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M. Lennarz

Bio: M. Lennarz is an academic researcher from University of Bonn. The author has contributed to research in topics: COPD & Autophagy. The author has an hindex of 9, co-authored 15 publications receiving 458 citations.

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Journal ArticleDOI
TL;DR: In this paper, the authors show that SARS-CoV-2 infection modulates cellular metabolism and limits autophagy, and identify druggable host pathways for virus inhibition.
Abstract: Viruses manipulate cellular metabolism and macromolecule recycling processes like autophagy. Dysregulated metabolism might lead to excessive inflammatory and autoimmune responses as observed in severe and long COVID-19 patients. Here we show that SARS-CoV-2 modulates cellular metabolism and reduces autophagy. Accordingly, compound-driven induction of autophagy limits SARS-CoV-2 propagation. In detail, SARS-CoV-2-infected cells show accumulation of key metabolites, activation of autophagy inhibitors (AKT1, SKP2) and reduction of proteins responsible for autophagy initiation (AMPK, TSC2, ULK1), membrane nucleation, and phagophore formation (BECN1, VPS34, ATG14), as well as autophagosome-lysosome fusion (BECN1, ATG14 oligomers). Consequently, phagophore-incorporated autophagy markers LC3B-II and P62 accumulate, which we confirm in a hamster model and lung samples of COVID-19 patients. Single-nucleus and single-cell sequencing of patient-derived lung and mucosal samples show differential transcriptional regulation of autophagy and immune genes depending on cell type, disease duration, and SARS-CoV-2 replication levels. Targeting of autophagic pathways by exogenous administration of the polyamines spermidine and spermine, the selective AKT1 inhibitor MK-2206, and the BECN1-stabilizing anthelmintic drug niclosamide inhibit SARS-CoV-2 propagation in vitro with IC50 values of 136.7, 7.67, 0.11, and 0.13 μM, respectively. Autophagy-inducing compounds reduce SARS-CoV-2 propagation in primary human lung cells and intestinal organoids emphasizing their potential as treatment options against COVID-19. Viruses manipulate host cell pathways to support infection. Here the authors show that SARS-CoV-2 infection modulates cellular metabolism and limits autophagy, and identify druggable host pathways for virus inhibition.

140 citations

Posted ContentDOI
15 Apr 2020-bioRxiv
TL;DR: It is shown that SARS-CoV-2 infection limits autophagy by interfering with multiple metabolic pathways and that compound-driven interventions aimed at Autophagy induction reduce Sars-Cov-2 propagation in vitro.
Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses an acute threat to public health and the world economy, especially because no approved specific drugs or vaccines are available. Pharmacological modulation of metabolism-dependent cellular pathways such as autophagy reduced propagation of highly pathogenic Middle East respiratory syndrome (MERS)-CoV. Here we show that SARS-CoV-2 infection limits autophagy by interfering with multiple metabolic pathways and that compound-driven interventions aimed at autophagy induction reduce SARS-CoV-2 propagation in vitro. In-depth analyses of autophagy signaling and metabolomics indicate that SARS-CoV-2 reduces glycolysis and protein translation by limiting activation of AMP-protein activated kinase (AMPK) and mammalian target of rapamycin complex 1 (mTORC1). Infection also downregulates autophagy-inducing spermidine, and facilitates AKT1/SKP2-dependent degradation of autophagy-initiating Beclin-1 (BECN1). Targeting of these pathways by exogenous administration of spermidine, AKT inhibitor MK-2206, and the Beclin-1 stabilizing, antihelminthic drug niclosamide inhibited SARS-CoV-2 propagation by 85, 88, and >99%, respectively. In sum, SARS-CoV-2 infection causally diminishes autophagy. A clinically approved and well-tolerated autophagy-inducing compound shows potential for evaluation as a treatment against SARS-CoV-2.

109 citations

Journal ArticleDOI
TL;DR: There was a highly significant association between patients with a chronic course of sarcoidosis and TLR4 gene polymorphisms and restriction fragment length polymorphism (RFLP) analysis.
Abstract: Summary The aetiology of sarcoidosis, an inflammatory granulomatous multi-system disorder, is unclear. It is thought to be the product of an unknown exogenous antigenic stimulus and an endogenous genetic susceptibility. Toll-like recep- tors (TLR) are signal molecules essential for the cellular response to bacterial cell wall components. Lipopolysaccharide (LPS), for example, binds to TLR 4. Tw o different polymorphisms for the TLR4 gene (Asp299Gly and Thr399Ile) have been described recently. This leads to a change in the extracellular matrix function of TLR4 and to impaired LPS signal transduction. We genotyped a total of 141 Caucasian patients with sarcoidosis and 141 healthy unrelated controls for the Asp299Gly and Thr399Ile polymorphisms in the TLR4 gene. The mutations were identified with polymerase chain reaction followed by restriction fragment length polymorphism (RFLP) analysis. Among sarcoido- sis patients the prevalence for each Asp299Gly and Thr399Ile mutant allele was 15·6% (22/141). In the control group the prevalence was 5·67% (8/141) ( P = 0·07). In the subgroup of patients with acute sarcoidosis there was no dif- ference in the control group ( P = 0·93), but there was a highly significant asso- ciation between patients with a chronic course of sarcoidosis and TLR4 gene polymorphisms ( P = = = 0·01).

98 citations

Journal ArticleDOI
01 Jun 2017-Brain
TL;DR: It is demonstrated that substantial progress in revealing the causes of Mendelian diseases can be made by exploring the non-coding sequences of the human genome by identifying mutations located deep in introns of POLR3A to be a frequent cause of hereditary spastic paraplegia and cerebellar ataxia.
Abstract: Despite extensive efforts, half of patients with rare movement disorders such as hereditary spastic paraplegias and cerebellar ataxias remain genetically unexplained, implicating novel genes and unrecognized mutations in known genes. Non-coding DNA variants are suspected to account for a substantial part of undiscovered causes of rare diseases. Here we identified mutations located deep in introns of POLR3A to be a frequent cause of hereditary spastic paraplegia and cerebellar ataxia. First, whole-exome sequencing findings in a recessive spastic ataxia family turned our attention to intronic variants in POLR3A, a gene previously associated with hypomyelinating leukodystrophy type 7. Next, we screened a cohort of hereditary spastic paraplegia and cerebellar ataxia cases (n = 618) for mutations in POLR3A and identified compound heterozygous POLR3A mutations in ∼3.1% of index cases. Interestingly, >80% of POLR3A mutation carriers presented the same deep-intronic mutation (c.1909+22G>A), which activates a cryptic splice site in a tissue and stage of development-specific manner and leads to a novel distinct and uniform phenotype. The phenotype is characterized by adolescent-onset progressive spastic ataxia with frequent occurrence of tremor, involvement of the central sensory tracts and dental problems (hypodontia, early onset of severe and aggressive periodontal disease). Instead of the typical hypomyelination magnetic resonance imaging pattern associated with classical POLR3A mutations, cases carrying c.1909+22G>A demonstrated hyperintensities along the superior cerebellar peduncles. These hyperintensities may represent the structural correlate to the cerebellar symptoms observed in these patients. The associated c.1909+22G>A variant was significantly enriched in 1139 cases with spastic ataxia-related phenotypes as compared to unrelated neurological and non-neurological phenotypes and healthy controls (P = 1.3 × 10-4). In this study we demonstrate that (i) autosomal-recessive mutations in POLR3A are a frequent cause of hereditary spastic ataxias, accounting for about 3% of hitherto genetically unclassified autosomal recessive and sporadic cases; and (ii) hypomyelination is frequently absent in POLR3A-related syndromes, especially when intronic mutations are present, and thus can no longer be considered as the unifying feature of POLR3A disease. Furthermore, our results demonstrate that substantial progress in revealing the causes of Mendelian diseases can be made by exploring the non-coding sequences of the human genome.

75 citations

Journal ArticleDOI
01 Mar 2006-Thorax
TL;DR: Familial clustering of the disease and the increased risk of relatives to develop sarcoidosis suggest that there might be a genetic predisposition to develop the disease.
Abstract: Sarcoidosis is an inflammatory granulomatous disorder that primarily affects the lungs and lymph nodes. Other organs such as the brain, eyes, heart, and skin can also be affected. The disease is characterised by non-caseating granulomas and an exaggerated cellular immune response caused by increased inflammatory activity.1 The course of the disease is acute and mild in approximately 20% of all patients. In most patients a chronic stage develops which can lead to lung fibrosis. Although the exact pathogenesis of sarcoidosis remains unclear, familial clustering of the disease and the increased risk of relatives to develop sarcoidosis suggest that there might be a genetic predisposition to develop the disease.2 A significant association was recently reported in Germany between sarcoidosis and a frequent single nucleotide polymorphism (SNP) in the BTNL2 gene, …

74 citations


Cited by
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DOI
05 Nov 2009
TL;DR: 结节病易误诊,据王洪武等~([1])收集国内18篇关于此第一印象中拟诊 结核5例,为此应引起临床对本 病诊
Abstract: 结节病易误诊,据王洪武等~([1])收集国内18篇关于此病误诊的文献,误诊率高达63.2%,当然有误诊就会有误治,如孙永昌等~([2])报道26例结节病在影像学检查诊断的第一印象中拟诊结核5例,其中就有2例完成规范的抗结核治疗,为此应引起临床对本病诊治的重视。

1,821 citations

Journal ArticleDOI
TL;DR: The identification and characterization of ADAM33, a putative asthma susceptibility gene identified by positional cloning in an outbred population, should provide insights into the pathogenesis and natural history of this common disease.
Abstract: Van Eerdewegh P, Little RD, Dupuis J, et al Nature 2002;418:426–430 To identify novel genetic polymorphisms associated with bronchial hyperresponsiveness (BHR) in asthma Four hundred sixty white affected sib-pair families from the United States and the United Kingdom with current asthma A genetic linkage analysis was performed for current asthma and BHR Case-control, transmission disequilibrium, and haplotype analyses were conducted to identify the gene(s) most commonly associated with asthma Novel genes of interest were …

1,002 citations

19 Apr 2011
TL;DR: Administration of spermidine markedly extended the lifespan of yeast, flies and worms, and human immune cells and inhibited oxidative stress in ageing mice, and found that enhanced autophagy is crucial for polyamine-induced suppression of necrosis and enhanced longevity.
Abstract: Ageing results from complex genetically and epigenetically programmed processes that are elicited in part by noxious or stressful events that cause programmed cell death Here, we report that administration of spermidine, a natural polyamine whose intracellular concentration declines during human ageing, markedly extended the lifespan of yeast, flies and worms, and human immune cells In addition, spermidine administration potently inhibited oxidative stress in ageing mice In ageing yeast, spermidine treatment triggered epigenetic deacetylation of histone H3 through inhibition of histone acetyltransferases (HAT), suppressing oxidative stress and necrosis Conversely, depletion of endogenous polyamines led to hyperacetylation, generation of reactive oxygen species, early necrotic death and decreased lifespan The altered acetylation status of the chromatin led to significant upregulation of various autophagy-related transcripts, triggering autophagy in yeast, flies, worms and human cells Finally, we found that enhanced autophagy is crucial for polyamine-induced suppression of necrosis and enhanced longevity

974 citations

Journal ArticleDOI
TL;DR: A pathway from the natively unfolded microtubule-associated protein Tau to a highly structured amyloid fibril underlies human Tauopathies and accounts for the greater seeding potency of brain aggregates.
Abstract: A pathway from the natively unfolded microtubule-associated protein Tau to a highly structured amyloid fibril underlies human Tauopathies. This ordered assembly causes disease and represents the gain of toxic function. In recent years, evidence has accumulated to suggest that Tau inclusions form first in a small number of brain cells, from where they propagate to other regions, resulting in neurodegeneration and disease. Propagation of pathology is often called prion-like, which refers to the capacity of an assembled protein to induce the same abnormal conformation in a protein of the same kind, initiating a self-amplifying cascade. In addition, prion-like encompasses the release of protein aggregates from brain cells and their uptake by neighboring cells. In mice, the intracerebral injection of Tau inclusions induces the ordered assembly of monomeric Tau, followed by its spreading to distant brain regions. Conformational differences between Tau aggregates from transgenic mouse brain and in vitro assembled recombinant protein account for the greater seeding potency of brain aggregates. Short fibrils constitute the major species of seed-competent Tau in the brains of transgenic mice. The existence of multiple human Tauopathies with distinct fibril morphologies has led to the suggestion that different molecular conformers (or strains) of aggregated Tau exist.

400 citations

Journal ArticleDOI
TL;DR: Findings suggest that in the absence of functional Trem2, early amyloidogenesis is accelerated due to reduced phagocytic clearance of amyloids seeds despite reduced plaque-associated ApoE.
Abstract: Coding variants in the triggering receptor expressed on myeloid cells 2 (TREM2) are associated with late-onset Alzheimer's disease (AD). We demonstrate that amyloid plaque seeding is increased in the absence of functional Trem2. Increased seeding is accompanied by decreased microglial clustering around newly seeded plaques and reduced plaque-associated apolipoprotein E (ApoE). Reduced ApoE deposition in plaques is also observed in brains of AD patients carrying TREM2 coding variants. Proteomic analyses and microglia depletion experiments revealed microglia as one origin of plaque-associated ApoE. Longitudinal amyloid small animal positron emission tomography demonstrates accelerated amyloidogenesis in Trem2 loss-of-function mutants at early stages, which progressed at a lower rate with aging. These findings suggest that in the absence of functional Trem2, early amyloidogenesis is accelerated due to reduced phagocytic clearance of amyloid seeds despite reduced plaque-associated ApoE.

303 citations