Intellectual and social disabilities are common comorbidities in adolescents and adults with MAGEL2 gene deficiency characterizing the Prader-Willi and Schaaf-Yang neurodevelopmental syndromes. The cellular and molecular mechanisms underlying the risk for autism in these syndromes are not understood. We ask whether vasopressin functions are altered by MAGEL2 deficiency and whether a treatment with vasopressin can alleviate the disabilities of social behavior. We used Magel2 knockout mice (adult males) combined with optogenetic or pharmacological tools to characterize disease modifications in the vasopressinergic brain system and monitor its impact on neurophysiological and behavioral functions. We find that the activation of vasopressin neurons and its projections in the lateral septum are inappropriate to perform a social habituation/discrimination task. Mechanistically, the lack of vasopressin impedes the deactivation of somatostatin neurons in the lateral septum, which predicts social discrimination deficits. Correction of vasopressin septal content by administration or optogenetic stimulation of projecting axons suppressed the activity of somatostatin neurons and ameliorated social behavior. This preclinical study identifies vasopressin in the lateral septum as a key factor in the pathophysiology.
Amélie M. Borie, Yann Dromard, Gilles Guillon, Aleksandra Olma, Maurice Manning, Françoise Muscatelli, Michel G. Desarmenien, Freddy Jeanneteau
The tumor microenvironment affects the outcome of radiotherapy against head and neck squamous cell carcinoma (HNSCC). We recently found that tolerogenic myeloid cells accumulate in circulation of HNSCC patients undergoing radiotherapy. Here, we analyzed tumor-containing lymph nodes biopsies collected from these patients. After two-weeks of radiotherapy, we found an increase in tumor-associated macrophages (TAMs) with activated STAT3, while CD8 T-cells were reduced as detected using multiplex IHC. Gene expression profiling indicated upregulation of M2 macrophage-related genes (CD163, CD206), immunosuppressive mediators (ARG1, LIF, TGFB1) and Th2 cytokines (IL4, IL5) in irradiated tumors. We next validated STAT3 as a potential target in human HNSCC-associated TAMs, using UM-SCC1 xenotransplants in humanized mice. Local injections of myeloid cell-targeted STAT3 antisense oligonucleotide (CpG-STAT3ASO) activated human DCs/macrophages, promoted CD8 T-cell recruitment and thereby arrested UM-SCC1 tumor growth. Furthermore, CpG-STAT3ASO synergized with tumor irradiation against syngeneic HPV+ mEERL and HPV– MOC2 HNSCC tumors in mice, triggering tumor regression and/or extending animal survival. The antitumor immune responses were CD8+ and CD4+ T-cell-dependent and associated with the activation of antigen-presenting cells (DCs/M1 macrophages) and increased CD8+ to regulatory T-cell ratio. Our observations suggest that targeted inhibition of STAT3 in tumor-associated myeloid cells augments the efficacy of radiotherapy against HNSCC.
Dayson Moreira, Sagus Sampath, Haejung Won, Seok Voon White, Yu-Lin Su, Marice Alcantara, Chongkai Wang, Peter P. Lee, Ellie Maghami, Erminia Massarelli, Marcin Kortylewski
The coronavirus disease 2019 (COVID 19) pandemic continues to cause morbidity and mortality. Since severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was identified as the cause for COVID 19, some have questioned whether exposure to seasonal common cold coronaviruses (CCCs) could provide tangible protection against SARS-CoV-2 infection or disease. In this issue of the JCI, Sager, et al. examined SARS-CoV-2 infections and outcomes from patients previously tested for CCC as part of a comprehensive respiratory panel using PCR and were segregated into negative (CCC–) or positive (CCC+) exposure. No differences were seen between groups in terms of susceptibility to SARS-CoV-2 infection. However, hospitalized patients with a documented history of CCC+ infection had lower rates of ICU admissions and higher rates of survival than hospitalized CCC– patients. While these findings are associative and not causative, they highlight evidence suggesting that previous CCC+ infection may influence the disease course of SARS-CoV-2 infection.
David K. Meyerholz, Stanley Perlman
Many individuals possess B cells capable of recognizing epitopes on the spike glycoprotein of SARS-CoV-2. In this issue of the JCI, Paschold and Simnica et al. interrogated the frequency of SARS-CoV-2–specific B cell receptor rearrangements in healthy subjects based on age and cancer status. The authors found that, while SARS-CoV-2–specific antibody signatures can be identified in the repertoires of young, healthy individuals, such sequences are less frequent in elderly subjects or cancer patients. Overall, this study sheds light on B cell repertoire restrictions that might lead to an unfavorable clinical course of COVID-19 infection in risk populations.
Andrew I. Flyak
ABSTRACTIndividuals harboring the loss-of-function (LOF) proprotein convertase subtilising/kexin type 9 Gln152His variation (PCSK9Q152H) have low circulating low-density lipoprotein (LDL) cholesterol levels and are therefore protected against cardiovascular disease (CVD). This uncleavable form of pro-PCSK9, however, is retained in the endoplasmic reticulum (ER) of liver hepatocytes where it would be expected to contribute to ER storage disease (ERSD); a heritable condition known to cause systemic ER stress and liver injury. Here, we examined liver function in members of several French-Canadian families known to carry the PCSK9Q152H variation. We report that PCSK9Q152H carriers exhibited marked hypocholesterolemia and normal liver function despite their lifelong state of ER PCSK9 retention. Mechanistically, hepatic overexpression of PCSK9Q152H using adeno-associated viruses in male mice greatly increased the stability of key ER stress response chaperones in liver hepatocytes and unexpectedly protected against ER stress and liver injury rather than to induce them. Our findings show that ER retention of PCSK9 not only reduced CVD risk in patients but may also protect against ERSD and other ER stress-driven conditions of the liver. In summary, we have uncovered a co-chaperone function for PCSK9Q152H that explains its hepatoprotective effects and generated a translational mouse model for further mechanistic insights into this clinically relevant LOF PCSK9 variant.
Paul F. Lebeau, Hanny Wassef, Jae Hyun Byun, Khrystyna Platko, Brandon Ason, Simon Jackson, Joshua Dobroff, Susan Shetterly, William G. Richards, Ali A. Al-Hashimi, Kevin D. Won, Majambu Mbikay, Annik Prat, An Tang, Guillaume Paré, Renata Pasqualini, Nabil G. Seidah, Wadih Arap, Michel Chretien, Richard C. Austin
TH17 cell subpopulations have been defined that contribute to inflammation and homeostasis, yet the characteristics of TH17 cells that contribute to host defense against infection are not clear. To elucidate the antimicrobial machinery of the TH17 subset, we studied the response to Cutibacterium acnes, a skin commensal that is resistant to IL-26, the only known TH17 secreted protein with direct antimicrobial activity. We generated C. acnes-specific antimicrobial TH17 clones (AMTH17) with varying antimicrobial activity against C. acnes, which we correlated by RNA-seq to the expression of transcripts encoding proteins that contribute to antimicrobial activity. Additionally, we validated that AMTH17-mediated killing of C. acnes as well as bacterial pathogens, was dependent on the secretion of granulysin, granzyme B, perforin and histone H2B. We found that AMTH17s can release fibrous structures composed of DNA decorated with the histone H2B that entangle C. acnes that we call T cell extracellular traps (TETs). Within acne lesions, H2B and IL-17 colocalized in CD4+ T cells, in proximity to TETs in the extracellular space composed of DNA decorated with H2B. This study identifies a functionally distinct subpopulation of TH17 cells with an ability to form TETs containing secreted antimicrobial proteins that capture and kill bacteria.
George W. Agak, Alice Mouton, Rosane Teles, Thomas A. Weston, Marco Morselli, Priscila R. Andrade, Matteo Pellegrini, Robert L. Modlin
BACKGROUND. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused over one million deaths worldwide, thus there is an urgent need to develop preventive and therapeutic strategies. The anti-tuberculosis vaccine Bacillus Calmette-Guérin (BCG) demonstrates non-specific protective innate immune-boosting effects. Here, we determined if history of BCG vaccination was associated with decreased SARS-CoV-2 infection and seroconversion in a retrospective observational study of a diverse cohort of health care workers (HCWs). METHODS. We assessed SARS-CoV-2 seroprevalence and collected medical questionnaires, including BCG vaccination status and pre-existing demographic and clinical characteristics, from an observational cohort of HCWs in a multi-site Los Angeles healthcare organization. We used multi-variate analysis to estimate if history of BCG vaccination was associated with decreased rates of SARS-CoV-2 infection and seroconversion. RESULTS. Of the 6,201 HCWs, 29.6% reported a history of BCG vaccination whereas 68.9% did not receive BCG vaccination. Seroprevalence of anti-SARS-CoV-2 IgG as well as incidence of self-reported clinical symptoms associated with COVID-19 were significantly decreased among HCWs with a history of BCG vaccination compared to those without BCG vaccination. After adjusting for age and sex, we found that history of BCG vaccination, but not meningococcal, pneumococcal or influenza vaccination, was associated with decreased SARS-CoV-2 IgG seroconversion. CONCLUSIONS. History of BCG vaccination was associated with decreased seroprevalence of anti-SARS-CoV-2 IgG and reduced reported COVID-19-related clinical symptoms in this cohort of HCWs. Therefore, large randomized prospective clinical trials of BCG vaccination are urgently needed to confirm if BCG vaccination can induced a protective effect against SARS-CoV2 infection. FUNDING. This work was supported by the National Institutes of Health, National Cancer Institute (U54 CA26059) and the Erika J. Glazer Family Foundation. Key words: SARS-CoV-2, COVID-19, Bacillus Calmette-Guérin, BCG, anti-SARS-CoV-2 IgG, healthcare workers, trained immunity.
Magali Noval Rivas, Joseph E. Ebinger, Min Wu, Nancy Sun, Jonathan Braun, Kimia Sobhani, Jennifer E. Van Eyk, Susan Cheng, Moshe Arditi
Bone is maintained by coupled activities of bone-forming osteoblasts/osteocytes and bone-resorbing osteoclasts. Alterations in this relationship can lead to pathologic bone loss, such as osteoporosis. It is well known that osteogenic cells support osteoclastogenesis via production of RANKL. Interestingly, our recently identified bone marrow mesenchymal cell population—marrow adipogenic lineage precursors (MALPs) that form a multi-dimensional cell network in bone—was computationally demonstrated to be the most interactive with monocyte-macrophage lineage cells through high and specific expression of several osteoclast regulatory factors, including RANKL. Using an adipocyte-specific Adipoq-Cre to label MALPs, we demonstrated that mice with RANKL deficiency in MALPs have a drastic increase in trabecular bone mass in long bones and vertebrae starting from 1 month of age, while their cortical bone appears normal. This phenotype was accompanied by diminished osteoclast number and attenuated bone formation at the trabecular bone surface. Reduced RANKL signaling in calvarial MALPs abolished osteolytic lesions after lipopolysaccharide (LPS) injections. Furthermore, in ovariectomized mice, elevated bone resorption was partially attenuated by RANKL deficiency in MALPs. In summary, our studies identified MALPs as a critical player in controlling bone remodeling during normal bone metabolism and pathological bone loss in a RANKL-dependent fashion.
Wei Yu, Leilei Zhong, Lutian Yao, Yulong Wei, Tao Gui, Ziqing Li, Hyunsoo Kim, Nicholas Holdreith, Xi Jiang, Wei Tong, Nathaniel A. Dyment, Xiaowei Sherry Liu, Shuying Yang, Yongwon Choi, Jaimo Ahn, Ling Qin
Human herpes simplex virus-1 (HSV-1) encephalitis can be caused by inborn errors of the TLR3 pathway resulting in impairment of central nervous system (CNS) cell-intrinsic antiviral immunity. Deficiencies of the TLR3 pathway impair cell-intrinsic immunity to vesicular stomatitis virus (VSV) and HSV-1 in fibroblasts, and to HSV-1 in cortical but not trigeminal neurons. The underlying molecular mechanism is thought to involve impaired IFN-a/b induction by the TLR3 recognition of dsRNA viral intermediates or by-products. However, we show here that human TLR3 controls constitutive levels of IFNB mRNA and secreted bioactive IFN-b protein, thereby also constitutive mRNA levels for IFN-stimulated genes (ISGs) in fibroblasts. Tlr3-/- mouse embryonic fibroblasts also have lower basal ISG levels. Moreover, human TLR3 controls basal levels of IFN-b secretion and ISGs mRNA in induced pluripotent stem cell-derived cortical neurons. Consistently, TLR3-deficient human fibroblasts and cortical neurons are vulnerable not only to both VSV and HSV-1, but also to several other families of viruses. The mechanism by which TLR3 restricts viral growth in human fibroblasts and cortical neurons in vitro, and by which the human central nervous system prevents infection by HSV-1 in vivo, is therefore based on the control of early viral infection by basal IFN-b immunity, rather than viral recognition triggering an amplification of IFN-a/b production.
Daxing Gao, Michael J. Ciancanelli, Peng Zhang, Oliver Harschnitz, Vincent Bondet, Mary Hasek, Jie Chen, Xin Mu, Yuval Itan, Aurélie Cobat, Vanessa Sancho-Shimizu, Benedetta Bigio, Lazaro Lorenzo, Gabriele Ciceri, Jessica L. McAlpine, Esperanza Anguiano, Emmanuelle Jouanguy, Damien Chaussabel, isabelle Meyts, Michael S. Diamond, Laurent Abel, Sun Hur, Gregory A. Smith, Luigi D. Notarangelo, Darragh Duffy, Lorenz Studer, Jean-Laurent Casanova, Shen-Ying Zhang
Katherine Uyhazi and renowned gene therapy pioneer Jean Bennett share their perspective on the 2020 Nobel Prize in Chemistry awarded to Emmanuelle Charpentier and Jennifer Doudna for their discovery of the CRISPR/Cas9 genetic scissors that have revolutionized genome editing.
Katherine E. Uyhazi, Jean Bennett
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