival despite costimulation blockade, and enhanced antitumor immunity in syngeneic models. Comparable findings were seen in WT mice treated with CoREST complex bivalent inhibitors, which also altered the phenotype of human Tregs and impaired their suppressive function. Our data point to the potential for therapeutic modulation of Treg functions by pharmacologic targeting of enzymatic components of the CoREST complex, and contribute to an understanding of the biochemical and molecular mechanisms by which Foxp3 represses large gene sets and maintains the unique properties of this key immune cell.

Authors

Yan Xiong, Liqing Wang, Eros Di Giorgio, Tatiana Akimova, Ulf H. Beier, Rongxiang Han, Matteo Trevisanut, Jay H. Kalin, Philip A. Cole, Wayne W. Hancock

Type I interferon response drives neuroinflammation and synapse loss in Alzheimer disease

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Abstract

Type I interferon (IFN) is a key cytokine that curbs viral infection and cell malignancy. Previously, we have demonstrated a potent IFN immunogenicity of nucleic acid (NA)-containing amyloid fibrils in the periphery. Here, we investigated whether IFN is associated with β-amyloidosis inside the brain and contributes to neuropathology. An IFN-stimulated gene (ISG) signature was detected in the brains of multiple murine Alzheimer disease (AD) models, a phenomenon also observed in wild-type mouse brain challenged with generic NA-containing amyloid fibrils. In vitro, microglia innately responded to NA-containing amyloid fibrils. In AD models, activated ISG-expressing microglia exclusively surrounded NA-positive amyloid β plaques, which accumulated in an age-dependent manner. Brain administration of rIFNβ resulted in microglial activation and complement C3-dependent synapse elimination in vivo. Conversely, selective IFN receptor blockade effectively diminished the ongoing microgliosis and synapse loss in AD models. Moreover, we detected activated ISG-expressing microglia enveloping NA-containing neuritic plaques in post-mortem brains of AD patients. Gene expression interrogation revealed that IFN pathway was grossly upregulated in clinical AD and significantly correlated with disease severity and complement activation. Therefore, IFN constitutes a pivotal element within the neuroinflammatory network of AD and critically contributes to neuropathogenic processes.

Authors

Ethan R. Roy, Baiping Wang, Ying-Wooi Wan, Gabriel S. Chiu, Allysa L. Cole, Zhuoran Yin, Nicholas E. Propson, Yin Xu, Joanna L. Jankowsky, Zhandong Liu, Virginia M.Y. Lee, John Q. Trojanowski, Stephen D. Ginsberg, Oleg Butovsky, Hui Zheng, Wei Cao

Pancreatic triglyceride lipase mediates lipotoxic systemic inflammation

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Abstract

Visceral adipose tissue plays a critical role in numerous diseases. While imaging studies often show adipose involvement in abdominal diseases, their outcomes may vary from being a mild self limited illness to one with systemic inflammation and organ failure. We therefore compared the pattern of visceral adipose injury during acute pancreatitis and acute diverticulitis to determine its role in organ failure. Acute pancreatitis-associated adipose tissue had ongoing lipolysis in the absence of adipocyte triglyceride lipase (ATGL). Pancreatic lipase injection into mouse visceral adipose tissue hydrolyzed adipose triglyceride and generated excess non-esterified fatty acids (NEFA), which caused organ failure in the absence of acute pancreatitis. Pancreatic triglyceride lipase (PNLIP) increased in adipose tissue during pancreatitis and entered adipocytes by multiple mechanisms, hydrolyzing adipose triglyceride and generating excessive NEFA. During pancreatitis, obese PNLIP knockout mice, unlike obese adipocyte-specific ATGL knockouts, had lower visceral adipose tissue lipolysis, milder inflammation, lesser organ failure, and improved survival. PNLIP knockout mice, unlike ATGL knockouts, were protected from adipocyte-induced pancreatic acinar injury without affecting NEFA signaling or acute pancreatitis induction. Therefore during pancreatitis, unlike diverticulitis, PNLIP leaked into visceral adipose tissue can cause excessive visceral adipose tissue lipolysis independent of adipocyte-autonomous ATGL, and thereby worsen organ failure.

Authors

Cristiane de Oliveira, Biswajit Khatua, Pawan Noel, Sergiy Kostenko, Arup Bag, Bijinu Balakrishnan, Krutika S. Patel, Andre A. Guerra, Melissa N. Martinez, Shubham Trivedi, Ann E. McCullough, Dora M. Lam-Himlin, Sarah Navina, Douglas O. Faigel, Norio Fukami, Rahul Pannala, Anna Evans Phillips, Georgios I. Papachristou, Erin E. Kershaw, Mark E. Lowe, Vijay P. Singh

Graft-versus-host disease reduces lymph node display of tissue-restricted self-antigens and promotes autoimmunity

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Abstract

Acute graft-versus-host disease (GVHD) is initially triggered by alloreactive T cells, which damage peripheral tissues and lymphoid organs. Subsequent transition to chronic GVHD involves the emergence of autoimmunity although the underlying mechanisms driving this process are unclear. Here, we tested the hypothesis that acute GVHD blocks peripheral tolerance of autoreactive T cells by impairing lymph node (LN) display of peripheral tissue-restricted antigens (PTA). At the initiation of GVHD, LN fibroblastic reticular cells (FRC) rapidly reduced expression of genes regulated by DEAF1, an Autoimmune Regulator-like transcription factor required for intra-nodal expression of PTA. Subsequently, GVHD led to the selective elimination of the FRC population, and blocked the repair pathways required for its regeneration. We used a transgenic mouse model to show that the loss of presentation of an intestinal PTA by FRC during GVHD resulted in the activation of auto-aggressive T cells and gut injury. Finally, we show that FRC normally expressed a unique PTA gene signature that was highly enriched for genes expressed in the target organs affected by chronic GVHD. In conclusion, acute GVHD damages and prevents repair of the FRC network, thus disabling an essential platform for purging auto-reactive T cells from the repertoire.

Authors

Simone Dertschnig, Pamela Evans, Pedro Santos e Sousa, Teresa Manzo, Ivana R. Ferrer, Hans J. Stauss, Clare L. Bennett, Ronjon Chakraverty

Prevention of Connexin43 remodeling protects against duchenne muscular dystrophy cardiomyopathy

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Abstract

Aberrant expression of the cardiac gap junction protein connexin-43 (Cx43) has been suggested to play a role in the development of cardiac disease in the mdx mouse model of Duchenne muscular dystrophy (DMD), however a mechanistic understanding of this association is lacking. Here, we identified a reduction of phosphorylation of Cx43 serines S325/S328/S330 in human and mouse DMD hearts. We hypothesized that hypo-phosphorylation of Cx43 serine-triplet triggers pathological Cx43 redistribution to the lateral sides of cardiomyocytes (remodeling). Therefore, we generated knock-in mdx mice in which the Cx43 serine-triplet was replaced with either phospho-mimicking glutamic acids (mdxS3E) or non-phosphorylatable alanines (mdxS3A). The mdxS3E but not mdxS3A mice were resistant to Cx43 remodeling with a corresponding reduction of Cx43 hemichannel activity. MdxS3E cardiomyocytes displayed improved intracellular Ca2+ signaling and a reduction of NOX2/reactive oxygen species (ROS) production. Furthermore, mdxS3E mice were protected against inducible arrhythmias, related lethality and the development of cardiomyopathy. Inhibition of microtubule polymerization by colchicine reduced both NOX2/ROS and oxidized CaMKII, increased S325/S328/S330 phosphorylation and prevented Cx43 remodeling in mdx hearts. Together, these results demonstrate a mechanism of dystrophic Cx43-remodeling and suggest that targeting Cx43 may be a therapeutic strategy to prevent heart dysfunction and arrhythmias in DMD patients.

Authors

Eric Himelman, Mauricio A. Lillo, Julie Nouet, J. Patrick Gonzalez, Qingshi Zhao, Lai-Hua Xie, Hong Li, Tong Liu, Xander H.T. Wehrens, Paul D. Lampe, Glenn I. Fishman, Natalia Shirokova, Jorge E. Contreras, Diego Fraidenraich