[Research Articles] Pan-caspase inhibition as a potential host-directed immunotherapy against MRSA and other bacterial skin infections
Staphylococcus aureus causes most skin infections in humans, and the emergence of methicillin-resistant S. aureus (MRSA) strains is a serious public health threat. There is an urgent clinical need for nonantibiotic immunotherapies to treat MRSA infections and prevent the spread of antibiotic resistance. Here, we investigated the pan-caspase inhibitor quinoline–valine–aspartic acid–difluorophenoxymethyl ketone (Q-VD-OPH) for efficacy against MRSA skin infection in mice. A single systemic dose of Q-VD-OPH decreased skin lesion sizes and reduced bacterial burden compared with vehicle-treated or untreated mic...
Source: Science Translational Medicine - July 7, 2021 Category: Biomedical Science Authors: Alphonse, M. P., Rubens, J. H., Ortines, R. V., Orlando, N. A., Patel, A. M., Dikeman, D., Wang, Y., Vuong, I., Joyce, D. P., Zhang, J., Mumtaz, M., Liu, H., Liu, Q., Youn, C., Patrick, G. J., Ravipati, A., Miller, R. J., Archer, N. K., Miller, L. S. Tags: Research Articles Source Type: research
[Research Articles] A recombinant commensal bacteria elicits heterologous antigen-specific immune responses during pharyngeal carriage
The human nasopharynx contains a stable microbial ecosystem of commensal and potentially pathogenic bacteria, which can elicit protective primary and secondary immune responses. Experimental intranasal infection of human adults with the commensal Neisseria lactamica produced safe, sustained pharyngeal colonization. This has potential utility as a vehicle for sustained release of antigen to the human mucosa, but commensals in general are thought to be immunologically tolerated. Here, we show that engineered N. lactamica, chromosomally transformed to express a heterologous vaccine antigen, safely induces systemic, antigen-sp...
Source: Science Translational Medicine - July 7, 2021 Category: Biomedical Science Authors: Laver, J. R., Gbesemete, D., Dale, A. P., Pounce, Z. C., Webb, C. N., Roche, E. F., Guy, J. M., Berreen, G., Belogiannis, K., Hill, A. R., Ibrahim, M. M., Ahmed, M., Cleary, D. W., Pandey, A. K., Humphries, H. E., Allen, L., de Graaf, H., Maiden, M. C., F Tags: Research Articles Source Type: research
[Editorial] Increasing threats from SARS-CoV-2 variants: Time to establish global surveillance
(Source: Science Translational Medicine)
Source: Science Translational Medicine - July 7, 2021 Category: Biomedical Science Authors: Layne, S. P., Taubenberger, J. K. Tags: Editorial Source Type: research
[Research Articles] Genome-encoded cytoplasmic double-stranded RNAs, found in C9ORF72 ALS-FTD brain, propagate neuronal loss
We report the presence of cytoplasmic double-stranded RNA (cdsRNA), an established trigger of innate immunity, in ALS-FTD brains carrying C9ORF72 intronic hexanucleotide expansions that included genomically encoded expansions of the G4C2 repeat sequences. The presence of cdsRNA in human brains was coincident with cytoplasmic TAR DNA binding protein 43 (TDP-43) inclusions, a pathologic hallmark of ALS/FTD. Introducing cdsRNA into cultured human neural cells induced type I interferon (IFN-I) signaling and death that was rescued by FDA-approved JAK inhibitors. In mice, genomically encoded dsRNAs expressed exclusively in a neu...
Source: Science Translational Medicine - July 7, 2021 Category: Biomedical Science Authors: Rodriguez, S., Sahin, A., Schrank, B. R., Al-Lawati, H., Costantino, I., Benz, E., Fard, D., Albers, A. D., Cao, L., Gomez, A. C., Evans, K., Ratti, E., Cudkowicz, M., Frosch, M. P., Talkowski, M., Sorger, P. K., Hyman, B. T., Albers, M. W. Tags: Research Articles Source Type: research
[Research Articles] Down-regulation of A20 promotes immune escape of lung adenocarcinomas
Inflammation is a well-known driver of lung tumorigenesis. One strategy by which tumor cells escape tight homeostatic control is by decreasing the expression of the potent anti-inflammatory protein tumor necrosis factor alpha–induced protein 3 (TNFAIP3), also known as A20. We observed that tumor cell intrinsic loss of A20 markedly enhanced lung tumorigenesis and was associated with reduced CD8+ T cell–mediated immune surveillance in patients with lung cancer and in mouse models. In mice, we observed that this effect was completely dependent on increased cellular sensitivity to interferon- (IFN-) signaling by ab...
Source: Science Translational Medicine - July 7, 2021 Category: Biomedical Science Authors: Breitenecker, K., Homolya, M., Luca, A. C., Lang, V., Trenk, C., Petroczi, G., Mohrherr, J., Horvath, J., Moritsch, S., Haas, L., Kurnaeva, M., Eferl, R., Stoiber, D., Moriggl, R., Bilban, M., Obenauf, A. C., Ferran, C., Dome, B., Laszlo, V., Gyorffy, B., Tags: Research Articles Source Type: research
[Reports] Undiagnosed SARS-CoV-2 seropositivity during the first 6 months of the COVID-19 pandemic in the United States
Asymptomatic SARS-CoV-2 infection and delayed implementation of diagnostics have led to poorly defined viral prevalence rates in the United States and elsewhere. To address this, we analyzed seropositivity in 9089 adults in the United States who had not been diagnosed previously with COVID-19. Individuals with characteristics that reflected the U.S. population (n = 27,716) were selected by quota sampling from 462,949 volunteers. Enrolled participants (n = 11,382) provided medical, geographic, demographic, and socioeconomic information and dried blood samples. Survey questions coincident with the Behavioral Risk Factor Surv...
Source: Science Translational Medicine - July 7, 2021 Category: Biomedical Science Authors: Kalish, H., Klumpp-Thomas, C., Hunsberger, S., Baus, H. A., Fay, M. P., Siripong, N., Wang, J., Hicks, J., Mehalko, J., Travers, J., Drew, M., Pauly, K., Spathies, J., Ngo, T., Adusei, K. M., Karkanitsa, M., Croker, J. A., Li, Y., Graubard, B. I., Czajkow Tags: Reports Source Type: research
[Research Articles] Bacterial cytoplasmic membranes synergistically enhance the antitumor activity of autologous cancer vaccines
Cancer vaccines based on resected tumors from patients have gained great interest as an individualized cancer treatment strategy. However, eliciting a robust therapeutic effect with personalized vaccines remains a challenge because of the weak immunogenicity of autologous tumor antigens. Utilizing exogenous prokaryotic constituents that act as adjuvants to enhance immunogenicity is a promising strategy to overcome this limitation. However, nonspecific stimulation of the immune system may elicit an undesirable immunopathological state. To specifically trigger sufficient antitumor reactivity without notable adverse effects, ...
Source: Science Translational Medicine - July 7, 2021 Category: Biomedical Science Authors: Chen, L., Qin, H., Zhao, R., Zhao, X., Lin, L., Chen, Y., Lin, Y., Li, Y., Qin, Y., Li, Y., Liu, S., Cheng, K., Chen, H., Shi, J., Anderson, G. J., Wu, Y., Zhao, Y., Nie, G. Tags: Research Articles Source Type: research
[Research Articles] Multicellular modeling of ciliopathy by combining iPS cells and microfluidic airway-on-a-chip technology
Mucociliary clearance is an essential lung function that facilitates the removal of inhaled pathogens and foreign matter unidirectionally from the airway tract and is innately achieved by coordinated ciliary beating of multiciliated cells. Should ciliary function become disturbed, mucus can accumulate in the airway causing subsequent obstruction and potentially recurrent pneumonia. However, it has been difficult to recapitulate unidirectional mucociliary flow using human-derived induced pluripotent stem cells (iPSCs) in vitro and the mechanism governing the flow has not yet been elucidated, hampering the proper humanized a...
Source: Science Translational Medicine - July 7, 2021 Category: Biomedical Science Authors: Sone, N., Konishi, S., Igura, K., Tamai, K., Ikeo, S., Korogi, Y., Kanagaki, S., Namba, T., Yamamoto, Y., Xu, Y., Takeuchi, K., Adachi, Y., Chen-Yoshikawa, T. F., Date, H., Hagiwara, M., Tsukita, S., Hirai, T., Torisawa, Y.-s., Gotoh, S. Tags: Research Articles Source Type: research
[Research Articles] Antibodies elicited by mRNA-1273 vaccination bind more broadly to the receptor binding domain than do those from SARS-CoV-2 infection
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with mutations in key antibody epitopes has raised concerns that antigenic evolution could erode adaptive immunity elicited by prior infection or vaccination. The susceptibility of immunity to viral evolution is shaped in part by the breadth of epitopes targeted by antibodies elicited by vaccination or natural infection. To investigate how human antibody responses to vaccines are influenced by viral mutations, we used deep mutational scanning to compare the specificity of polyclonal antibodies elicited by either two doses of the mRNA-127...
Source: Science Translational Medicine - June 30, 2021 Category: Biomedical Science Authors: Greaney, A. J., Loes, A. N., Gentles, L. E., Crawford, K. H. D., Starr, T. N., Malone, K. D., Chu, H. Y., Bloom, J. D. Tags: Research Articles Source Type: research
[Research Articles] Inhibiting DNA-PK induces glioma stem cell differentiation and sensitizes glioblastoma to radiation in mice
Glioblastoma (GBM), a lethal primary brain tumor, contains glioma stem cells (GSCs) that promote malignant progression and therapeutic resistance. SOX2 is a core transcription factor that maintains the properties of stem cells, including GSCs, but mechanisms associated with posttranslational SOX2 regulation in GSCs remain elusive. Here, we report that DNA-dependent protein kinase (DNA-PK) governs SOX2 stability through phosphorylation, resulting in GSC maintenance. Mass spectrometric analyses of SOX2-binding proteins showed that DNA-PK interacted with SOX2 in GSCs. The DNA-PK catalytic subunit (DNA-PKcs) was preferentially...
Source: Science Translational Medicine - June 30, 2021 Category: Biomedical Science Authors: Fang, X., Huang, Z., Zhai, K., Huang, Q., Tao, W., Kim, L., Wu, Q., Almasan, A., Yu, J. S., Li, X., Stark, G. R., Rich, J. N., Bao, S. Tags: Research Articles Source Type: research
[Research Articles] Gene therapy knockdown of Hippo signaling induces cardiomyocyte renewal in pigs after myocardial infarction
Human heart failure, a leading cause of death worldwide, is a prominent example of a chronic disease that may result from poor cell renewal. The Hippo signaling pathway is an inhibitory kinase cascade that represses adult heart muscle cell (cardiomyocyte) proliferation and renewal after myocardial infarction in genetically modified mice. Here, we investigated an adeno-associated virus 9 (AAV9)–based gene therapy to locally knock down the Hippo pathway gene Salvador (Sav) in border zone cardiomyocytes in a pig model of ischemia/reperfusion-induced myocardial infarction. Two weeks after myocardial infarction, when pigs...
Source: Science Translational Medicine - June 30, 2021 Category: Biomedical Science Authors: Liu, S., Li, K., Wagner Florencio, L., Tang, L., Heallen, T. R., Leach, J. P., Wang, Y., Grisanti, F., Willerson, J. T., Perin, E. C., Zhang, S., Martin, J. F. Tags: Research Articles Source Type: research
[Research Articles] Selectins impair regulatory T cell function and contribute to systemic lupus erythematosus pathogenesis
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by a loss of tolerance toward self-nucleic acids, autoantibody production, interferon expression and signaling, and a defect in the regulatory T (Treg) cell compartment. In this work, we identified that platelets from patients with active SLE preferentially interacted with Treg cells via the P-selectin/P-selectin glycoprotein ligand-1 (PSGL-1) axis. Selectin interaction with PSGL-1 blocked the regulatory and suppressive properties of Treg cells and particularly follicular Treg cells by triggering Syk phosphorylation and an increase in intracy...
Source: Science Translational Medicine - June 30, 2021 Category: Biomedical Science Authors: Scherlinger, M., Guillotin, V., Douchet, I., Vacher, P., Boizard-Moracchini, A., Guegan, J.-P., Garreau, A., Merillon, N., Vermorel, A., Ribeiro, E., Machelart, I., Lazaro, E., Couzi, L., Duffau, P., Barnetche, T., Pellegrin, J.-L., Viallard, J.-F., Saleh Tags: Research Articles Source Type: research
[Research Articles] Circulating proteins protect against renal decline and progression to end-stage renal disease in patients with diabetes
Diabetic kidney disease (DKD) and its major clinical manifestation, progressive renal decline that leads to end-stage renal disease (ESRD), are a major health burden for individuals with diabetes. The disease process that underlies progressive renal decline comprises factors that increase risk as well as factors that protect against this outcome. Using untargeted proteomic profiling of circulating proteins from individuals in two independent cohorts with type 1 and type 2 diabetes and varying stages of DKD followed for 7 to 15 years, we identified three elevated plasma proteins—fibroblast growth factor 20 (OR, 0.69; ...
Source: Science Translational Medicine - June 30, 2021 Category: Biomedical Science Authors: Md Dom, Z. I., Satake, E., Skupien, J., Krolewski, B., ONeil, K., Willency, J. A., Dillon, S. T., Wilson, J. M., Kobayashi, H., Ihara, K., Libermann, T. A., Pragnell, M., Duffin, K. L., Krolewski, A. S. Tags: Research Articles Source Type: research
[Research Articles] Neutrophils initiate and exacerbate Stevens-Johnson syndrome and toxic epidermal necrolysis
We describe a mechanism by which neutrophils triggered inflammation during early phases of SJS/TEN. Skin-infiltrating CD8+ T cells produced lipocalin-2 in a drug-specific manner, which triggered the formation of neutrophil extracellular traps (NETs) in early lesional skin. Neutrophils undergoing NETosis released LL-37, an antimicrobial peptide, which induced formyl peptide receptor 1 (FPR1) expression by keratinocytes. FPR1 expression caused keratinocytes to be vulnerable to necroptosis that caused further release of LL-37 by necroptotic keratinocytes and induced FPR1 expression on surrounding keratinocytes, which likely a...
Source: Science Translational Medicine - June 30, 2021 Category: Biomedical Science Authors: Kinoshita, M., Ogawa, Y., Hama, N., Ujiie, I., Hasegawa, A., Nakajima, S., Nomura, T., Adachi, J., Sato, T., Koizumi, S., Shimada, S., Fujita, Y., Takahashi, H., Mizukawa, Y., Tomonaga, T., Nagao, K., Abe, R., Kawamura, T. Tags: Research Articles Source Type: research
[Research Articles] Paired box 6 programs essential exocytotic genes in the regulation of glucose-stimulated insulin secretion and glucose homeostasis
The paired box 6 (PAX6) transcription factor is crucial for normal pancreatic islet development and function. Heterozygous mutations of PAX6 are associated with impaired insulin secretion and early-onset diabetes mellitus in humans. However, the molecular mechanism of PAX6 in controlling insulin secretion in human beta cells and its pathophysiological role in type 2 diabetes (T2D) remain ambiguous. We investigated the molecular pathway of PAX6 in the regulation of insulin secretion and the potential therapeutic value of PAX6 in T2D by using human pancreatic beta cell line EndoC-βH1, the db/db mouse model, and primary ...
Source: Science Translational Medicine - June 30, 2021 Category: Biomedical Science Authors: So, W. Y., Liu, W. N., Teo, A. K. K., Rutter, G. A., Han, W. Tags: Research Articles Source Type: research
