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Transcriptomic Profiles of Post-Smolt Atlantic Salmon Challenged With Developmental and Comparative Immunology 81 (2018) 348e362 Contents lists available at ScienceDirect Developmental and Comparative Immunology journal homepage: www.elsevier.com/locate/dci Transcriptomic profiles of post-smolt Atlantic salmon challenged with Piscirickettsia salmonis reveal a strategy to evade the adaptive immune response and modify cell-autonomous immunity * Marco Rozas-Serri , Andrea Pena,~ Lucerina Maldonado Pathovet Laboratory Ltd., Puerto Montt, Chile article info abstract Article history: Piscirickettsiosis is the main bacterial disease affecting the Chilean salmon farming industry and is Received 13 November 2017 responsible for high economic losses. The development of effective strategies to control piscirickettsiosis Received in revised form has been limited in part by insufficient knowledge of the host response. The aim of this study was to use 23 December 2017 RNA sequencing to describe the transcriptional profiles of the responses of post-smolt Atlantic salmon Accepted 23 December 2017 infected with LF-89-like or EM-90-like Piscirickettsia salmonis. Enrichment and pathway analyses of the Available online 27 December 2017 differentially expressed genes revealed several central signatures following infection, including positive regulation of DC-SIGN and TLR5 signalling, which converged at the NF-kB level to modulate the pro- Keywords: fl fi RNA-seq in ammatory cytokine response, particularly in the PS-EM-90-infected sh. P. salmonis induced an Piscirickettsiosis IFN-inducible response (e.g., IRF-1 and GBP-1) but inhibited the humoral and cell-mediated immune Piscirickettsia salmonis responses. P. salmonis induced significant cytoskeletal reorganization but decreased lysosomal protease LF-89 activity and caused the degradation of proteins associated with cellular stress. Infection with these EM-90 isolates also delayed protein transport, antigen processing, vesicle trafficking and autophagy. Both P. salmonis isolates promoted cell survival and proliferation and inhibited apoptosis. Both groups of Trojan fish used similar pathways to modulate the immune response at 5 dpi, but the transcriptomic profiles in the head kidneys of the cohabitant fish infected with PS-LF-89 and PS-MS-90 were relatively different at day 35 post-infection of the Trojan fish, probably due to the different degree of pathogenicity of each isolate. Our study showed the most important biological mechanisms used by P. salmonis, regardless of the isolate, to evade the immune response, maintain the viability of host cells and increase intracellular replication and persistence at the infection site. These results improve the understanding of the mechanisms by which P. salmonis interacts with its host and may serve as a basis for the develop- ment of effective strategies for the control of piscirickettsiosis. © 2017 Elsevier Ltd. All rights reserved. 1. Introduction LF-89-like (PS-LF-89) and EM-90-like (PS-EM-90) field isolates have genomic differences that may induce different degrees of virulence Salmonid rickettsial septicaemia (SRS) or Piscirickettsiosis is the (Bohle et al., 2014) as well as differences in pathogenesis (Rozas- major bacterial disease threatening Chilean salmon culture and is Serri et al., 2017a) and immunity (Rozas-Serri et al., 2017b). responsible for elevated economic losses (Rozas and Enriquez, The innate immune system is the first line of defence against 2014). The aetiological agent of SRS (Piscirickettsia salmonis) pathogenic agents, and its main function is the early recognition of (Fryer et al., 1992) belongs to family Piscirickettsiaceae, which also pathogens and the activation of an adequate pro-inflammatory includes the genera Francisella, Coxiella and Legionella (Mauel et al., response (Medzhitov, 2007). IL-12 promotes the transformation 1999). P. salmonis isolates show a high level of similarity, although of T helper cells (Th1) and stimulates the secretion of IFN-g and IL- the EM-90 isolate is considered separately (Mauel et al., 1999). The 2, which in turn regulate the proliferation of T cells, maturation of þ CD8 T cells and activation of the cellular immune response aimed at controlling intracellular pathogens (Yamane and Paul, 2012). * Corresponding author. In vitro infection of rainbow trout macrophages (Alvarez et al., E-mail addresses: [email protected] (M. Rozas-Serri), andrea.pena@ 2016) and in vivo infection of post-smolt Atlantic salmon (Rozas- pathovet.cl (A. Pena),~ [email protected] (L. Maldonado). https://doi.org/10.1016/j.dci.2017.12.023 0145-305X/© 2017 Elsevier Ltd. All rights reserved. M. Rozas-Serri et al. / Developmental and Comparative Immunology 81 (2018) 348e362 349 Serri et al., 2017b) with P. salmonis induce overexpression of IL-10 salinity. The cohabitation challenge was performed using an in- and downregulate IL-12 expression, thereby contributing to inac- fectious dose of 105.6 colony-forming units/0.1 mL of P. salmonis LF- tivation of the antibacterial response and promotion of the survival 89-like and EM-90-like. The cohabitation trial was conducted in and intracellular replication of the bacterium. three identical independent recirculation systems, each with three Similar to Francisella, control of P. salmonis requires stimulation 1000-L tanks containing aerated artificial seawater (12 C, 15%) À of adaptive cellular immunity; however, the mechanisms by which with the water flow regulated to 1.2 changes per hour (L h 1). Each the processes associated with this type of immunity are directed system possessed independent mechanical filtration (a filter with 3 against these two species of bacteria remain poorly understood layers of quartz stone of different sizes, 1 layer of zeolite and 1 layer (Conlan, 2011; Rozas and Enriquez, 2014). The different expression of charcoal). The first recirculation system consisted of two tanks patterns of immunity-related genes in the head kidneys of Atlantic with 150 fish; each tank contained 55 fish (henceforth called Trojan salmon infected with P. salmonis confirm activation of the innate fish) that had received i.p. injections of 0.1 mL of the PS-LF-89 immune response and inhibition of the adaptive immune response inoculum and were marked by cutting off the upper lobe of the (Rise et al., 2004; Rozas-Serri et al., 2017b; Tacchi et al., 2011). The tail and 95 healthy fish as cohabitants. The second recirculation pathogenesis of intracellular infection entails a continuous battle system also consisted of two tanks, but the Trojan fish had received between the defence mechanisms of the host and specific mecha- i.p injections of 0.1 mL of the PS-EM-90 inoculum. The third recir- nisms utilized by the bacterium to evade the immune response and culation system consisted of two tanks with 150 uninfected control to promote intracellular replication and survival. This process is fish in which the same proportion of fish (n ¼ 55) received i.p. in- described as cell-autonomous immunity, which is defined as the jections of 0.1 mL sterile saline solution (0.9%) as the infected tanks. ability of a host cell to eliminate an invasive infectious agent, and Head-kidney tissues were collected from 5 Trojan fish and 5 control includes the production of pro-inflammatory cytokines, chemo- fish per tank at 5 days post-inoculation (dpi) and from 5 cohabitant tactic migration of immune cells to the site of infection and fish and 5 control fish at 35 dpi of the Trojan fish per tank. Thus, at manipulation of vesicle trafficking to avoid lysosomal toxicity and each time point, 10 fish from the control and treatments were autophagy (Mostowy and Shenoy, 2015). The cytoskeleton plays a divided into 2 replicate pools with 5 fish each. The head-kidney crucial role in antigen presentation, T cell signalling and adaptive tissues from the 2 replicates were placed into 5 mL of RNAlater™ immune responses (Angus and Griffiths, 2013). (Ambion, Austin, TX, USA). After 24 h of temporary storage at 4 C, Cell-autonomous immunity is controlled by interferon, which samples immersed in RNA Later™ were transferred to a À80 C induces the expression of genes as a strategy against bacterial ultra-low temperature freezer prior to preparation of the RNA. The infection (MacMicking, 2012). Infection of macrophages is a com- fish were fed commercial food daily. The water temperature, the mon strategy used by intracellular bacteria to colonize and spread dissolved oxygen concentration and the salinity were recorded. The into host cells (Mostowy and Shenoy, 2015). P. salmonis also infects experiment was terminated 61 days after challenge of the Trojan macrophages and multiplies in replicative vacuoles (McCarthy fish. All animal procedures were conducted in strict accordance et al., 2008; Rojas et al., 2009) using a Type IV secretion system with the recommendations in the Guide of Use of Animals for (TIVSS) that is referred to as Dot/Icm to establish an effective Research of Universidad Austral de Chile and were approved by the infection by altering phagocytosis, cytotoxicity and apoptosis and Committee on the Ethics of Animals for Research. inhibiting phagosome-lysosome fusion in vitro (Gomez et al., 2013). However, little is known about the mechanisms used by P. salmonis 2.2. RNA extraction to sustain its evasion strategy within the host in vivo. Generally, P. salmonis induces the downregulation of genes The head kidneys were sampled from five fish per tank ac- encoding pro-apoptotic proteins, the upregulation of genes cording to the time schedule, and total RNA was extracted using the involved in cellular proliferation
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