phage-therapy-application-to-counteract-pseudomonas-aeruginosa

Phage Therapy Application to Counteract <em>Pseudomonas aeruginosa</em> Infection in Cystic Fibrosis Zebrafish Embryos

Antimicrobial resistance, a major consequence of diagnostic uncertainty and antimicrobial overprescription, is an increasingly recognized cause of severe ...

Università degli Studi di Milano, LITA

Prox1, the vertebrate homolog of prospero in Drosophila melanogaster, is a divergent homeogene that regulates cell proliferation, fate determination and differentiation during vertebrate embryonic development.

Crucial role of zebrafish prox1 in hypothalamic catecholaminergic neurons development.

El sistema de l&iacute;nea lateral en el pez cebra se compone de una serie de &oacute;rganos llamados neuromasts, que se distribuyen sobre la superficie del cuerpo. Neuromasts contienen racimos de c&eacute;lulas ciliadas, rodeados por c&eacute;lulas accesorias.

El pez cebra prospero hom&oacute;logo prox1 es necesaria para la diferenciaci&oacute;n de la c&eacute;lula de pelo de mechanosensory y funcionalidad en la l&iacute;nea lateral.

&#x6591;&#x9A6C;&#x9C7C;&#x7684;&#x4FA7;&#x7EBF;&#x7CFB;&#x7EDF;&#x7531;&#x4E00;&#x7CFB;&#x5217;&#x5668;&#x5B98;&#x53EB;&#x505A; neuromasts&#xFF0C;&#x8FD9;&#x5206;&#x5E03;&#x5728;&#x4F53;&#x8868;&#x7684;&#x7EC4;&#x6210;&#x3002;Neuromasts &#x5305;&#x542B;&#x7FA4;&#x96C6;&#x7684;&#x6BDB;&#x7EC6;&#x80DE;&#xFF0C;&#x8F85;&#x52A9;&#x7EC6;&#x80DE;&#x6240;&#x5305;&#x56F4;&#x3002;

&#x6591;&#x9A6C;&#x9C7C;&#x666E;&#x6D1B;&#x65AF;&#x540C;&#x7CFB;&#x7269; prox1 &#x662F; mechanosensory &#x6BDB;&#x7EC6;&#x80DE;&#x5206;&#x5316;&#x548C;&#x529F;&#x80FD;&#x7684;&#x4FA7;&#x7EBF;&#x6240;&#x5FC5;&#x9700;&#x7684;&#x3002;

The lateral line system in zebrafish is composed of a series of organs called neuromasts, which are distributed over the body surface. Neuromasts contain clusters of hair cells, surrounded by accessory cells.

The zebrafish prospero homolog prox1 is required for mechanosensory hair cell differentiation and functionality in the lateral line.

Le syst&egrave;me de la ligne lat&eacute;rale chez le poisson z&egrave;bre est compos&eacute; d&#39;une s&eacute;rie d&#39;organes appel&eacute;s neuromasts, qui sont r&eacute;partis sur la surface du corps. Neuromasts contiennent des amas de cellules cili&eacute;es, entour&eacute;es de cellules accessoires.

Le poisson-z&egrave;bre prospero homologue prox1 est requis pour la diff&eacute;renciation des cellules de cheveux m&eacute;canosensoriels et fonctionnalit&eacute; dans la ligne lat&eacute;rale.

Das Seitenlinienorgan-System im Zebrafisch besteht aus einer Reihe von Organen, genannt Neuromasts, die &uuml;ber die K&ouml;rperoberfl&auml;che verteilt sind. Neuromasts enthalten Cluster von Haarzellen, umgeben von Zubeh&ouml;r-Zellen.

Der Zebrab&auml;rbling Prospero Homolog prox1 ist erforderlich f&uuml;r Mechanosensory Haar Zelldifferenzierung und Funktionalit&auml;t in die Seitenlinie.

Il sistema della linea laterale in zebrafish &egrave; composto da una serie di organi chiamato neuromasts, che sono distribuiti sopra la superficie del corpo. Neuromasts contengono ammassi di cellule ciliate, circondate da cellule accessorio.

Il Danio rerio prospero omologo prox1 &egrave; necessaria per la differenziazione delle cellule dei capelli che mechanosensory e funzionalit&agrave; in linea laterale.

&#x5074;&#x7DDA;&#x30B7;&#x30B9;&#x30C6;&#x30E0; &#x30BC;&#x30D6;&#x30E9;&#x30D5;&#x30A3;&#x30C3;&#x30B7;&#x30E5;&#x4F53;&#x8868;&#x9762;&#x4E0A;&#x306B;&#x5206;&#x6563;&#x3055;&#x308C;&#x308B;&#x30AA;&#x30A4;&#x30AB;&#x30EF;&#x3068;&#x547C;&#x3070;&#x308C;&#x308B;&#x5668;&#x5B98;&#x306E;&#x30B7;&#x30EA;&#x30FC;&#x30BA;&#x3067;&#x69CB;&#x6210;&#x3055;&#x308C;&#x307E;&#x3059;&#x3002;&#x30AA;&#x30A4;&#x30AB;&#x30EF;&#x306B;&#x306F;&#x30A2;&#x30AF;&#x30BB;&#x30B5;&#x30EA;&#x30FC;&#x7D30;&#x80DE;&#x306B;&#x3088;&#x3063;&#x3066;&#x56F2;&#x307E;&#x308C;&#x305F;&#x6709;&#x6BDB;&#x7D30;&#x80DE;&#x306E;&#x30AF;&#x30E9;&#x30B9;&#x30BF;&#x30FC;&#x304C;&#x542B;&#x307E;&#x308C;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;

&#x30BC;&#x30D6;&#x30E9;&#x30D5;&#x30A3;&#x30C3;&#x30B7;&#x30E5; &#x30D7;&#x30ED;&#x30B9;&#x30DA;&#x30ED; &#x30DB;&#x30E2;&#x30ED;&#x30B0; prox1 &#x306F;&#x6A5F;&#x68B0;&#x523A;&#x6FC0;&#x53D7;&#x5BB9;&#x6BDB;&#x7D30;&#x80DE;&#x306E;&#x5206;&#x5316;&#x3068;&#x5074;&#x7DDA;&#x306E;&#x6A5F;&#x80FD;&#x304C;&#x5FC5;&#x8981;&#x3067;&#x3059;&#x3002;

Zebrafish&#xC758; &#xCE21;&#xBA74; &#xB77C;&#xC778; &#xC2DC;&#xC2A4;&#xD15C; &#xC7A5;&#xAE30; &#xC2E0;&#xCCB4; &#xD45C;&#xBA74;&#xC744; &#xD1B5;&#xD574; &#xBC30;&#xD3EC; &#xD558;&#xB294; neuromasts &#xB77C;&#xB294; &#xC77C;&#xB828;&#xC758; &#xAD6C;&#xC131; &#xB429;&#xB2C8;&#xB2E4;. Neuromasts &#xC561;&#xC138;&#xC11C;&#xB9AC; &#xC140;&#xC73C;&#xB85C; &#xB458;&#xB7EC;&#xC2F8;&#xC778; &#xC138;&#xD3EC; &#xD074;&#xB7EC;&#xC2A4;&#xD130; &#xD3EC;&#xD568;.

Zebrafish &#xC9C0;&#xC8FC; &#xB2D8; &#xCCB4; prox1&#xB294; mechanosensory &#xBA38;&#xB9AC; &#xC138;&#xD3EC; &#xBD84;&#xD654;&#xC640; &#xAE30;&#xB2A5; &#xCE21;&#xBA74; &#xB77C;&#xC778;&#xC5D0; &#xD544;&#xC694; &#xD569;&#xB2C8;&#xB2E4;.

The nucleophosmin 1 gene () is the most frequently mutated gene in acute myeloid leukemia. Notably,  mutations are always accompanied by additional mutations such as those in cohesin genes , , , and  but not in the cohesin regulator, nipped B-like (). In this work, we analyzed a cohort of adult patients with acute myeloid leukemia and  mutation and observed a specific reduction in the expression of  but not in other cohesin genes. In our zebrafish model, overexpression of the mutated form of  also induced downregulation of , the zebrafish ortholog of human  To investigate the hematopoietic phenotype and the interaction between mutated  and , we generated a zebrafish model with  downregulation which showed an increased number of myeloid progenitors. This phenotype was due to hyper-activation of the canonical Wnt pathway: myeloid cells blocked in an undifferentiated state could be rescued when the Wnt pathway was inhibited by  mRNA injection or indomethacin administration. Our results reveal, for the first time, a role for  during zebrafish hematopoiesis and suggest that an interplay between  may regulate myeloid differentiation in zebrafish and humans through the canonical Wnt pathway and that dysregulation of these interactions may drive leukemic transformation.

: a new player in myeloid cell differentiation.

Cystic fibrosis (CF) is a hereditary disease due to mutations in the CFTR gene and causes mortality in humans mainly due to respiratory infections caused by Pseudomonas aeruginosa. In a previous work we used phage therapy, which is a treatment with a mix of phages, to actively counteract acute P. aeruginosa infections in mice and Galleria mellonella larvae. In this work we apply phage therapy to the treatment of P. aeruginosa PAO1 infections in a CF zebrafish model. The structure of the CFTR channel is evolutionary conserved between fish and mammals and cftr-loss-of-function zebrafish embryos show a phenotype that recapitulates the human disease, in particular with destruction of the pancreas. We show that phage therapy is able to decrease lethality, bacterial burden, and the pro-inflammatory response caused by PAO1 infection. In addition, phage administration relieves the constitutive inflammatory state of CF embryos. To our knowledge, this is the first time that phage therapy is used to cure P. aeruginosa infections in a CF animal model. We also find that the curative effect against PAO1 infections is improved by combining phages and antibiotic treatments, opening a useful therapeutic approach that could reduce antibiotic doses and time of administration.

Article	Year
Crucial role of zebrafish prox1 in hypothalamic catecholaminergic neurons development. BMC developmental biology\| PubMed ID: 18331627	2008
The zebrafish prospero homolog prox1 is required for mechanosensory hair cell differentiation and functionality in the lateral line. BMC developmental biology\| PubMed ID: 19948062	2009
: a new player in myeloid cell differentiation. Haematologica\| PubMed ID: 30630974	2019
Phage therapy against Pseudomonas aeruginosa infections in a cystic fibrosis zebrafish model. Scientific reports\| PubMed ID: 30728389	2019

Anna Pistocchi

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