SARS-CoV-2 has resulted in over 450 million confirmed cases since 2019. Although several vaccines have been certified by World Health Organization and are being vaccinated on a global scale, it has been reported that multiple SARS-CoV-2 variants can escape neutralisation by antibodies, resulting in vaccine breakthrough infections. Bacillus Calmette-Guérin (BCG) is known to induce heterologous protection based on trained immune responses. Here, we investigated whether BCG-induced trained immunity protected against SARS-CoV-2 challenge in the K18-hACE2 mouse model. Our data demonstrates that intravenous BCG vaccination induces robust trained innate immune responses and provides protection against wild-type SARS-CoV-2 as well as the B.1.617.1 and B.1.617.2 variants. Further studies suggest that myeloid cell differentiation and activation of the glycolysis pathway are associated with BCG-induced training immunity in the K18-hACE2 mice. Overall, our study provides the experimental evidence that establishes a causal relationship between intravenous BCG vaccination and protection against SARS-CoV-2 challenge.
Bao-Zhong Zhang, Huiping Shuai, Hua-rui Gong, Jing-Chu Hu, Bingpeng Yan, Terrence Tsz-Tai Yuen, Ye-Fan Hu, Chaemin Yoon, Xiao-Lei Wang, Yuxin Hou, Xuansheng Lin, Xiner Huang, Renhao Li, Yee Man Au-Yeung, Wenjun Li, Bingjie Hu, Yue Chai, Ming Yue, Jian-Piao Cai, Guang Sheng Ling, Ivan Fan-Ngai Hung, Kwok-Yung Yuen, Jasper Fuk-Woo Chan, Jian-Dong Huang, Hin Chu
Bacteria have evolved to cope with the detrimental effects of reactive oxygen species (ROS) using their essential molecular components. Catalase, a heme-containing tetramer protein expressed universally in most of the aerobic bacteria, plays an indispensable role in scavenging excess hydrogen peroxide (H2O2). Here, through utilization of wild-type and catalase-deficient mutants, we identified catalase as an endogenous therapeutic target of 400-420 nm blue light. Catalase residing inside bacteria could be effectively inactivated by blue light, subsequently rendering the pathogens extremely vulnerable to H2O2 and H2O2-producing agents. As a result, photoinactivation of catalase and H2O2 synergistically eliminate a wide range of catalase-positive planktonic bacteria and P. aeruginosa inside biofilms. In addition, photoinactivation of catalase is shown to facilitate macrophages to defend against intracellular pathogens. The antimicrobial efficacy of catalase photoinactivation is further validated using a Pseudomonas aeruginosa-induced mice abrasion model. Taken together, our findings offer a catalase-targeting phototherapy approach against multidrug-resistant bacterial infections.
Pu-Ting Dong, Sebastian Jusuf, Jie Hui, Yuewei Zhan, Yifan Zhu, George Y. Liu, Ji-Xin Cheng
Greater than 25% of all men develop an inguinal hernia in their lifetime, and more than 20 million inguinal hernia repair surgeries are performed worldwide each year. The mechanisms causing abdominal muscle weakness, the formation of inguinal hernias, or their recurrence are largely unknown. We previously reported that excessively produced estrogen in the lower abdominal muscles (LAM) triggers extensive LAM fibrosis, leading to hernia formation in a transgenic male mouse model expressing the human aromatase gene (Aromhum). To understand the cellular basis of estrogen-driven muscle fibrosis, we performed single-cell RNA-sequencing on LAM tissue from Aromhum and wild-type littermates. We found a fibroblast-like cell group comprised of six clusters, two of which were validated for their enrichment in Aromhum LAM tissue. One of the novel hernia-associated fibroblast clusters in Aromhum was enriched for the estrogen receptor-α gene (Esr1Hi). Esr1Hi fibroblasts maximally expressed estrogen target genes and seemed to serve as the progenitors of another cluster expressing ECM-altering enzymes (Mmp3Hi) and upregulate expression of pro-inflammatory, pro-fibrotic genes. The discovery of these two novel and unique hernia-associated fibroblasts may lead to the development of novel treatments that can non-surgically prevent or reverse inguinal hernias.
Tanvi Potluri, Matthew J. Taylor, Jonah J. Stulberg, Richard L. Lieber, Hong Zhao, Serdar E. Bulun
BACKGROUND. Measuring the immune response to SARS-CoV-2 enables assessment of past infection and protective immunity. SARS-CoV-2 infection induces humoral and T-cell responses, but these responses vary with disease severity and individual characteristics. METHODS. A T-cell receptor (TCR) immunosequencing assay was conducted using small-volume blood samples from 302 individuals recovered from COVID-19. Correlations between the magnitude of the T-cell response and neutralizing antibody (nAb) titers or indicators of disease severity were evaluated. Sensitivity of T-cell testing was assessed and compared to serologic testing. RESULTS. SARS-CoV-2–specific T-cell responses were significantly correlated with nAb titers and clinical indicators of disease severity, including hospitalization, fever, and difficulty breathing. Despite modest declines in depth and breadth of T-cell responses during convalescence, high sensitivity was observed until at least 6 months after infection, with overall sensitivity ~5% greater than serology tests for identifying prior SARS-CoV-2 infection. Improved performance of T-cell testing was most apparent in recovered, non-hospitalized individuals sampled >150 days after initial illness, suggesting greater sensitivity than serology at later timepoints and in individuals with less severe disease. T-cell testing identified SARS-CoV-2 infection in 68% (55/81) of samples with undetectable nAb titers (<1:40) and in 37% (13/35) of samples negative by 3 antibody assays. CONCLUSION. These results support TCR-based testing as a scalable, reliable measure of past SARS-CoV-2 infection with clinical value beyond serology. FUNDING. Adaptive Biotechnologies, Frederick National Laboratory for Cancer Research, National Institutes of Allergy and Infectious Diseases, Fred Hutchinson Joel Meyers Endowment; Fast Grants, American Society for Transplantation and Cell Therapy.
Rebecca Elyanow, Thomas M. Snyder, Sudeb C. Dalai, Rachel M. Gittelman, Jim Boonyaratanakornkit, Anna Wald, Stacy Selke, Mark H. Wener, Chihiro Morishima, Alexander L. Greninger, Michael Gale Jr., Tien-Ying Hsiang, Lichen Jing, Michael R. Holbrook, Ian M. Kaplan, H. Jabran Zahid, Damon H. May, Jonathan M. Carlson, Lance Baldo, Thomas Manley, Harlan S. Robins, David M. Koelle
Molecular signaling in the tumor microenvironment (TME) is complex, and crosstalks among various cell compartments in supporting metastasis remain poorly understood. In particular, the role of vascular pericytes, a critical cellular component in the TME, in cancer invasion and metastasis warrants further investigation. Here we report an elevation of FGF-2 signaling in both nasopharyngeal carcinoma (NPC) patient samples and xenograft mouse models promotes NPC metastasis. Mechanistically, tumor cell-derived FGF-2 strongly promoted pericyte proliferation and pericyte-specific expression of an orphan chemokine (C-X-C motif) ligand 14 (CXCL14) via FGFR1- AHR signaling. Gain and loss-of-function experiments validated that pericyte-derived CXCL14 promoted macrophage recruitment and polarization towards an M2-like phenotype. Genetic knockdown of FGF2 or genetic depletion of tumoral pericytes blocked CXCL14 expression and tumor-associated macrophage (TAM) infiltration. Pharmacological inhibition of TAMs by clodronate liposomes treatment resulted in a reduction of FGF-2-induced pulmonary metastasis. Together, these findings shed light on the inflammatory role of tumoral pericytes in promoting TAM-mediated metastasis. We provide mechanistic insight into an FGF-2-FGFR1-pericyte-CXCL14-TAM stromal communication axis in NPC and propose an effective anti-metastasis therapy concept by targeting a pericyte-derived inflammation for NPC or FGF-2-high tumors.
Yujie Wang, Qi Sun, Ying Ye, Xiaoting Sun, Sisi Xie, Yuhang Zhan, Jian Song, Xiaoqin Fan, Bin Zhang, Ming Yang, Lei Lv, Kayoko Hosaka, Yunlong Yang, Guohui Nie
T cells play a prominent role in orchestrating the adaptive immune response to viral diseases and are a key component in understanding variability in SARS-CoV-2 infection severity and immunity. How the T cell response to SARS-CoV-2 infection and vaccination relates to clinical presentation, other components of the immune response, and subsequent immunity remains poorly understood. A population-based swab survey of the municipality of Vo’, Italy, conducted after the initial SARS-CoV-2 outbreak, uncovered a high frequency of asymptomatic infected individuals and their role in transmission. We sampled the T-cell receptor repertoire structure of the entire Vo’ population 2 months after the initial survey and followed up positive cases at 9 and 15 months post infection. We found that 97.0% (98/101) of cases had elevated levels of T-cell receptors associated with SARS-CoV-2 antigens at 2 months. T-cell frequency (depth) was increased in individuals with more severe disease. Both depth and diversity (breadth) of the T-cell receptor repertoire were also positively associated with neutralizing antibody titers, driven mostly by helper CD4+ T cells directed towards antigens from spike protein. At the later time points, detection of SARS-CoV-2 associated T cells remained high, with 90.7% (78/96) and 86.2% (25/29) of individuals having detectable signal at 9 and 15 months, respectively. Notably, at 9 months, T-cell signal was detectable in 84.6% (22/26) of cases who were initially asymptomatic. Forty-three individuals had been vaccinated by month fifteen, all presenting with a positive T-cell signal and showing a significant increase in T cells, specifically directed against spike protein. Taken together, these results demonstrate the central role of the T-cell response in mounting a comprehensive immune defense against SARS-CoV-2 that persists out to 15 months.
Rachel M. Gittelman, Enrico Lavezzo, Thomas M. Snyder, H. Jabran Zahid, Cara L. Carty, Rebecca Elyanow, Sudeb C. Dalai, Ilan Kirsch, Lance Baldo, Laura Manuto, Elisa Franchin, Claudia Del Vecchio, Monia Pacenti, Caterina Boldrin, Margherita Cattai, Francesca Saluzzo, Andrea Padoan, Mario Plebani, Fabio Simeoni, Jessica Bordini, Nicola I. Lorè, Dejan Lazarević, Daniela Maria Cirillo, Paolo Ghia, Stefano Toppo, Jonathan M. Carlson, Harlan S. Robins, Andrea Crisanti, Giovanni Tonon
Systemic therapies for pancreatic ductal adenocarcinoma (PDAC) remain unsatisfactory. Clinical prognosis is particularly poor for tumor subtypes with activating aberrations in the MYC pathway creating an urgent need for novel therapeutic targets. To unbiasedly find novel MYC-associated epigenetic dependencies, we conducted a drug screen in pancreatic cancer cell lines. Here, we found protein arginine N-methyltransferase 5 (PRMT5) inhibitors to trigger a MYC-associated dependency. In human and murine PDACs, a robust connection of MYC and PRMT5 was detected. By the use of gain- and loss-of-function models, we confirm the increased efficacy of PRMT5 inhibitors in MYC deregulated PDACs. Although inhibition of PRMT5 is inducing DNA-damage and arresting PDAC cells in the G2/M-phase of the cell cycle, apoptotic cell death was executed predominantly in cells with high MYC expression. Experiments in primary patient-derived PDAC models demonstrated the existence of a highly PRMT5 inhibitor sensitive subtype. Our work suggests developing PRMT5 inhibitor-based therapies for PDAC.
Felix Orben, Katharina Lankes, Christian Schneeweis, Zonera Hassan, Hannah Jakubowsky, Lukas Krauß, Fabio Boniolo, Carolin Schneider, Arlett P.G. Schäfer, Janine Murr, Christoph Schlag, Bo Kong, Rupert Öllinger, Chengdong Wang, Georg Beyer, Ujjwal Mukund Mahajan, Yonggan Xue, Julia Mayerle, Roland M. Schmid, Bernhard Kuster, Roland Rad, Christian J. Braun, Matthias Wirth, Maximilian Reichert, Dieter Saur, Günter Schneider
Idiopathic pulmonary fibrosis (IPF) is a fatal disease with limited treatment options. The role of the developmental transcription factor Sine Oculis homeobox homolog 1 (SIX1) in the pathophysiology of lung fibrosis is not known. IPF lung tissue samples and IPF-derived alveolar type II cells (AT2) showed a significant increase in SIX1 mRNA and protein levels, and the SIX1 transcriptional co-activators EYA1 and EYA2 were elevated. Six1 was also upregulated in bleomycin (BLM)-treated mice and in a model of spontaneous lung fibrosis driven by deletion of Telomeric Repeat Binding Factor 1 (Trf1) in AT2 cells. Conditional deletion of Six1 in AT2 cells prevented or halted BLM-induced lung fibrosis as measured by a significant reduction in histological burden of fibrosis, reduced fibrotic mediator expression and improved lung function. These effects were associated with increased macrophage migration inhibitory factor (MIF) in lung epithelial cells in vivo following SIX1 overexpression in BLM-induced fibrosis. A MIF promoter-driven luciferase assay demonstrated direct binding of Six1 to the 5’-TCAGG-3’ consensus sequence of the MIF promoter, identifying a likely mechanism of SIX1-driven MIF expression in the pathogenesis of lung fibrosis, and providing a novel pathway for targeting in IPF therapy.
Cory Wilson, Tinne C.J. Mertens, Pooja Shivshankar, Weizen Bi, Scott D. Collum, Nancy Wareing, Junsuk Ko, Tingting Weng, Ram P. Naikawadi, Paul J. Wolters, Pascal Maire, Soma S.K. Jyothula, Rajarajan A. Thandavarayan, Dewei Ren, Nathan D. Elrod, Eric J. Wagner, Howard J. Huang, Burton F. Dickey, Heide L. Ford, Harry Karmouty-Quintana
Pain emanating from the female reproductive tract is notoriously difficult to be treated and the prevalence of transient pelvic pain has been placed as high as 70-80% in women surveyed. Although sex hormones, especially estrogen, are thought to underlie enhanced pain perception in females, the underlying molecular and cellular mechanisms are not completely understood. Here we show that the pain-initiating TRPA1 channel is required for pain-related behaviors in a mouse model of estrogen-induced uterine pain in ovariectomized female mice. Surprisingly, 2- and 4-hydroxylated estrogen metabolites (HEMs) in the estrogen hydroxylation pathway, but not estrone, estradiol and 16-HEMs, directly increase nociceptor hyperactivity through TRPA1 and TRPV1 channels, and picomolar concentrations of 2- and 4-hydroxylation estrone (OHE1) can sensitize TRPA1 channel function. Moreover, both TRPA1 and TRPV1 are expressed in uterine-innervating primary nociceptors and their expressions are increased in the estrogen-induced uterine pain model. Importantly, pretreatment of 2- or 4-OHE1 recapitulates estrogen-induced uterine pain-like behaviors and intraplantar injections of 2- and 4-OHE1 directly produce a TRPA1-dependent mechanical hypersensitivity. Our findings demonstrate that TRPA1 is critically involved in estrogen-induced uterine pain-like behaviors, which may provide a potential drug target for treating female reproductive tract pain.
Zili Xie, Jing Feng, Tao Cai, Ronald McCarthy, Mark D. Eschbach II, Yuhui Wang, Yonghui Zhao, Zhihua Yi, Kaikai Zang, Yi Yuan, Xueming Hu, Fengxian Li, Qin Liu, Aditi Das, Sarah K. England, Hongzhen Hu
Sex/gender disparity in asthma is recognized, and suggests a modulatory role for sex-steroids, particularly estrogen. However, studies including our own show a dichotomous role for estrogen in airway remodeling, making it unclear whether sex hormones are protective or detrimental in asthma, and suggesting a need to explore mechanisms upstream or independent of estrogen. We hypothesize that Kisspeptin (Kp)/KISS1R signaling serves this role. Airway smooth muscle (ASM) is a key structural cell type that contributes to remodeling in asthma. We explored the role of Kp/KISS1R in regulating ASM proliferation. We report novel data that Kp and KISS1R are expressed in human airways, especially ASM, with lower expression in ASM from females compared to males, and asthmatics showing lowest expression compared to non-asthmatics. Proliferation studies showed that cleaved forms of Kp, particularly Kp-10 mitigates PDGF-induced ASM proliferation. Pharmacological inhibition and shRNA knockdown of KISS1R increased basal ASM proliferation, further amplified by PDGF. The anti-proliferative effect of Kp-10 in ASM was found to be mediated by inhibition of MAPK-ERK-Akt pathways, with altered expression of PCNA, C/EBP-alpha, Ki-67, Cyclin-D1, and Cyclin-E leading to cell-cycle arrest at G0/G1 phase. Overall, we demonstrate the importance of Kp/KISS1R signaling in regulating ASM proliferation and a potentially novel therapeutic avenue to blunt remodeling in asthma.
Niyati A. Borkar, Nilesh Sudhakar Ambhore, Rama Satyanarayana Raju Kalidhindi, Christina M. Pabelick, Y.S. Prakash, Venkatachalem Sathish
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