Amantadine disrupts lysosomal gene expression: A hypothesis for COVID19 treatment

AbstractLysosomes adopt dynamic, tubular states that regulate antigen presentation, phagosome resolution and autophagy. To date, tubular lysosomes have been studied either by inducing autophagy or by activating immune cells, both of which lead to cell states where lysosomal gene expression differs from the resting state. Therefore, it has been challenging to pinpoint the specific biochemical properties lysosomes acquire upon tubulation that could drive their functionality. We describe a DNA-based assembly that tubulates lysosomes in macrophages without activating them. Lumenal proteolytic activity maps at single lysosome resolution revealed that tubular lysosomes were less degradative. Further, they showed striking proximal to distal lumenal pH and Ca2+ gradients. Such gradients had been predicted, but never previously observed. We now identify a role for tubular lysosomes whereby they poise resting macrophages for phagocytosis. The ability to tubulate lysosomes without having to starve or activate immune cells may help reveal new roles for tubular lysosomes.

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“Amantadine disrupts lysosomal gene expression; potential therapy for COVID19”

10.1101/2020.04.05.026187 ◽

2020 ◽

Cited By ~ 3

Author(s):

Sandra P. Smieszek ◽

Bart P Przychodzen ◽

Mihael H Polymeropoulos

Keyword(s):

Gene Expression ◽

Gene Expression Analysis ◽

Cathepsin L ◽

Drug Screen ◽

Direct Inhibition ◽

The Us ◽

Lysosomotropic Agent ◽

A Cell ◽

Expression Potential ◽

Lysosomal Gene

AbstractSARS-coronavirus 2 is the causal agent of the COVID-19 outbreak. SARS-Cov-2 entry into a cell is dependent upon binding of the viral spike (S) protein to cellular receptor and on cleavage of the spike protein by the host cell proteases such as Cathepsin L and Cathepsin B. CTSL/B are crucial elements of lysosomal pathway and both enzymes are almost exclusively located in the lysosomes.CTSL disruption offers potential for CoVID-19 therapies. The mechanisms of disruption include: decreasing expression of CTSL, direct inhibition of CTSL activity and affecting the conditions of CTSL environment (increase pH in lysosomes).We have conducted a high throughput drug screen gene expression analysis to identify compounds that would downregulate the expression of CTSL/CTSB. One of the top significant results shown to downregulate the expression of the CTSL gene is Amantadine. Amantadine was approved by the US Food and Drug Administration in 1968 as a prophylactic agent for influenza and later for Parkinson’s disease. It is available as a generic drug..Amantadine in addition to downregulating CTSL appears to further disrupt lysosomal pathway, hence interfering with the capacity of the virus to replicate. It acts as a lysosomotropic agent altering the CTSL functional environment. We hypothesize that Amantadine could decrease the viral load in SARS-CoV-2 positive patients and as such it may serve as a potent therapeutic decreasing the replication and infectivity of the virus likely leading to better clinical outcomes. Clinical studies will be needed to examine the therapeutic utility of amantadine in COVID-19 infection.

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Tubular lysosomes harbor active ion gradients and poise macrophages for phagocytosis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2113174118 ◽

2021 ◽

Vol 118 (41) ◽

pp. e2113174118

Author(s):

Bhavyashree Suresh ◽

Anand Saminathan ◽

Kasturi Chakraborty ◽

Matthew Zajac ◽

Chang Cui ◽

...

Keyword(s):

Gene Expression ◽

Antigen Presentation ◽

Proteolytic Activity ◽

Immune Cells ◽

Resting State ◽

Biochemical Properties ◽

Ion Gradients ◽

Luminal Ph ◽

Lysosomal Gene

Lysosomes adopt dynamic, tubular states that regulate antigen presentation, phagosome resolution, and autophagy. Tubular lysosomes are studied either by inducing autophagy or by activating immune cells, both of which lead to cell states where lysosomal gene expression differs from the resting state. Therefore, it has been challenging to pinpoint the biochemical properties lysosomes acquire upon tubulation that could drive their functionality. Here we describe a DNA-based assembly that tubulates lysosomes in macrophages without activating them. Proteolytic activity maps at single-lysosome resolution revealed that tubular lysosomes were less degradative and showed proximal to distal luminal pH and Ca2+ gradients. Such gradients had been predicted but never previously observed. We identify a role for tubular lysosomes in promoting phagocytosis and activating MMP9. The ability to tubulate lysosomes without starving or activating immune cells may help reveal new roles for tubular lysosomes.

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Reprogramming of lysosomal gene expression by interleukin-4 and Stat6

BMC Genomics ◽

10.1186/1471-2164-14-853 ◽

2013 ◽

Vol 14 (1) ◽

pp. 853 ◽

Cited By ~ 13

Author(s):

Louise M Brignull ◽

Zsolt Czimmerer ◽

Hafida Saidi ◽

Bence Daniel ◽

Izabel Villela ◽

...

Keyword(s):

Gene Expression ◽

Interleukin 4 ◽

Lysosomal Gene

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Genome-wide analyses in neuronal cells reveal that upstream transcription factors regulate lysosomal gene expression

FEBS Journal ◽

10.1111/febs.13650 ◽

2016 ◽

Vol 283 (6) ◽

pp. 1077-1087 ◽

Cited By ~ 3

Author(s):

Tomoyuki Yamanaka ◽

Asako Tosaki ◽

Masaru Kurosawa ◽

Tomomi Shimogori ◽

Nobutaka Hattori ◽

...

Keyword(s):

Gene Expression ◽

Transcription Factors ◽

Neuronal Cells ◽

Genome Wide ◽

Lysosomal Gene

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Decision letter for "Retinal Defocus and Form‐Deprivation Induced Regional Differential Gene Expression of BMPs in Chick RPE"

10.1002/cne.24957/v1/decision1 ◽

2020 ◽

Keyword(s):

Gene Expression ◽

Differential Gene Expression ◽

Differential Gene

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Decision letter for "Early postnatal gene expression in the developing neocortex of prairie voles ( Microtus ochrogaster ) is related to parental rearing style"

10.1002/cne.24856/v2/decision1 ◽

2020 ◽

Keyword(s):

Gene Expression ◽

Microtus Ochrogaster ◽

Prairie Voles ◽

Developing Neocortex ◽

Parental Rearing

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Molecular and Microscopic Analysis of Altered Gene Expression in Transgenic and Gene Targeted Mice

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100162521 ◽

1996 ◽

Vol 54 ◽

pp. 12-13

Author(s):

W. K. Jones ◽

J. Robbins

Keyword(s):

Gene Expression ◽

Pulmonary Veins ◽

Microscopic Analysis ◽

Mouse Tissue ◽

Adult Heart ◽

Heavy Chains ◽

Altered Gene Expression ◽

Altered Gene ◽

Pulmonary Myocardium

Two myosin heavy chains (MyHC) are expressed in the mammalian heart and are differentially regulated during development. In the mouse, the α-MyHC is expressed constitutively in the atrium. At birth, the β-MyHC is downregulated and replaced by the α-MyHC, which is the sole cardiac MyHC isoform in the adult heart. We have employed transgenic and gene-targeting methodologies to study the regulation of cardiac MyHC gene expression and the functional and developmental consequences of altered α-MyHC expression in the mouse.We previously characterized an α-MyHC promoter capable of driving tissue-specific and developmentally correct expression of a CAT (chloramphenicol acetyltransferase) marker in the mouse. Tissue surveys detected a small amount of CAT activity in the lung (Fig. 1a). The results of in situ hybridization analyses indicated that the pattern of CAT transcript in the adult heart (Fig. 1b, top panel) is the same as that of α-MyHC (Fig. 1b, lower panel). The α-MyHC gene is expressed in a layer of cardiac muscle (pulmonary myocardium) associated with the pulmonary veins (Fig. 1c). These studies extend our understanding of α-MyHC expression and delimit a third cardiac compartment.

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