To delineate the in vivo role of different costimulatory signals in activating and expanding highly functional virus-specific cytotoxic CD8+ T cells, we designed synTacs, infusible biologics which recapitulate antigen-specific T-cell activation signals delivered by antigen-presenting cells. We constructed synTacs consisting of dimeric Fc-domain scaffolds linking CD28- or 4-1BB-specific ligands to HLA-A2 MHC molecules covalently-tethered to HIV- or CMV-derived peptides. Treatment of HIV-infected donor PBMCs with synTacs bearing HIV- or CMV-derived peptides induced vigorous and selective ex vivo expansion of highly functional HIV- and/or CMV-specific CD8+ T cells, respectively, with potent anti-viral activities. Intravenous injection of HIV or CMV-specific synTacs into immunodeficient mice intrasplenically engrafted with donor PBMCs markedly and selectively expanded HIV-specific (32-fold) or CMV-specific (46-fold) human CD8+ T cells populating their spleens, respectively. Notably, these expanded HIV or CMV-specific CD8+ T cells directed potent in vivo suppression of HIV or CMV infections, respectively, in the humanized mice providing strong rationale for consideration of synTac-based approaches as a therapeutic strategy to cure HIV and treat CMV and other viral infections. The synTac platform flexibility supports facile delineation of in vivo effects of different costimulatory signals on patient-derived virus-specific CD8+ T cells, enabling optimization of individualized therapies, including HIV cure strategies.
Mengyan Li, Scott J. Garforth, Kaitlyn E. O’Connor, Hang Su, Danica M. Lee, Alev Celikgil, Rodolfo J. Chaparro, Ronald D. Seidel, R. Brad Jones, Ravit Arav-Boger, Steven C. Almo, Harris Goldstein
Genome-wide association studies (GWAS) involve testing genetic variants across the genomes of many individuals to identify genotype-phenotype associations. GWAS have enabled the identification of numerous genomic biomarkers in various complex human diseases including infectious ones. However, few of these studies are relevant for clinical practice or at the bedside. In this issue of the JCI, Nakanishi et al. characterized the clinical implications of a major genetic risk factor for COVID-19 severity and its age-dependent effect, using individual-level data in a large international multi-center consortium. This study indicates that a common COVID-19 genetic risk factor (rs10490770) associates with increased risks of morbidity and mortality, suggesting potential implications for future clinical risk management. How can the genomic biomarkers identified by GWAS be associated with the clinical outcomes of an infectious disease? In this commentary, we evaluate the advantages and limitations of this approach.
Vito Luigi Colona, Michela Bianocolella, Antonio Novelli, Giuseppe Novelli
Contrasting with the predicted anorexigenic effect of increasing brain serotonin signaling, long-term use of selective serotonin reuptake inhibitors (SSRIs) antidepressants correlates with body weight gain. This adverse outcome increases the risk of transitioning to obesity and interferes with treatment compliance. Here we show that orally administered fluoxetine (Flx), a widely prescribed SSRI, increased body weight by enhancing food intake in healthy mice at two different time points and through two distinct mechanisms. Within hours, Flx decreased the activity of a subset of brainstem serotonergic neurons by triggering autoinhibitory signaling through the Htr1a receptor. Upon longer treatment Flx blunted Htr2c expression/signaling, decreased the phosphorylation of Creb and Stat3 and dampened the production of POMC/α-MSH in hypothalamic neurons, thereby increasing food intake. Accordingly, exogenous stimulation of the melanocortin 4 receptor (MC4R) by co-treating mice with Flx and lipocalin-2, an anorexigenic hormone signaling through this receptor, normalized feeding and body weight. Flx and other SSRIs also inhibit CREB/STAT3 phosphorylation in a human neuronal cell line suggesting that these non-canonical effects could also occur in long-term users of SSRIs. By defining the molecular basis of the long-term SSRIs-associated weight gain this study proposes a therapeutic strategy to counter it.
Maria Jose Ortuno, Marc Schneeberger, Anoj Ilanges, François Marchildon, Kyle Pellegrino, Jeffrey M. Friedman, Patricia Ducy
BACKGROUND. A long-held dream of scientists is to transfer information directly to the visual cortex of blind individuals, thereby restoring a rudimentary form of sight. However, no clinically available cortical visual prosthesis yet exists. METHODS.We implanted an intracortical microelectrode array consisting of 96 electrodes in the visual cortex of a 57-year-old person with complete blindness for a six- month period. We measured thresholds and the characteristics of the visual percepts elicited by intracortical microstimulation. RESULTS. Implantation and subsequent explantation of intracortical microelectrodes were carried out without complications. The mean stimulation threshold for single electrodes was 66.8 ± 36.5 μA. We consistently obtained high-quality recordings from visually deprived neurons and the stimulation parameters remained stable over time. Simultaneous stimulation via multiple electrodes were associated with a significant reduction in thresholds (p<0.001, ANOVA test) and evoked discriminable phosphene percepts, allowing the blind participant to identify some letters and recognize object boundaries. Furthermore, we observed a learning process that helped the subject to recognize complex patterns over time. CONCLUSIONS. Our results demonstrate the safety and efficacy of chronic intracortical microstimulation via a large number of electrodes in human visual cortex, showing its high potential for restoring functional vision in the blind. TRIAL REGISTRATION. ClinicalTrials.gov identifier NCT02983370. FUNDING. Funding was provided by grant RTI2018-098969-B-100 from the Spanish Ministerio de Ciencia Innovación y Universidades, by grant PROMETEO/2019/119 from the Generalitat Valenciana (Spain), by the Bidons Egara Research Chair of the University Miguel Hernández (Spain) and by the John Moran Eye Center of the University of Utah (US).
Eduardo Fernández, Arantxa Alfaro, Cristina Soto-Sánchez, Pablo González-López, Antonio M. Lozano Ortega, Sebastian Peña, María Dolores Grima, Alfonso Rodil, Bernardeta Gómez, Xing Chen, Pieter R. Roelfsema, John D. Rolston, Tyler S. Davis, Richard A. Normann
Immune checkpoint inhibitors (ICB) have significantly prolonged patient survival across multiple tumor types, particularly in melanoma. Interestingly, gender specific differences in response to ICB have been observed with males getting more benefit than females, although the mechanism(s) underlying this difference are unknown. Mining published transcriptomic datasets, we determined that response to ICBs is influenced by the functionality of intratumoral macrophages. This puts into context our observation that estrogens (E2) working through the estrogen receptor (ERα) stimulate melanoma growth in murine models by skewing macrophage polarization towards an immune-suppressive state that promotes CD8+ T cell dysfunction/exhaustion and ICB resistance. This activity was not evident in mice harboring a macrophage specific depletion of ERα confirming a direct role for estrogen signaling within myeloid cells in establishing an immunosuppressed state. Inhibition of ERα using fulvestrant, a selective estrogen receptor downregulator (SERD) decreases tumor growth, stimulates adaptive immunity and increases the antitumor efficacy of ICBs. Further, a gene signature that reads on ER activity in macrophages predicted survival in ICB treated melanoma patients. These results highlight the importance of E2/ER as a regulator of intratumoral macrophage polarization; an activity that can be therapeutically targeted to reverse immune suppression and increase ICB efficacy.
Binita Chakraborty, Jovita Byemerwa, Jonathan H. Shepherd, Corinne N. Haines, Robert Baldi, Weida Gong, Wen Liu, Debarati Mukherjee, Sandeep Artham, Felicia Lim, Yeeun Bae, Olivia Brueckner, Kendall Heetderks, Suzanne E. Wardell, Brent A. Hanks, Charles M. Perou, Ching-Yi Chang, Donald P. McDonnell
Although Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) vaccines have shown efficacy against SARS-CoV-2, it is unknown if coronavirus vaccines can also protect against other coronaviruses that may infect humans in the future. Here, we show that coronavirus vaccines elicit cross-protective immune responses against heterologous coronaviruses. In particular, we show that a Severe Acute Respiratory Syndrome Coronavirus 1 (SARS-CoV-1) vaccine developed in 2004 and known to protect against SARS-CoV-1, confers robust heterologous protection against SARS-CoV-2 in mice. Similarly, prior coronavirus infections conferred heterologous protection against distinct coronaviruses. Cross-reactive immunity was also reported in Coronavirus Disease 2019 (COVID-19) patients and humans who received SARS-CoV-2 vaccines, and transfer of plasma from these individuals into mice improved protection against coronavirus challenges. These findings provide the first demonstration that coronavirus vaccines (and prior coronavirus infections) can confer broad protection against heterologous coronaviruses, providing a rationale for universal coronavirus vaccines.
Tanushree Dangi, Nicole Palacio, Sarah Sanchez, Mincheol Park, Jake Class, Lavanya Visvabharathy, Thomas Ciucci, Igor J. Koralnik, Justin M. Richner, Pablo Penaloza-MacMaster
Central obesity with cardiometabolic syndrome (CMS) is a major global contributor to human disease, and effective therapies are needed. Here, we show inhibiting cyclic-GMP selective phosphodiesterase-9A (PDE9-I) in both ovariectomized female or male mice suppresses pre-established severe diet-induced obesity/CMS with or without superimposed mild cardiac pressure-load. PDE9-I reduces total body, inguinal, hepatic, and myocardial fat, stimulating mitochondrial activity in brown and white fat, and improving CMS, without significantly altering activity or food intake. PDE9 localized at mitochondria, and its inhibition in vitro stimulated lipolysis and mitochondrial respiration in adipocytes and myocytes coupled to PPARα-dependent gene regulation. PPARα upregulation was required to achieve the lipolytic, anti-obesity, and metabolic effects of PDE9-I. All these PDE9-I induced changes were not observed in obese/CMS non-ovariectomized females, indicating a strong sexual dimorphism. We found that PPARα chromatin binding was re-oriented away from fat-metabolism regulating genes when stimulated in the presence of co-activated estrogen receptor-alpha, and this may underly the dimorphism. These findings have translational relevance given that PDE9-I is already being studied in humans for indications including heart failure, and efficacy against obesity/CMS would enhance its therapeutic utility.
Sumita Mishra, Nandhini Sadagopan, Brittany Dunkerly-Eyring, Susana Rodriguez, Dylan C. Sarver, Ryan P. Ceddia, Sean A. Murphy, Hildur Knutsdottir, Vivek P. Jani, Deepthi Ashok, Christian U. Oeing, Brian O'Rourke, Jon A. Gangoiti, Dorothy D. Sears, G. William Wong, Sheila Collins, David Kass
Human monoclonal antibodies were used here to study the mechanism of neuron intoxication by tetanus neurotoxin and to evaluate them as a safe preventive and therapeutic substitute of hyperimmune sera for tetanus in mice. By screening memory B cells of immune donors, we selected two monoclonal antibodies specific for tetanus neurotoxin with exceptionally high neutralizing activities, which were extensively characterized both structurally and functionally. We found that these antibodies interfere with the binding and translocation of the neurotoxin into neurons by interacting with two epitopes, whose definition pinpoints crucial events in the cellular pathogenesis of tetanus. This information explains the unprecedented neutralization ability of these antibodies, which were found to be exceptionally potent in preventing experimental tetanus when injected in mice long before the neurotoxin. Moreover, their Fab derivatives neutralized tetanus neurotoxin in post-exposure experiments, suggesting their potential therapeutic use via intrathecal injection. As such, these human monoclonal antibodies, as well as their Fab derivatives, meet all requirements for being considered for prophylaxis and therapy of human tetanus and are ready for clinical trials.
Marco Pirazzini, Alessandro Grinzato, Davide Corti, Sonia Barbieri, Oneda Leka, Francesca Vallese, Marika Tonellato, Chiara Silacci-Fregni, Luca Piccoli, Eaazhisai Kandiah, Giampietro Schiavo, Giuseppe Zanotti, Antonio Lanzavecchia, Cesare Montecucco
BACKGROUND. Gingivitis and periodontitis are prevalent inflammatory diseases of the periodontal tissues. Current treatments are often ineffective or do not prevent disease recurrence. Uncontrolled complement activation and resulting chronic gingival inflammation is a hallmark of periodontal diseases. We determined efficacy and safety of a complement 3-targeted therapeutic, AMY-101, locally administered in adults with periodontal inflammation. METHODS. Thirty-two patients with gingival inflammation were enrolled into a randomized, placebo-controlled, double-blind, split-mouth design phase 2a trial, after dose-escalation study to select safe and effective dose with additional 8 patients. Half of the mouth was randomly assigned to AMY-101 (0.1mg/site) or placebo injections at sites of inflammation, administered on days 0, 7 and 14 and evaluated for safety and efficacy outcomes at days 28, 60 and 90. The primary efficacy outcome was change in gingival inflammation, measured by modified gingival index (MGI), and secondary outcomes included changes in bleeding-on-probing (BOP), amount of plaque, pocket depth, clinical attachment level, and gingival crevicular fluid levels of matrix metalloproteinases (MMPs) over 90 days. RESULTS. A once-per-week intragingival injection of AMY-101 for 3 weeks was safe and well-tolerated in all participants resulting in significant (P<0.001) reductions in clinical indices measuring gingival inflammation (MGI and BOP). AMY-101 significantly (P<0.05) reduced MMP-8 and MMP-9 levels, indicators of inflammatory tissue destruction. These therapeutic effects persisted for at least 3 months post-treatment. CONCLUSION. AMY-101 causes significant and sustainable reduction in gingival inflammation without adverse events and merits further investigation for the treatment of periodontitis and other oral or peri-implant inflammatory conditions. TRIAL REGISTRATION. ClinicalTrials.gov: NCT03694444. FUNDING. Amyndas Pharmaceuticals. Amyndas contributed to the design and conducts of the clinical trial and in the writing of the manuscript.
Hatice Hasturk, George Hajishengallis, John D. Lambris, Dimitrios C. Mastellos, Despina Yancopoulou
Insulin resistance is a cornerstone of obesity related complications such as type 2 diabetes, metabolic syndrome, and non-alcoholic fatty liver disease. A high rate of lipolysis is known to be associated with insulin resistance, and inhibiting adipose tissue lipolysis improves obesity-related insulin resistance. Here, we demonstrate that inhibition of 5-HT signaling through serotonin receptor 2B (HTR2B) in adipose tissues ameliorates insulin resistance by reducing lipolysis in visceral adipocytes. Chronic high-fat diet (HFD) feeding increased Htr2b expression in eWAT, resulting in the increased HTR2B signaling in visceral white adipose tissue. Moreover, HTR2B expression in white adipose tissue was increased in obese humans and positively correlated with metabolic parameters. We further found that adipocyte-specific Htr2b-knockout mice are resistant to high-fat diet (HFD)-induced insulin resistance, visceral adipose tissue inflammation, and hepatic steatosis. Enhanced 5-HT signaling through HTR2B directly activated lipolysis through phosphorylation of hormone sensitive lipase in visceral adipocytes. Moreover, treatment with a selective HTR2B antagonist attenuated HFD-induced insulin resistance, visceral tissue inflammation, and hepatic steatosis. Thus, adipose HTR2B signaling could be a potential therapeutic target for treatment of obesity-related insulin resistance.
Won Gun Choi, Wonsuk Choi, Tae Jung Oh, Hye-Na Cha, Inseon Hwang, Yun Kyung Lee, Seung Yeon Lee, Hyemi Shin, Ajin Lim, Dongryeol Ryu, Jae Myoung Suh, So-Young Park, Sung Hee Choi, Hail Kim
Nucleoside-modified mRNA vaccines have gained global attention because of COVID-19. We evaluated a similar vaccine approach for preventing a chronic latent genital infection rather than an acute respiratory infection. We used animal models to compare an HSV-2 trivalent nucleoside-modified mRNA vaccine with the same antigens prepared as proteins with an emphasis on antigen-specific memory B cell responses and immune correlates of protection. In guinea pigs, serum neutralizing antibody titers were higher at one month and declined far less by eight months in mRNA- than protein-immunized animals. Both vaccines protected against death and genital lesions when infected one month after immunization; however, protection was more durable in the mRNA than protein group when infected after eight months, an interval representing >15% of the animal’s lifespan. Serum and vaginal neutralizing antibody titers correlated with protection against infection as measured by genital lesions and vaginal virus titers two days post infection. In mice, the mRNA vaccine generated more antigen-specific memory B cells than the protein vaccine at early times post immunization that persisted for up to one year. High neutralizing titers and robust B cell immune memory likely explain the more durable protection by the HSV-2 mRNA vaccine.
Sita Awasthi, James J. Knox, Angela Desmond, Mohamad-Gabriel Alameh, Brian T. Gaudette, John M. Lubinski, Alexis Naughton, Lauren M. Hook, Kevin P. Egan, Ying K. Tam, Norbert Pardi, David Allman, Eline T. Luning Prak, Michael P. Cancro, Drew Weissman, Gary H. Cohen, Harvey M. Friedman
BACKGROUND. SARS-CoV-2 infection in pregnancy is associated with a higher risk of pregnancy-related complications and neonatal respiratory distress and hospitalization. Effectiveness of SARS-CoV-2 vaccines in pregnant women is not known. METHODS. All women with confirmed pregnancy who presented to the national referral hospital in Qatar between December 20, 2020 and May 30, 2021 with at least one SARS-CoV-2 test and not testing prior to pregnancy were included. We determined the vaccine effectiveness of mRNA vaccines in preventing confirmed SARS-CoV-2 infection during pregnancy using both cohort and test-negative case-control designs. Analyses were adjusted for age group, nationality, and gestational age. RESULTS. Among 4,534 pregnant women, there were 407 vaccinated and unvaccinated women in the matched cohort analysis. Vaccine effectiveness was 87.6% (95%CI 44.1-97.2%) ≥ 14 days after the second dose. There were 386 test-positive and 834 matched women in the test-negative case-control analysis. Vaccine effectiveness was 86.8% (95%CI 47.5-98.5) ≥ 14 days after the second dose. Adjustment for age, nationality and gestational age yielded similar results for both designs. In the test-negative analysis, vaccine effectiveness ≥ 14 days after the first dose but before the second dose was 40.8% (95% CI 0.0-80.4). Of the 386 test-positive pregnant women, 74 were Alpha variant, 163 were Beta variant, and 156 were variants of unknown status. There were nine severe/critical disease cases, and no deaths in the PCR-positive pregnant women, all among unvaccinated. CONCLUSIONS. The mRNA vaccines provide high level of protection against documented SARS-CoV-2 infection, which supports including pregnant women in vaccination campaigns.
Adeel A. Butt, Hiam Chemaitelly, Abdullatif Al Khal, Peter V Coyle, Huda Saleh, Anvar Kaleeckal, Ali N. Latif, Roberto Bertollini, Abdul Badi Abou-Samra, Laith J. Abu-Raddad
Ferroptosis, an iron-dependent non-apoptotic cell death, is a highly regulated tumor suppressing process. However, functions and mechanisms of RNA binding proteins in regulation of evasion of ferroptosis during lung cancer progression are still largely unknown. Here we reported that the RNA binding protein RBMS1 participated in lung cancer development through mediating ferroptosis evasion. Through an shRNA-mediated systematic screen, we discovered that RBMS1 was a key ferroptosis regulator. Clinically, RBMS1 was elevated in lung cancer and its high expression was associated with reduced patient survival. Conversely, depletion of RBMS1 inhibited lung cancer progression both in vivo and in vitro. Mechanistically, RBMS1 interacted with the translation initiation factor eIF3d directly to bridge the 3'- and 5'-UTRs of SLC7A11. RBMS1 ablation inhibited the translation of SLC7A11, reduced SLC7A11-mediated cystine uptake and promotes ferroptosis. In a drug screen that targeted RBMS1, we further uncovered that nortriptyline hydrochloride decreased the level of RBMS1, thereby promoting ferroptosis. Importantly, RBMS1 depletion or inhibition by nortriptyline hydrochloride sensitized radioresistant lung cancer cells to radiotherapy. Our findings established RBMS1 as a translational regulator of ferroptosis and a prognostic factor with therapeutic potentials and clinical values.
Wenjing Zhang, Yu Sun, Lu Bai, Lili Zhi, Yun Yang, Qingzhi Zhao, Chaoqun Chen, Yangfan Qi, Wenting Gao, Wenxia He, Luning Wang, Dan Chen, Shujun Fan, Huan Chen, Hai-Long Piao, Qinglong Qiao, Zhaochao Xu, Jinrui Zhang, Jinyao Zhao, Sirui Zhang, Yue Yin, Chao Peng, Xiaoling Li, Quentin Liu, Han Liu, Yang Wang
The capacity of respiratory viruses to undergo evolution within the respiratory tract raises the possibility of evolution under the selective pressure of the host environment or drug treatment. Long-term infections in immunocompromised hosts are potential drivers of viral evolution and development of infectious variants. We show that intra-host evolution in chronic human parainfluenza virus 3 (HPIV3) infection in immunocompromised individuals elicited mutations that favor viral entry and persistence, suggesting that similar processes may operate across enveloped respiratory viruses. We profiled longitudinal HPIV3 infections from two immunocompromised individuals that persisted for 278 and 98 days. Mutations accrued in the HPIV3 attachment protein hemagglutinin-neuraminidase (HN), including the first in vivo mutation in HN’s receptor binding site responsible for activating the viral fusion process. Fixation of this mutation was associated with exposure to a drug that cleaves host cell sialic acid moieties. Longitudinal adaptation of HN was associated with features that promote viral entry and persistence in cells, including greater avidity for sialic acid and more active fusion activity in vitro, but not with antibody escape. Long term infection thus led to mutations promoting viral persistence, suggesting that host-directed therapeutics may support the evolution of viruses that alter their biophysical characteristics to persist in the face of these agents in vivo.
Alexander L. Greninger, Ksenia Rybkina, Michelle J. Lin, Jennifer Drew-Bear, Tara C. Marcink, Ryan C. Shean, Negar Makhsous, Michael Boeckh, Olivia Harder, Francesca Bovier, Shana R. Burstein, Stefan Niewiesk, Bert K. Rima, Matteo Porotto, Anne Moscona
Cutaneous leishmaniasis (CL) is caused by Leishmania donovani in Sri Lanka. Pentavalent antimonials (e.g. sodium stibogluconate; SSG) remain first line drugs for CL with no new effective treatments emerging. We studied whole blood and lesion transcriptomes from Sri Lankan CL patients at presentation and during SSG treatment. From lesions but not whole blood, we identified differential expression of immune-related genes, including immune checkpoint molecules, after onset of treatment. Using spatial profiling and RNA-FISH, we confirmed reduced expression of PD-L1 and IDO1 proteins on treatment in lesions of a second validation cohort and further demonstrated significantly higher expression of these checkpoint molecules on parasite-infected compared to non-infected lesional CD68+ monocytes / macrophages. Crucially, early reduction in PD-L1 but not IDO1 expression was predictive of rate of clinical cure (HR = 4.88) and occurred in parallel with reduction in parasite load. Our data support a model whereby the initial anti-leishmanial activity of antimonial drugs alleviates checkpoint inhibition on T cells, facilitating immune-drug synergism and clinical cure. Our findings demonstrate that PD-L1 expression can be used as predictor of rapidity of clinical response to SSG treatment in Sri Lanka and support further evaluation of PD-L1 as a host directed therapy target in leishmaniasis.
Nidhi S. Dey, Sujai Senaratne, Vijani Somaratne, Nayani P. Madarasinghe, Bimalka Seneviratne, Sarah Forrester, Marcela Montes de Oca, Luiza Campos Reis, Srija Moulik, Pegine B. Walrad, Mitali Chatterjee, Hiro Goto, Renu Wickremasinghe, Dimitris Lagos, Paul M. Kaye, Shalindra Ranasinghe
Air pollution is a well-known contributor to asthma. Air toxics are hazardous air pollutants that cause or may cause serious health effects. While individual air toxics have been associated with asthma, only a limited number of studies have specifically examined combinations of air toxics associated with the disease. We geocoded air toxic levels from the US National Air Toxics Assessment (NATA) to residential locations for participants of our AiRway in Asthma (ARIA) study. We then applied Data-driven ExposurE Profile extraction (DEEP), a novel machine learning-based method, to discover combinations of early-life air toxics associated with current use of daily asthma controller medication, lifetime emergency department visit for asthma, and lifetime overnight hospitalization for asthma. We discovered 20 multi-air toxic combinations and 18 single air toxics associated with at least one outcome. The multi-air toxic combinations included those containing acrylic acid, ethylidene dichloride, and hydroquinone, and they were significantly associated with asthma outcomes with odds ratios of 1.60 to 3.19. Several air toxic members of the combinations would not have been identified by single air toxic analyses, supporting the use of machine learning-based methods designed to detect combinatorial effects. Our findings provide knowledge about air toxic combinations associated with childhood asthma.
Yan-Chak Li, Hsiao-Hsien Leon Hsu, Yoojin Chun, Po-Hsiang Chiu, Zoe Arditi, Luz Claudio, Gaurav Pandey, Supinda Bunyavanich
BACKGROUND. There is considerable variability in COVID-19 outcomes amongst younger adults—and some of this variation may be due to genetic predisposition. METHODS. We combined individual level data from 13,888 COVID-19 patients (N=7,185 hospitalized) from 17 cohorts in nine countries to assess the association of the major common COVID-19 genetic risk factor (chromosome 3 locus tagged by rs10490770) with mortality, COVID-19-related complications and laboratory values. We next performed meta-analyses using FinnGen and the Columbia University COVID-19 Biobank. RESULTS. We found that rs10490770 risk allele carriers experienced an increased risk of all-cause mortality (HR 1.4, 95%CI 1.2–1.7). Risk allele carriers had increased odds of several COVID-19 complications: severe respiratory failure (OR 2.1, 95%CI 1.6-2.6), venous thromboembolism (OR 1.7, 95%CI 1.2-2.4), and hepatic injury (OR 1.5, 95%CI 1.2-2.0). Risk allele carriers ≤60 years had higher odds of death or severe respiratory failure (OR 2.7, 95%CI 1.8-3.9) compared to those >60 years (OR 1.5, 95%CI 1.2-1.8, interaction-p=0.038). Amongst individuals ≤60 years who died or experienced severe respiratory failure, 32.3% were risk variant carriers, compared to 13.9% of those not experiencing these outcomes. The genetic risk improved the prediction of death or severe respiratory failure similarly to, or better than, most established clinical risk factors. CONCLUSIONS. The major common COVID-19 genetic risk factor is associated with increased risks of morbidity and mortality, which are more pronounced amongst individuals ≤60 years. The effect was similar in magnitude and more common than most established clinical risk factors, suggesting potential implications for future clinical risk management.
Tomoko Nakanishi, Sara Pigazzini, Frauke Degenhardt, Mattia Cordioli, Guillaume Butler-Laporte, Douglas Maya-Miles, Luis Bujanda, Youssef Bouysran, Mari E.K. Niemi, Adriana Palom, David Ellinghaus, Atlas Khan, Manuel Martínez-Bueno, Selina Rolker, Sara Amitrano, Luisa Roade Tato, Francesca Fava, Christoph D. Spinner, Daniele Prati, David Bernardo, Federico Garcia, Gilles Darcis, Israel Fernandez-Cadenas, Jan Cato Holter, Jesus M. Banales, Robert Frithiof, Krzysztof Kiryluk, Stefano Duga, Rosanna Asselta, Alexandre C. Pereira, Manuel Romero-Gómez, Beatriz Nafría-Jiménez, Johannes R. Hov, Isabelle Migeotte, Alessandra Renieri, Anna M. Planas, Kerstin U. Ludwig, Maria Buti, Souad Rahmouni, Marta E. Alarcón-Riquelme, Eva C. Schulte, Andre Franke, Tom H. Karlsen, Luca Valenti, Hugo Zeberg, J. Brent Richards, Andrea Ganna
Emerging evidence has shown that open reading frames inside lncRNA could encode micropeptides. However, their roles in cellular energy metabolism and tumor progression remain largely unknown. Here, we identified a 94-amino acid-length micropeptide encoded by lncRNA LINC00467 in colorectal cancer. We also characterized its conservation across higher mammals, localization to mitochondria, and the concerted local functions. This peptide enhanced the ATP synthase construction by interacting with the subunit α and γ (ATP5A and ATP5C), increased ATP synthase activity and mitochondrial oxygen consumption rate, and thereby promoted colorectal cancer cell proliferation. Hence, this micropeptide was termed as “ATP synthase associated peptide” (ASAP). Furthermore, loss of ASAP suppressed patient-derived xenograft growth with attenuated ATP synthase activity and mitochondrial ATP production. Clinically, high expression of ASAP and LINC00467 predicted poor prognosis of colorectal cancer patients. Taken together, our findings revealed a colorectal cancer-associated micropeptide as a vital player in mitochondrial metabolism and provided a therapeutic target for colorectal cancer.
Qiwei Ge, Dingjiacheng Jia, Dong Cen, Yadong Qi, Chengyu Shi, Junhong Li, Lingjie Sang, Luo-jia Yang, Jiamin He, Aifu Lin, Shujie Chen, Liangjing Wang
Epoxyeicosatrienoic acids (EETs) have potent anti-inflammatory properties. Hydrolysis of EETs by soluble epoxide hydrolase (sEH/EPHX2) to less active diols attenuates their anti-inflammatory effects. Macrophage activation is critical to many inflammatory responses; however, the role of EETs and sEH in regulating macrophage function remains unknown. Lung bacterial clearance of S. pneumoniae was impaired in Ephx2-deficient (Ephx2-/-) mice and in mice treated with an sEH inhibitor. The EET receptor antagonist, EEZE, restored lung clearance of S. pneumoniae in Ephx2-/- mice. Ephx2-/- mice had normal lung Il-1β, Il-6 and Tnfα expression and macrophage recruitment to lungs during S. pneumoniae infection; however, Ephx2 disruption attenuated proinflammatory cytokine induction, Tlr2 and Pgylrp1 receptor upregulation and Rac1/2 and Cdc42 activation in PGN-stimulated macrophages. Consistent with these observations, Ephx2-/-macrophages displayed reduced phagocytosis of S. pneumoniae in vivo and in vitro. Heterologous overexpression of TLR2 and PGLYRP1 in Ephx2-/- macrophages restored macrophage activation and phagocytosis. Human macrophage function was similarly regulated by EETs. Together, these results demonstrate that EETs reduce macrophage activation and phagocytosis of S. pneumoniae through down-regulation of TLR2 and PGLYRP1 expression. Defining the role of EETs and sEH in macrophage function may lead to development of new therapeutic approaches for bacterial diseases.
Hong Li, J. Alyce Bradbury, Matthew L. Edin, Joan P. Graves, Artiom Gruzdev, Jennifer Cheng, Samantha L. Hoopes, Laura Miller-Degraff, Michael B. Fessler, Stavros Garantziotis, Shepherd H. Schurman, Darryl Craig Zeldin
Bladder cancer is a genetically heterogeneous disease and novel therapeutic strategies are needed to expand treatment options and improve clinical outcomes. Here we identified a unique subset of urothelial tumors with focal amplification of the RAF1 (CRAF) kinase gene. RAF1-amplified tumors had activation of the RAF/MEK/ERK signaling pathway and exhibited a luminal gene expression pattern. Genetic studies demonstrated that RAF1-amplified tumors were dependent upon RAF1 activity for survival, and RAF1-activated cell lines and patient-derived models were sensitive to available and emerging RAF inhibitors as well as combined RAF plus MEK inhibition. Furthermore, we found that bladder tumors with HRAS or NRAS activating mutations were dependent on RAF1-mediated signaling and were sensitive to RAF1-targeted therapy. Together, these data identified RAF1 activation as a novel dependency in a subset comprising nearly 20% of urothelial tumors and suggested that targeting RAF1-mediated signaling represents a rationale therapeutic strategy.
Raie T. Bekele, Amruta S. Samant, Amin H. Nassar, Jonathan So, Elizabeth P. Garcia, Catherine R. Curran, Justin H. Hwang, David L. Mayhew, Anwesha Nag, Aaron R. Thorner, Judit Börcsök, Zsofia Sztupinszki, Chong-Xian Pan, Joaquim Bellmunt, David J. Kwiatkowski, Guru P. Sonpavde, Eliezer M. Van Allen, Kent W. Mouw