The SARS-CoV-2 spike protein is the main antigen in all approved COVID-19 vaccines and is also the only target for monoclonal antibody therapies. Immune responses to other viral antigens are generated after SARS-CoV-2 infection, but their contribution to the antiviral response remains unclear. Here, we interrogate whether nucleocapsid-specific antibodies can improve protection against SARSCoV-2. We first immunized mice with a nucleocapsid-based vaccine, and then transferred sera from these mice into naïve mice, followed by challenge with SARS-CoV-2. We show that mice that received nucleocapsid-specific sera or a nucleocapsid-specific monoclonal antibody (mAb) exhibited enhanced control of SARS-CoV-2. Nucleocapsid-specific antibodies elicited NK-mediated antibodydependent cellular cytotoxicity (ADCC) against infected cells. These findings provide the first demonstration in the coronavirus literature that antibody responses specific to the nucleocapsid protein can improve viral clearance, providing a rationale for the clinical evaluation of nucleocapsid-based monoclonal antibody therapies to treat COVID-19.
Tanushree Dangi, Sarah Sanchez, Jacob Class, Michelle C. Richner, Lavanya Visvabharathy, Young Rock Chung, Kirsten Bentley, Richard J. Stanton, Igor J. Koralnik, Justin M. Richner, Pablo Penaloza-MacMaster
Prevalent copy number alteration (CNA) is the most prominent genetic characteristic associated with ovarian cancer (OV) development, but its role in immune evasion has not been fully elucidated. In this study, we identified RAD21, a key component of the cohesin complex, as a frequently amplified oncogene that could modulate immnue response in OV. Through interrogating RAD21-regulated transcriptional program we found that RAD21 directly interacts with YAP/TEAD4 transcriptional co-repressors and recruits NuRD complex to suppress interferon (IFN) signaling. In multiple clinical cohorts, RAD21 overexpression is inversely correlated with IFN signature gene expression in OV. We further demonstrated in murine syngeneic tumor models that RAD21 ablation potentiated anti-PD-1 efficacy with increased intratumoral CD8+ T-cell effector activity. Our study identified a previously unrecognized RAD21-YAP/TEAD4-NuRD co-repressor complex in immune modulation, and thus provided a potential target and biomarker for precision immunotherapy in OV.
Peng Deng, Zining Wang, Jinghong Chen, Shini Liu, Xiaosai Yao, Shaoyan Liu, Lizhen Liu, Zhaoliang Yu, Yulin Huang, Zhongtang Xiong, Rong Xiao, Jiuping Gao, Weiting Liang, Jieping Chen, Hui Liu, Jing Han Hong, Jason Yongsheng Chan, Peiyong Guan, Jianfeng Chen, Yali Wang, Jiaxin Yin, Jundong Li, Min Zheng, Chao Zhang, Penghui Zhou, Tiebang Kang, Bin Tean Teh, Qiang Yu, Zhixiang Zuo, Qingping Jiang, Jihong Liu, Ying Xiong, Xiaojun Xia, Jing Tan
The various functions of the skeleton are influenced by extracellular cues, hormones and neurotransmitters. One type of neuronal regulation favors bone mass accrual by inhibiting sympathetic nervous system activity. This observation raises questions about the transcriptional mechanisms regulating catecholamine synthesis. Using a combination of genetic and pharmacological studies we have found that the histone deacetylase SIRT1 is a transcriptional modulator of the neuronal control of bone mass. Neuronal SIRT1 reduced bone mass by increasing SNS signaling. SIRT1 did so by increasing expression of monoamine oxidase A (MAO-A), a SIRT1 target that reduces brain serotonin levels by inducing its catabolism, and by suppressing Tph2 expression and serotonin synthesis in the brainstem. SIRT1 upregulated brain catecholamine synthesis indirectly through serotonin but did not directly affect Dbh expression in the locus coeruleus. These results help understand skeletal changes associated with SSRIs and may have implications for treating skeletal and metabolic diseases.
Na Luo, Ioanna Mosialou, Mattia Capulli, Brygida Bisikirska, Chyuan-Sheng Lin, Yung-yu Huang, Peter Timothy Shyu, X. Edward Guo, Aris Economides, J. John Mann, Stavroula Kousteni
Platelets and megakaryocytes are critical players in immune responses. Recent reports suggest infection and inflammation alter the megakaryocyte and platelet transcriptome to induce altered platelet reactivity. We examined if non-viral sepsis induces differential platelet gene expression and reactivity. Non-viral sepsis upregulated IFITM3, an interferon responsive gene that restricts viral replication. As IFITM3 has been linked to clathrin-mediated endocytosis, we examined if IFITM3 promoted endocytosis of alpha granule proteins. Interferon stimulation enhanced fibrinogen endocytosis in megakaryocytes and platelets from Ifitm+/+ mice, but not Ifitm-/- mice. IFITM3 overexpression or deletion in megakaryocytes demonstrated IFITM3 was necessary and sufficient to regulate fibrinogen endocytosis. Mechanistically, IFITM3 interacts with clathrin and αIIb and altered their plasma membrane localization into lipid rafts. In vivo interferon administration increased fibrinogen endocytosis, platelet reactivity, and thrombosis in an IFITM-dependent manner. In contrast, Ifitm-/- mice were completely rescued from interferon-induced platelet hyperreactivity and thrombosis. During murine sepsis, platelets from Ifitm+/+ mice demonstrated increased fibrinogen content and platelet reactivity, which was dependent on interferon-alpha and IFITMs. Platelets from patients with non-viral sepsis had increases in platelet IFITM3 expression, fibrinogen content, and hyperreactivity. These data identify IFITM3 as a regulator of platelet endocytosis, hyperreactivity, and thrombosis during inflammatory stress.
Robert A. Campbell, Bhanu Kanth Manne, Meenakshi Banerjee, Elizabeth A. Middleton, Abigail Ajanel, Hansjorg Schwertz, Frederik Denorme, Chris Stubben, Emilie Montenont, Samantha Saperstein, Lauren Page, Neal D. Tolley, Diana L. Lim, Samuel M. Brown, Colin K. Grissom, Douglas W. Sborov, Anandi Krishnan, Matthew T. Rondina
People with kidney disease are disproportionately affected by atherosclerosis for unclear reasons. Soluble urokinase plasminogen activator receptor (suPAR) is an immune-derived mediator of kidney disease, levels of which are strongly associated with cardiovascular outcomes. We assessed suPAR’s pathogenic involvement in atherosclerosis using epidemiologic, genetic, and experimental approaches. We found serum suPAR levels to be predictive of coronary artery calcification and cardiovascular events in 5,406 participants without known coronary disease. In a genome-wide association meta-analysis including over 25,000 individuals, we identified a missense variant in the PLAUR gene (rs4760) confirmed experimentally to lead to higher suPAR levels. Mendelian randomization analysis in the UK Biobank using rs4760 indicated a causal association between genetically predicted suPAR levels and atherosclerotic phenotypes. In an experimental model of atherosclerosis, Pcsk9 transfection in mice over-expressing suPAR (suPARTg) led to substantially increased atherosclerotic plaques with necrotic cores and macrophage infiltration compared to wild-type mice, despite similar cholesterol levels. Pre-atherosclerosis, aortas of suPARTg mice excreted higher levels of CCL2 and had higher monocyte counts compared to wild-type aortas. Aortic and circulating suPARTg monocytes exhibited a pro-inflammatory profile and enhanced chemotaxis. These findings characterize suPAR as a pathogenic factor for atherosclerosis acting at least partially through modulation of monocyte function.
George Hindy, Daniel J. Tyrrell, Alexi Vasbinder, Changli Wei, Feriel Presswalla, Hui Wang, Pennelope K. Blakely, Ayse Bilge Ozel, Sarah E. Graham, Grace H. Holton, Joseph Dowsett, Akl C. Fahed, Kingsley-Michael Amadi, Grace K. Erne, Annika Tekumulla, Anis Ismail, Christopher Launius, Nona Sotoodehnia, James S. Pankow, Lise Wegner Thørner, Christian Erikstrup, Ole Birger Pedersen, Karina Banasik, Søren Brunak, Henrik Ullum, Jesper Eugen-Olsen, Sisse Rye Ostrowski, Mary E. Haas, Jonas B. Nielsen, Luca A. Lotta, Gunnar Engström, Olle Melander, Marju Orho-Melander, Lili Zhao, Venkatesh L. Murthy, David J. Pinsky, Cristen J. Willer, Susan R. Heckbert, Jochen Reiser, Daniel R. Goldstein, Karl C. Desch, Salim S. Hayek
Testosterone is the canonical growth factor of prostate cancer but can paradoxically suppress its growth when present at supraphysiological levels. We have previously demonstrated that the cyclical administration of supraphysiological androgen (SPA), termed Bipolar Androgen Therapy (BAT), can result in tumor regression and clinical benefit for patients with castration-resistant prostate cancer. However, predictors and mechanisms of response and resistance have been ill-defined. Here we show that growth inhibition of prostate cancer models by SPA required high androgen receptor (AR) activity and was driven in part by downregulation of MYC. Using matched sequential patient biopsies, we show that high pre-treatment AR activity predicted downregulation of MYC, clinical response, and prolonged progression-free and overall survival for patients on BAT. BAT induced strong downregulation of AR in all patients, which is shown to be a primary mechanism of acquired resistance to SPA. Acquired resistance could be overcome by alternating SPA with the AR inhibitor enzalutamide, which induced adaptive upregulation of AR and re-sensitized prostate cancer to SPA. This work identifies high AR activity as a predictive biomarker of response to BAT and supports a treatment paradigm for prostate cancer involving alternating between AR inhibition and activation.
Laura A. Sena, Rajendra Kumar, David E. Sanin, Elizabeth A. Thompson, D. Marc Rosen, Susan L. Dalrymple, Lizamma Antony, Yuhan Yang, Carolina Gomes-Alexandre, Jessica L. Hicks, Tracy Jones, Kiara A. Bowers, Jillian N. Eskra, Jennifer Meyers, Anuj Gupta, Alyza Skaist, Srinivasan Yegnasubramanian, Jun Luo, W. Nathaniel Brennen, Sushant K. Kachhap, Emmanuel S. Antonarakis, Angelo M. De Marzo, John T. Isaacs, Mark C. Markowski, Samuel R. Denmeade
During cutaneous tick attachment, the feeding cavity becomes a site of transmission for tick salivary compounds and tick-borne pathogens. However, the immunological consequences of tick feeding on human skin remain unclear. Here, we assessed human skin and blood samples upon tick bite and developed a human skin explant model mimicking Ixodes ricinus bite and tick-borne pathogen infection. Following tick attachment, we observed rapidly occurring patterns of immunomodulation including increase in neutrophils and cutaneous B and T cells. T cells up-regulated tissue-residency markers, while lymphocytic cytokine production was impaired. In early stages of Borrelia burgdorferi model infections, we detected strain-specific immune responses and close spatial relationships of macrophages and spirochetes. Pre-incubation of spirochetes with tick salivary gland extracts hampered accumulation of immune cells and increased spirochete loads. Collectively, we showed that tick feeding exerts profound changes on the skin immune network, which interfere with the primary response against tick-borne pathogens.
Johanna Strobl, Verena Muendler, Sophie Müller, Anna Gindl, Sara Berent, Anna-Margarita Schötta, Lisa Kleissl, Clement Staud, Anna Redl, Luisa Unterluggauer, Ana Elena Aguilar González, Sophie Therese Weninger, Denise Atzmüller, Romana Klasinc, Gerold Stanek, Mateusz Markowicz, Hannes Stockinger, Georg Stary
Fusion oncoproteins are the initiating event in the pathogenesis of many pediatric AML. The CBFA2T3-GLIS2 (C/G) fusion is a product of a cryptic translocation primarily seen in infants and early childhood and is associated with dismal outcome. Here, we demonstrate that the expression of the C/G oncogenic fusion protein promotes the transformation of human cord blood hematopoietic stem/progenitor cells (CB HSPCs) in an endothelial cell (EC) co-culture system, that recapitulates the transcriptome, morphology and immunophenotype of C/G AML and induces highly aggressive leukemia in xenograft models. Interrogating the transcriptome of C/G-CB cells and primary C/G AML identified a library of C/G fusion-specific genes that are potential targets for therapy. We developed chimeric antigen receptor (CAR) T cells directed against one of the targets, FOLR1, and demonstrated their pre-clinical efficacy against C/G AML using in vitro and xenograft models. FOLR1 is also expressed in renal and pulmonary epithelium, raising concerns for toxicity that must be addressed for the clinical application of this therapy. Our findings underscore the role of the endothelial niche in promoting leukemic transformation of C/G-transduced CB HSPCs. Furthermore, this work has broad implications for studies of leukemogenesis applicable to a variety of oncogenic fusion-driven pediatric leukemias, providing a robust and tractable model system to characterize the molecular mechanisms of leukemogenesis and identify biomarkers for disease diagnosis and targets for therapy.
Quy Le, Brandon Hadland, Jenny L. Smith, Amanda Leonti, Benjamin J. Huang, Rhonda Ries, Tiffany A. Hylkema, Sommer Castro, Thao T. Tang, Cyd N. McKay, LaKeisha Perkins, Laura Pardo, Jay Sarthy, Amy K. Beckman, Robin Williams, Rhonda Idemmili, Scott Furlan, Takashi Ishida, Lindsey Call, Shivani Srivastava, Anisha M. Loeb, Filippo Milano, Suzan Imren, Shelli M. Morris, Fiona Pakiam, James M. Olson, Michael R. Loken, Lisa Eidenschink Brodersen, Stanley R. Riddell, Katherine Tarlock, Irwin D. Bernstein, Keith R. Loeb, Soheil Meshinchi
Astrocytes are highly heterogenic in their phenotype and function, which contribute to CNS disease, repair and aging; however, the molecular mechanism of their functional states remains largely unknown. Here we show that activation of sirtuin 1 (SIRT1), a protein deacetylase, plays an important role in the detrimental actions of reactive astrocytes, whereas its inactivation endorsed these cells with anti-inflammatory functions that inhibited the production of proinflammatory mediators by myeloid cells/microglia and promoted the differentiation of oligodendrocyte progenitor cells. Mice with astrocyte-specific Sirt1 knockout had suppressed progression of experimental autoimmune encephalomyelitis (EAE), an animal model of CNS inflammatory demyelinating diseases. Ongoing EAE was also suppressed when Sirt1 expression in astrocytes was diminished by CRISPR/Cas vector, resulting in reduced demyelination, decreased numbers of T cells, and increased rate of IL-10-producing macrophages/microglia in the CNS, whereas peripheral immune response remained unaffected. Mechanistically, Sirt1-/- astrocytes expressed a range of nuclear factor erythroid-derived 2-like 2 (Nfe2l2) target genes, and Nfe2l2 deficiency shifted the beneficial action of Sirt1-/- astrocytes to a detrimental one. These findings identify a novel approach for switching functional state of reactive astrocytes and facilitate the development of astrocyte-targeting therapies for inflammatory neurodegenerative diseases such as multiple sclerosis.
Weifeng Zhang, Dan Xiao, Xing Li, Yuan Zhang, Javad Rasouli, Giacomo Casella, Alexandra Boehm, Daniel Hwang, Larissa L.W. Ishikawa, Rodolfo Thome, Bogoljub Ciric, Mark T. Curtis, Abdolmohamad Rostami, Guang-Xian Zhang
Preterm birth is the leading cause of death in children under 5 years of age. Premature infants who receive life-saving oxygen therapy often develop bronchopulmonary dysplasia (BPD), a chronic lung disease. Infants with BPD are at a high risk of abnormal neurodevelopment, including motor and cognitive difficulties. While neural progenitor cells (NPCs) are crucial for proper brain development, it is unclear whether they play a role in BPD-associated neurodevelopmental deficits. Here, we showed that hyperoxia-induced experimental BPD in newborn mice led to life-long impairments in cerebrovascular structure and function, as well as impairments in NPC self-renewal and neurogenesis. A neurosphere assay utilizing non-human primate preterm baboon NPCs confirmed impairment in NPC function. Moreover, gene expression profiling revealed that genes involved in cell proliferation, angiogenesis, vascular autoregulation, neuronal formation, and neurotransmission were dysregulated following neonatal hyperoxia. These impairments were associated with motor and cognitive decline in aging hyperoxia-exposed mice, reminiscent of deficits observed in patients with BPD. Altogether, our findings established a relationship between BPD and abnormal neurodevelopmental outcomes and identified molecular and cellular players of neonatal brain injury that persist throughout adulthood, that may be targeted for early intervention to aid this vulnerable patient population.
Marissa A. Lithopoulos, Xavier Toussay, Shumei Zhong, Liqun Xu, Shamimunisa B. Mustafa, Julie Ouellette, Moises Freitas-Andrade, Cesar C. Comin, Hayam A. Bassam, Adam N. Baker, Yiren Sun, Michael Wakem, Alvaro G. Moreira, Cynthia L. Blanco, Arul Vadivel, Catherine Tsilfidis, Steven R. Seidner, Ruth S. Slack, Diane C. Lagace, Jing Wang, Baptiste Lacoste, Bernard Thébaud
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