To identify genetic dependencies and hence uncover treatment targets for diffuse intrinsic pontine glioma (DIPG), Duchatel et al. employed a multiomic analysis pipeline that uncovered PIK3CA as targetable molecular dependency across DIPG patient models, highlighting the therapeutic potential of the blood-brain barrier penetrant PI3K inhibitor paxalisib. The cover art presents a model whereby the connectivity of these cancers can be harnessed using integrated technologies to identify potential therapeutic strategies. Image credit: somersault18:24.
SARS-CoV-2 infection of the upper airway and the subsequent immune response are early, critical factors in COVID-19 pathogenesis. By studying infection of human biopsies in vitro and in a hamster model in vivo, we demonstrated a transition in nasal tropism from olfactory to respiratory epithelium as the virus evolved. Analyzing each variant revealed that SARS-CoV-2 WA1 or Delta infect a proportion of olfactory neurons in addition to the primary target sustentacular cells. The Delta variant possessed broader cellular invasion capacity into the submucosa, while Omicron displayed enhanced nasal respiratory infection and longer retention in the sinonasal epithelium. The olfactory neuronal infection by WA1 and the subsequent olfactory bulb transport via axon were more pronounced in younger hosts. In addition, the observed viral clearance delay and phagocytic dysfunction in aged olfactory mucosa were accompanied by a decline of phagocytosis related genes. Furthermore, robust basal stem cell activation contributed to neuroepithelial regeneration and restores ACE2 expression post-infection. Together, our study characterized the nasal tropism of SARS-CoV-2 strains, immune clearance, and regeneration post infection. The shifting characteristics of viral infection at the airway portal provides insight into the variability of COVID-19 clinical features, particularly long COVID, and may suggest differing strategies for early local intervention.
Mengfei Chen, Andrew Pekosz, Jason S. Villano, Wenjuan Shen, Ruifeng Zhou, Heather Kulaga, Zhexuan Li, Amy Smith, Asiana Gurung, Sarah E. Beck, Kenneth W. Witwer, Joseph L. Mankowski, Murugappan Ramanathan Jr., Nicholas R. Rowan, Andrew P. Lane
In lung, thromboxane A2 (TXA2) activates the TP receptor to induce pro-inflammatory and bronchoconstrictor effects. Thus, TP receptor antagonists and TXA2 synthase inhibitors have been tested as potential asthma therapeutics in humans. Th9 cells play key roles in asthma and regulate the lung immune response to allergens. Herein, we found that TXA2 reduces Th9 cell differentiation during allergic lung inflammation. Th9 cells were decreased ~2-fold and airway hyperresponsiveness was attenuated in lungs of allergic mice treated with TXA2. Naïve CD4+ T cell differentiation to Th9 cells and IL-9 production was inhibited dose-dependently by TXA2 in vitro. TP receptor deficient mice had a ~2-fold increase in numbers of Th9 cells in lungs in vivo after OVA exposure compared to wild type (WT) mice. Naïve CD4+ T cells from TP deficient mice exhibited increased Th9 cell differentiation and IL-9 production in vitro compared to CD4+ T cells from WT mice. TXA2 also suppressed Th2 and enhanced Treg differentiation both in vitro and in vivo. Thus, in contrast to its acute, pro-inflammatory effects, TXA2 also has longer-lasting immunosuppressive effects that attenuate the Th9 differentiation that drives asthma progression. These findings may explain the paradoxical failure of anti-thromboxane therapies in the treatment of asthma.
Hong Li, J. Alyce Bradbury, Matthew L. Edin, Artiom Gruzdev, Huiling Li, Joan P. Graves, Laura M. DeGraff, Fred B. Lih, Chiguang Feng, Erin R. Wolf, Carl D. Bortner, Stephanie J. London, Matthew A. Sparks, Thomas M. Coffman, Darryl C. Zeldin
Fotios Spyropoulos, Apabrita Ayan Das, Markus Waldeck-Weiermair, Shambhu Yadav, Arvind K. Pandey, Ruby Guo, Taylor A. Covington, Venkata Thulabandu, Kosmas Kosmas, Benjamin Steinhorn, Mark Perella, Xiaoli Liu, Helen Christou, Thomas Michel
Macrophage immune checkpoint inhibitors, such as anti-CD47 antibodies, show promise in clinical trials for solid and hematologic malignancies. However, the best strategies to use these therapies remain unknown, and ongoing studies suggest they may be most effective when used in combination with other anticancer agents. Here, we developed a novel screening platform to identify drugs that render lung cancer cells more vulnerable to macrophage attack, and we identified therapeutic synergy exists between genotype-directed therapies and anti-CD47 antibodies. In validation studies, we found the combination of genotype-directed therapies and CD47 blockade elicited robust phagocytosis and eliminated persister cells in vitro and maximized anti-tumor responses in vivo. Importantly, these findings broadly applied to lung cancers with various RTK/MAPK pathway alterations—including EGFR mutations, ALK fusions, or KRASG12C mutations. We observed downregulation of β2-microglobulin and CD73 as molecular mechanisms contributing to enhanced sensitivity to macrophage attack. Our findings demonstrate that dual inhibition of the RTK/MAPK pathway and the CD47/SIRPa axis is a promising immunotherapeutic strategy. Our study provides strong rationale for testing this therapeutic combination in patients with lung cancers bearing driver mutations.
Kyle Vaccaro, Juliet Allen, Troy W. Whitfield, Asaf Maoz, Sarah Reeves, José Velarde, Dian Yang, Anna Meglan, Juliano Ribeiro, Jasmine Blandin, Nicole Phan, George W. Bell, Aaron Hata, Kipp Weiskopf
BACKGROUND. Weakly virulent environmental mycobacteria (EM) can cause severe disease in HLA-DRB1*15:02 or 16:02 adult individuals harboring neutralizing anti-IFN-γ autoantibodies (nAIGAs). The overall prevalence of nAIGA in a general population are unknown as is the the penetrance of nAIGA in HLA-DRB1*15:02 or 16:02 individuals, and the proportion of patients with unexplained, adult-onset EM infections carrying nAIGAs. METHODS. This study analyzed the detection and neutralization of anti-IFN-γ autoantibodies (auto-Abs) from 8,430 healthy individuals of the general population, 257 HLA-DRB1*15:02 or 16:02 carriers, 1,063 patients with autoimmune disease, and 497 patients with unexplained severe disease due to EM. RESULTS. We find that anti-IFN-γ autoantibodies detected in 4,148 of 8,430 healthy individuals (49.2%) from the general population of an unknown HLA-DRB1 genotype are not neutralizing. Moreover, we do not find nAIGAs in 257 individuals carrying HLA-DRB1* 15:02 or 16:02, including 71 individuals with detectable anti-IFN-g autoantibodies (27.6%). Additionally, nAIGA are absent in 1,063 patients with an autoimmune disease. Furthermore, we find only a few other autoantibodies in seven patients with nAIGAs tested. Finally, seven of 497 patients (1.4%) with unexplained severe disease due to EM harbored nAIGA. Yet, nAIGA are absent in the remaining 41 patients who are HLA-DRB1*15:02 or 16:02, the 45 patients with IFN-g autoantibodies, and the five patients with HLA-DRB1*15:02 or 16:02 and IFN-g autoantibodies . CONCLUSION. These findings suggest that nAIGAs are isolated and that their penetrance in HLA-DRB1*15:02 or 16:02 individuals is low, implying that they may be triggered by rare germline or somatic variants. In contrast, the risk of mycobacterial disease in patients with nAIGAs is high, confirming that these nAIGAs are causal of EM disease. FUNDING. The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH) (R01AI095983), the National Center for Advancing Translational Sciences (NCATS), the NIH Clinical and Translational Science Award (CTSA) program (UL1 TR001866), and partly by French National Research Agency (ANR).
Jessica N. Peel, Rui Yang, Tom Le Voyer, Adrian Gervais, Jérémie Rosain, Paul Bastard, Anish Behere, Axel Cederholm, Aaron Bodansky, Yoann Seeleuthner, Clément Conil, Jing-Ya Ding, Wei-Te Lei, Lucy Bizien, Camille Soudee, Mélanie Migaud, Masato Ogishi, Ahmad Yatim, Danyel Lee, Jonathan Bohlen, Thomas Perpoint, Laura Perez, Fernando Messina, Roxana Genet, Ludovic Karkowski, Mathieu Blot, Emmanuel Lafont, Laurie Toullec, Claire Goulvestre, Souad Mehlal-Sedkaoui, Jérôme Sallette, Fernando Martin, Anne Puel, Emmanuelle Jouanguy, Mark S. Anderson, Nils Landegren, Pierre Tiberghien, Laurent Abel, Stéphanie Boisson-Dupuis, Jacinta Bustamante, Cheng-Lung Ku, Jean-Laurent Casanova
JCI celebrates a century of publishing scientific discoveries with a special collection highlighting major innovations in medicine and key contributing mechanistic studies.
The lungs are regularly exposed to airborne irritants, pathogens, and other sources of inflammation that cause injury to the lung epithelium and its underlying structure. Repair and regeneration are essential for healthy lung function throughout life, yet these processes can also influence development and progression of acute and chronic conditions. Series editor Suzanne Herold developed this review series on lung inflammatory injury and tissue repair to reveal the many cell populations involved in normal and aberrant reparative responses. Ranging from discussion of lung stroma and vasculature to adaptive and innate immune systems, the reviews in this series describe the many complex mechanisms that influence pathogen-, inflammation-, and aging-driven injury to the lung and can contribute to aberrant healing, resolution of inflammation, and fibrosis. Reviews also discuss a wide range of potential therapies targeting injury and repair processes that represent promising progress toward better clinical options for patients with acute and chronic lung conditions.
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