Abstract
Photobacterium damselae subsp. piscicida (Phdp) is a Gram-negative bacterium that infects a large number of marine fish species in Europe, Asia, and America, both in aquacultures and in the natural environment. Among the affected hosts are economically important cultured fish, such as sea bream (Sparus aurata), sea bass (Dicentrarchus labrax), yellowtail (Seriola quinqueradiata), and cobia (Rachycentron canadum). The best characterized virulence factor of Phdp is the Apoptosis-Inducing Protein of 56 kDa (AIP56), a secreted AB-type toxin that has been shown to induce apoptosis of sea bass phagocytes during infection. AIP56 has an A subunit that displays metalloprotease activity against NF-kB p65 and a B subunit that mediates binding and internalization of the A subunit in susceptible cells. Despite the fact that the aip56 gene is highly prevalent in Phdp isolates from different fish species, the toxicity of AIP56 has only been studied in sea bass. In the present study, the toxicity of AIP56 for sea bream was evaluated. Ex vivo assays showed that sea bream phagocytes are resistant to AIP56 cytotoxicity and that resistance was associated with an inefficient internalization of the toxin by those cells. Accordingly, in vivo intoxication assays revealed that sea bream is much more resistant to AIP56-induced lethality than sea bass. These findings, showing that the effect of AIP56 is different in sea bass and sea bream, set the basis for future studies to characterize the effects of AIP56 and to fully elucidate its virulence role in different Phdp susceptible hosts.
Highlights
AIP56 (Apoptosis-Inducing Protein of 56 kDa) is an AB toxin secreted by virulent strains of Photobacterium damselae subsp. piscicida (Phdp) [1], a Gram-negative bacterium that causes a septicemic infection that leads to high mortalities in a large number of wild and cultured warm water marine fish species in Europe, Asia, and North America [2]
We started by analyzing the susceptibility of the sea bream professional phagocytes—acidophilic granulocytes, which are the functional equivalents to mammalian neutrophils, and macrophages [25,26,27]—to AIP56 ex vivo
We used peritoneal leukocytes collected from undisturbed peritoneal cavities, composed mainly by neutrophilic and eosinophilic granulocytes or leukocytes collected 12 days after i.p. injection of Incomplete Freund’s Adjuvant (IFA), that were highly enriched in monocytes/macrophages (88% of the total population)
Summary
AIP56 (Apoptosis-Inducing Protein of 56 kDa) is an AB toxin secreted by virulent strains of Photobacterium damselae subsp. piscicida (Phdp) [1], a Gram-negative bacterium that causes a septicemic infection that leads to high mortalities in a large number of wild and cultured warm water marine fish species in Europe, Asia, and North America [2]. Studies in sea bass have shown that AIP56 is secreted and systemically disseminated during infection and causes apoptosis of macrophages and neutrophils, leading to their extensive lysis by post-apoptotic secondary necrosis [1,8,14]. The toxicity of AIP56 for sea bream, another economically important fish species susceptible to Phdp infections, was investigated. Studies performed in sea bass and mouse macrophages have shown that intoxication by AIP56 is a multi-step process that begins with clathrin-dependent endocytosis, followed by low pH-dependent translocation of the toxin from the endosomes into the cytosol, where it cleaves NF-kB p65 [15]. Sea from 0.9–4.2 μg/g body weight, indicating that this fish species is highly resistant to bArIePa5m6 tmoxoirctiatlyi.tySewaabsrheaomwemvoertoablistyerwveads ihnoewxepveerrimobesnetr4v,eidn iwn heixcphe2ri.m2 oernt0.42, μingwAhIPic5h62/.g2 boor d0y.2wμegigAhItPr5e6s/ugltbedodiny 1w0e0i%ghatnrdes3u0l%tedmionrt1a0l0it%y, raensdpe3c0t%ivemlyo. rNtaelviteyr,threeslpesesc,tidveeslpyi.teNtehveienrcthreealessesd, sduescpeiptetitbhileitiyncorfetahsiesdbasutcshceopftsibeialibtyreoafmtshitso bAaItPch56o, fthseearebsurelatsmosf teoxpAeIrPim56e,ntth4e croesnufilrtsmoedf ethxepehriigmheenrtre4sicsotannfciremoefdsetahberehaigmhetor irnetsoisxtiacnatcieono,fwsheaenbcroeammpatroedinttoosxeicaabtiaosns, awsh9e0n%cmomorptaalrietyd wtoassoeabsbearvsse,daasft9e0r%injmecotirotanliotfysewaabsaossbsweirtvhe0d.2aμftgerAiInPj5e6ct/iognboodf ysewaebigahsts, cwoimthp0a.r2edμgtoAthIPe 5360/%g mboodrytalwiteyigohbta, icnoemdpinarseeda btoretahme 3w0i%thmthoerstamliteydoobstea.inTehde ionbseravberdesaema bwrietahmthmeosratmalietydwosaes. cTahueseodbsbeyrvtheedtsoexainbarenadminmvoolrvteadlitiytswcaatsalcyatuicseadctibvyityth, aestonxoinmaonrtdalintywvoalsveodbsietsrvceadtalayftiecr aicntjievcittiyo,nasofntohme voerthailcitley owra2s.2obμsge/rvgedboadftyerwienijgechttioonf othfethceatvaelyhtiicclealolyr i2n.2acμtigv/egAboIPd5y6wAAeIiVgAhAt.of the catalytically inactive AIP56AAIVAA
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