TY  - JOUR
AB  - Hospital-acquired pneumonia caused by Staphylococcus aureus is associated with patient morbidity and mortality, despite adequate antibiotic therapy. This illustrates the need for treatments beyond antibiotics. The pore-forming heptameric toxin α-hemolysin (Hla) is a major pathogenicity factor of S. aureus and a clinically validated target. We identify quinoxalinediones (QDS) as highly potent Hla inhibitors, conferring protection against the hallmarks of Hla-induced pathogenicity such as Ca2+ influx, cytotoxicity, hemolysis, and monolayer destruction. The effects were exerted across major Hla subtypes in all relevant cell types. QDS prevented the formation of functional pores by interacting with Hla near the phospholipid-binding site. The QDS analog, H052, was active in mouse models of S. aureus lung infections, when administered prophylactically or therapeutically, either as monotherapy or when given in combination with the antibiotic linezolid. The study provides evidence that complex bacterial toxins can be targeted in vivo by drug-like small molecules.
AU  - Shekhar, A.*
AU  - Di Lucrezia, R.*
AU  - Jerye, K.*
AU  - Korotkov, V.S.*
AU  - Harmrolfs, K.*
AU  - Rox, K.*
AU  - Weich, H.A.*
AU  - Ghai, I.*
AU  - Delhommel, F.
AU  - Becher, I.*
AU  - Degenhart, C.*
AU  - Fansa, E.*
AU  - Unger, A.*
AU  - Habenberger, P.*
AU  - Klebl, B.*
AU  - Lukat, P.*
AU  - Schmelz, S.*
AU  - Henke, S.*
AU  - Borgert, S.*
AU  - Lang, J.C.*
AU  - Sasse, F.*
AU  - Diestel, R.*
AU  - Richter, C.*
AU  - Schneider-Daum, N.*
AU  - Hinkelmann, B.*
AU  - Niemz, J.*
AU  - Lehr, C.M.*
AU  - Jänsch, L.*
AU  - Huehn, J.*
AU  - Alm, R.*
AU  - Savitski, M.M.*
AU  - Welte, T.*
AU  - Hesterkamp, T.*
AU  - Sattler, M.
AU  - Winterhalter, M.*
AU  - Blankenfeldt, W.*
AU  - Medina, E.*
AU  - Bilitewski, U.*
AU  - Dinkel, K.*
AU  - Brönstrup, M.*
C1  - 73973
C2  - 57254
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
SP  - 560-572.e21
TI  - Highly potent quinoxalinediones inhibit α-hemolysin and ameliorate Staphylococcus aureus lung infections.
JO  - Cell Host Microbe
VL  - 33
IS  - 4
PB  - Cell Press
PY  - 2025
SN  - 1931-3128
ER  - 

TY  - JOUR
AB  - SARS-CoV-2 infection is associated with long-lasting neurological symptoms, although the underlying mechanisms remain unclear. Using optical clearing and imaging, we observed the accumulation of SARS-CoV-2 spike protein in the skull-meninges-brain axis of human COVID-19 patients, persisting long after viral clearance. Further, biomarkers of neurodegeneration were elevated in the cerebrospinal fluid from long COVID patients, and proteomic analysis of human skull, meninges, and brain samples revealed dysregulated inflammatory pathways and neurodegeneration-associated changes. Similar distribution patterns of the spike protein were observed in SARS-CoV-2-infected mice. Injection of spike protein alone was sufficient to induce neuroinflammation, proteome changes in the skull-meninges-brain axis, anxiety-like behavior, and exacerbated outcomes in mouse models of stroke and traumatic brain injury. Vaccination reduced but did not eliminate spike protein accumulation after infection in mice. Our findings suggest persistent spike protein at the brain borders may contribute to lasting neurological sequelae of COVID-19.
AU  - Rong, Z.
AU  - Mai, H.
AU  - Ebert, G.
AU  - Kapoor, S.
AU  - Puelles, V.G.*
AU  - Czogalla, J.*
AU  - Hu, S.*
AU  - Su, J.
AU  - Prtvar, D.*
AU  - Singh, I.
AU  - Schädler, J.*
AU  - Delbridge, C.*
AU  - Steinke, H.*
AU  - Frenzel, H.*
AU  - Schmidt, K.*
AU  - Braun, C.*
AU  - Bruch, G.*
AU  - Ruf, V.*
AU  - Ali, M.
AU  - Sühs, K.W.*
AU  - Nemati, M.*
AU  - Hopfner, F.*
AU  - Ulukaya, S.
AU  - Jeridi, D.
AU  - Mistretta, D.
AU  - Caliskan, Ö.S.
AU  - Wettengel, J.M.
AU  - Cherif, F.*
AU  - Kolabas, Z.I.
AU  - Molbay, M.
AU  - Horvath, I.
AU  - Zhao, S.
AU  - Krahmer, N.
AU  - Yildirim, A.Ö.
AU  - Ussar, S.
AU  - Herms, J.*
AU  - Huber, T.B.*
AU  - Tahirovic, S.*
AU  - Schwarzmaier, S.M.*
AU  - Plesnila, N.*
AU  - Höglinger, G.*
AU  - Ondruschka, B.*
AU  - Bechmann, I.*
AU  - Protzer, U.
AU  - Elsner, M.
AU  - Bhatia, H.S.
AU  - Hellal, F.
AU  - Ertürk, A.
C1  - 72590
C2  - 56659
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
SP  - 2112-2130.e10
TI  - Persistence of spike protein at the skull-meninges-brain axis may contribute to the neurological sequelae of COVID-19.
JO  - Cell Host Microbe
VL  - 32
IS  - 12
PB  - Cell Press
PY  - 2024
SN  - 1931-3128
ER  - 

TY  - JOUR
AB  - Stunting, a severe and multigenerational growth impairment, globally affects 22% of children under the age of 5 years. Stunted children have altered gut bacterial communities with higher proportions of Proteobacteria, a phylum with several known human pathogens. Despite the links between an altered gut microbiota and stunting, the role of bacteriophages, highly abundant bacterial viruses, is unknown. Here, we describe the gut bacterial and bacteriophage communities of Bangladeshi stunted children younger than 38 months. We show that these children harbor distinct gut bacteriophages relative to their non-stunted counterparts. In vitro, these gut bacteriophages are infectious and can regulate bacterial abundance and composition in an age-specific manner, highlighting their possible role in the pathophysiology of child stunting. Specifically, Proteobacteria from non-stunted children increased in the presence of phages from younger stunted children, suggesting that phages could contribute to the bacterial community changes observed in child stunting.
AU  - Mirzaei, M.K.*
AU  - Khan, M.A.A.*
AU  - Ghosh, P.*
AU  - Taranu, Z.E.*
AU  - Taguer, M.*
AU  - Ru, J.
AU  - Chowdhury, R.*
AU  - Kabir, M.M.*
AU  - Deng, L.
AU  - Mondal, D.*
AU  - Maurice, C.F.*
C1  - 58875
C2  - 48395
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
SP  - 199-212
TI  - Bacteriophages isolated from stunted children can regulate gut bacterial communities in an age-specific manner.
JO  - Cell Host Microbe
VL  - 27
IS  - 2
PB  - Cell Press
PY  - 2020
SN  - 1931-3128
ER  - 

TY  - JOUR
AB  - Lifestyle, obesity, and the gut microbiome are important risk factors for metabolic disorders. We demonstrate in 1,976 subjects of a German population cohort (KORA) that specific microbiota members show 24-h oscillations in their relative abundance and identified 13 taxa with disrupted rhythmicity in type 2 diabetes (T2D). Cross-validated prediction models based on this signature similarly classified T2D. In an independent cohort (FoCus), disruption of microbial oscillation and the model for T2D classification was confirmed in 1,363 subjects. This arrhythmic risk signature was able to predict T2D in 699 KORA subjects 5 years after initial sampling, being most effective in combination with BMI, Shotgun metagenomic analysis functionally linked 26 metabolic pathways to the diurnal oscillation of gut bacteria. Thus, a cohort-specific risk pattern of arrhythmic taxa enables classification and prediction of T2D, suggesting a functional link between circadian rhythms and the microbiome in metabolic diseases.
AU  - Reitmeier, S.*
AU  - Kiessling, S.*
AU  - Clavel, T.*
AU  - List, M.*
AU  - Almeida, E.L.*
AU  - Ghosh, T.S.*
AU  - Neuhaus, K.*
AU  - Grallert, H.
AU  - Linseisen, J.
AU  - Skurk, T.*
AU  - Brandl, B.*
AU  - Breuninger, T.
AU  - Troll, M.
AU  - Rathmann, W.*
AU  - Linkohr, B.
AU  - Hauner, H.*
AU  - Laudes, M.*
AU  - Franke, A.*
AU  - Le Roy, C.I.*
AU  - Bell, J.T.*
AU  - Spector, T.*
AU  - Baumbach, J.*
AU  - O'Toole, P.W.*
AU  - Peters, A.
AU  - Haller, D.*
C1  - 59714
C2  - 48958
CY  - 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
SP  - 258-272.e6
TI  - Arrhythmic gut microbiome signatures predict risk of type 2 diabetes.
JO  - Cell Host Microbe
VL  - 28
IS  - 2
PB  - Cell Press
PY  - 2020
SN  - 1931-3128
ER  - 

TY  - JOUR
AB  - The early life formation of the immunological and microbial environment of the human lower airways remains unknown. In this issue of Cell Host & Microbe, Pattaroni et al. (2018) shed light on this critical period, which is important for maturation or dysregulation of the microbiome and immune responses and disease development.
AU  - von Mutius, E.
C1  - 54964
C2  - 46014
SP  - 758-759
TI  - Intimate crosstalk in lower airways at the beginning of life.
JO  - Cell Host Microbe
VL  - 24
IS  - 6
PY  - 2018
SN  - 1931-3128
ER  - 

TY  - JOUR
AB  - Efficient clearance of bacteremia prevents life-threatening disease. Platelet binding to intravascular bacteria, a process involving platelet glycoprotein GPIb and bacterial opsonization with activated complement C3, influences blood clearance and anti-infective immunity. Using intravital microscopy of the bloodstream of mice infected with Listeria monocytogenes, we show that bacterial clearance is not a uniform process but a "dual-track" mechanism consisting of parallel "fast" and "slow" pathways. "Slow clearance" is regulated by time-dependent bacterial opsonization, stochastic platelet binding, and capture of bacteria-platelet-complexes via the complement receptor of the immunoglobulin superfamily, CRIg. The mechanism spares some bacteria from "fast clearance" and rapid destruction in the liver via Kupffer cell scavenger receptors, keeping them available for adaptive immunity induction by splenic CD8α(+) dendritic cells. We consistently find "fast" and "slow" clearance patterns for a broad panel of other Gram+ and Gram- bacteria. Thus, dual-track clearance balances rapid restoration of blood sterility with induction of specific antibacterial immunity.
AU  - Broadley, S.P.*
AU  - Plaumann, A.*
AU  - Coletti, R.*
AU  - Lehmann, C.*
AU  - Wanisch, A.*
AU  - Seidlmeier, A.*
AU  - Esser, K.
AU  - Luo, S.
AU  - Rämer, P.C.*
AU  - Massberg, S.*
AU  - Busch, D.H.*
AU  - van Lookeren Campagne, M.*
AU  - Verschoor, A.*
C1  - 48904
C2  - 41473
CY  - Cambridge
SP  - 36-48
TI  - Dual-track clearance of circulating bacteria balances rapid restoration of blood sterility with induction of adaptive immunity.
JO  - Cell Host Microbe
VL  - 20
IS  - 1
PB  - Cell Press
PY  - 2016
SN  - 1931-3128
ER  - 

TY  - JOUR
AB  - During cell entry, non-enveloped viruses undergo partial uncoating to expose membrane lytic proteins for gaining access to the cytoplasm. We report that adenovirus uses membrane piercing to induce and hijack cellular wound removal processes that facilitate further membrane disruption and infection. Incoming adenovirus stimulates calcium influx and lysosomal exocytosis, a membrane repair mechanism resulting in release of acid sphingomyelinase (ASMase) and degradation of sphingomyelin to ceramide lipids in the plasma membrane. Lysosomal exocytosis is triggered by small plasma membrane lesions induced by the viral membrane lytic protein-VI, which is exposed upon mechanical cues from virus receptors, followed by virus endocytosis into leaky endosomes. Chemical inhibition or RNA interference of ASMase slows virus endocytosis, inhibits virus escape to the cytosol, and reduces infection. Ceramide enhances binding of protein-VI to lipid membranes and protein-VI-induced membrane rupture. Thus, adenovirus uses a positive feedback loop between virus uncoating and lipid signaling for efficient membrane penetration.
AU  - Luisoni, S.*
AU  - Suomalainen, M.*
AU  - Boucke, K.*
AU  - Tanner, L.B.*
AU  - Wenk, M.R.*
AU  - Guan, X.L.*
AU  - Grzybek, M.
AU  - Coskun, Ü.
AU  - Greber, U.F.*
C1  - 46303
C2  - 37489
CY  - Cambridge
SP  - 75-85
TI  - Co-option of membrane wounding enables virus penetration into cells.
JO  - Cell Host Microbe
VL  - 18
IS  - 1
PB  - Cell Press
PY  - 2015
SN  - 1931-3128
ER  - 

TY  - JOUR
AB  - Critical cell surface immunoreceptors downregulated during HIV infection have previously been identified using non-systematic, candidate approaches. To gain a comprehensive, unbiased overview of how HIV infection remodels the T cell surface, we took a distinct, systems-level, quantitative proteomic approach. >100 plasma membrane proteins, many without characterized immune functions, were downregulated during HIV infection. Host factors targeted by the viral accessory proteins Vpu or Nef included the amino acid transporter SNAT1 and the serine carriers SERINC3/5. We focused on SNAT1, a β-TrCP-dependent Vpu substrate. SNAT1 antagonism was acquired by Vpu variants from the lineage of SIVcpz/HIV-1 viruses responsible for pandemic AIDS. We found marked SNAT1 induction in activated primary human CD4+ T cells, and used Consumption and Release (CoRe) metabolomics to identify alanine as an endogenous SNAT1 substrate required for T cell mitogenesis. Downregulation of SNAT1 therefore defines a unique paradigm of HIV interference with immunometabolism.
AU  - Matheson, N.J.*
AU  - Sumner, J.*
AU  - Wals, K.*
AU  - Rapiteanu, R.*
AU  - Weekes, M.P.*
AU  - Vigan, R.*
AU  - Weinelt, J.*
AU  - Schindler, M.
AU  - Antrobus, R.*
AU  - Costa, A.S.H.*
AU  - Frezza, C.*
AU  - Clish, C.B.*
AU  - Neil, S.J.D.*
AU  - Lehner, P.J.*
C1  - 47123
C2  - 39206
SP  - 409-423
TI  - Cell surface proteomic map of HIV infection reveals antagonism of amino acid metabolism by Vpu and Nef.
JO  - Cell Host Microbe
VL  - 18
IS  - 4
PY  - 2015
SN  - 1931-3128
ER  - 

TY  - JOUR
AB  - Hepatitis B virus (HBV) integration in hepatocellular carcinoma (HCC) is a poorly understood event. In a recent Cancer Cell paper, Lau et al. (2014) describe a HBV-human fusion transcript (HBx-LINE1) that functions as a lncRNA, influences the epithelial-mesenchymal transition, and correlates with reduced patient survival and tumor formation in mice.
AU  - Heikenwälder, M.
AU  - Protzer, U.
C1  - 30870
C2  - 33986
CY  - Cambridge
SP  - 249-250
TI  - LINE(1)s of evidence in HBV-driven liver cancer.
JO  - Cell Host Microbe
VL  - 15
IS  - 3
PB  - Cell Press
PY  - 2014
SN  - 1931-3128
ER  - 

TY  - JOUR
AB  - While conceptual principles governing plant immunity are becoming clear, its systems-level organization and the evolutionary dynamic of the host-pathogen interface are still obscure. We generated a systematic protein-protein interaction network of virulence effectors from the ascomycete pathogen Golovinomyces orontii and Arabidopsis thaliana host proteins. We combined this data set with corresponding data for the eubacterial pathogen Pseudomonas syringae and the oomycete pathogen Hyaloperonospora arabidopsidis. The resulting network identifies host proteins onto which intraspecies and interspecies pathogen effectors converge. Phenotyping of 124 Arabidopsis effector-interactor mutants revealed a correlation between intraspecies and interspecies convergence and several altered immune response phenotypes. Several effectors and the most heavily targeted host protein colocalized in subnuclear foci. Products of adaptively selected Arabidopsis genes are enriched for interactions with effector targets. Our data suggest the existence of a molecular host-pathogen interface that is conserved across Arabidopsis accessions, while evolutionary adaptation occurs in the immediate network neighborhood of effector targets.
AU  - Weßling, R.*
AU  - Epple, P.*
AU  - Altmann, S.*
AU  - He, Y.*
AU  - Yang, L.*
AU  - Henz, S.R.*
AU  - McDonald, N.*
AU  - Wiley, K.*
AU  - Bader, K.C.
AU  - Gläßer, C.
AU  - Mukhtar, M.S.*
AU  - Haigis, S.*
AU  - Ghamsari, L.*
AU  - Stephens, A.E.*
AU  - Ecker, J.R.*
AU  - Vidal, M.*
AU  - Jones, J.D.*
AU  - Mayer, K.F.X.
AU  - ver Loren van Themaat, E.*
AU  - Weigel, D.*
AU  - Schulze-Lefert, P.*
AU  - Dangl, J.L.*
AU  - Panstruga, R.*
AU  - Braun, P.*
C1  - 32169
C2  - 34976
CY  - Cambridge
SP  - 364-375
TI  - Convergent targeting of a common host protein-network by pathogen effectors from three kingdoms of life.
JO  - Cell Host Microbe
VL  - 16
IS  - 3
PB  - Cell Press
PY  - 2014
SN  - 1931-3128
ER  - 

TY  - JOUR
AB  - Chromoblastomycosis is a chronic skin infection caused by the fungus Fonsecaea pedrosoi. Exploring the reasons underlying the chronic nature of F. pedrosoi infection in a murine model of chromoblastomycosis, we find that chronicity develops due to a lack of pattern recognition receptor (PRR) costimulation. F. pedrosoi was recognized primarily by C-type lectin receptors (CLRs), but not by Toll-like receptors (TLRs), which resulted in the defective induction of proinflammatory cytokines. Inflammatory responses to F. pedrosoi could be reinstated by TLR costimulation, but also required the CLR Mincle and signaling via the Syk/CARD9 pathway. Importantly, exogenously administering TLR ligands helped clear F. pedrosoi infection in vivo. These results demonstrate how a failure in innate recognition can result in chronic infection, highlight the importance of coordinated PRR signaling, and provide proof of the principle that exogenously applied PRR agonists can be used therapeutically.
AU  - Sousa, M.*
AU  - Reid, D.M.*
AU  - Schweighoffer, E.*
AU  - Tybulewicz, V.*
AU  - Ruland, J.
AU  - Langhorne, J.*
AU  - Yamasaki, S.*
AU  - Taylor, P.R.*
AU  - Almeida, S.R.*
AU  - Brown, G.D.
C1  - 5273
C2  - 28645
SP  - 436-443
TI  - Restoration of pattern recognition receptor costimulation to treat chromoblastomycosis, a chronic fungal infection of the skin.
JO  - Cell Host Microbe
VL  - 9
IS  - 5
PB  - Elsevier
PY  - 2011
SN  - 1931-3128
ER  - 

TY  - JOUR
AB  - The mRNA targets of microRNAs (miRNAs) can be identified by immunoprecipitation of Argonaute (Ago) protein-containing RNA-induced silencing complexes (RISCs) followed by microarray analysis (RIP-Chip). Here we used Ago2-based RIP-Chip to identify transcripts targeted by Kaposi's sarcoma-associated herpesvirus (KSHV) miRNAs (n = 114), Epstein-Barr virus (EBV) miRNAs (n = 44), and cellular miRNAs (n = 2337) in six latently infected or stably transduced human B cell lines. Of the six KSHV miRNA targets chosen for validation, four showed regulation via their 3'UTR, while two showed regulation via binding sites within coding sequences. Two genes governing cellular transport processes (TOMM22 and IPO7) were confirmed to be targeted by EBV miRNAs. A significant number of viral miRNA targets were upregulated in infected cells, suggesting that viral miRNAs preferentially target cellular genes induced upon infection. Transcript half-life both of cellular and viral miRNA targets negatively correlated with recruitment to RISC complexes, indicating that RIP-Chip offers a quantitative estimate of miRNA function.
AU  - Dölken, L.*
AU  - Malterer, G.*
AU  - Erhard, F.*
AU  - Kothe, S.*
AU  - Friedel, C.C.*
AU  - Suffert, G.*
AU  - Marcinowski, L.*
AU  - Motsch, N.*
AU  - Barth, S.*
AU  - Beitzinger, M.*
AU  - Lieber, D.*
AU  - Bailer, S.M.*
AU  - Hoffmann, R.*
AU  - Ruzsics, Z.*
AU  - Kremmer, E.
AU  - Pfeffer, S.*
AU  - Zimmer, R.*
AU  - Koszinowski, U.H.*
AU  - Grässer, F.*
AU  - Meister, G.*
AU  - Haas, J.*
C1  - 4844
C2  - 28045
SP  - 324-334
TI  - Systematic analysis of viral and cellular microRNA targets in cells latently infected with human γ-herpesviruses by RISC immunoprecipitation assay.
JO  - Cell Host Microbe
VL  - 7
IS  - 4
PB  - Cell Press
PY  - 2010
SN  - 1931-3128
ER  -