Transferrin and ferritin response to bacterial infection: The role of the liver and brain in fish

IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Portugal.
Developmental and comparative immunology (Impact Factor: 2.82). 08/2009; 33(7):848-57. DOI: 10.1016/j.dci.2009.02.001
Source: PubMed


Iron is essential for growth and survival, but it is also toxic when in excess. Thus, there is a tight regulation of iron that is accomplished by the interaction of several genes including the iron transporter transferrin and iron storage protein ferritin. These genes are also known to be involved in response to infection. The aim of this study was to understand the role of transferrin and ferritin in infection and iron metabolism in fish. Thus, sea bass transferrin and ferritin H cDNAs were isolated from liver, cloned and characterized. Transferrin constitutive expression was found to be highest in the liver, but also with significant expression in the brain, particularly in the highly vascularized region connecting the inferior lobe of the hypothalamus and the saccus vasculosus. Ferritin, on the other hand, was expressed in all tested organs, but also significantly higher in the liver. Fish were subjected to either experimental bacterial infection or iron modulation and transferrin and ferritin mRNA expression levels were analyzed, along with several iron regulatory parameters. Transferrin expression was found to decrease in the liver and increase in the brain in response to infection and to increase in the liver in iron deficiency. Ferritin expression was found to inversely reflect transferrin in the liver, increasing in infection and iron overload and decreasing in iron deficiency, whereas in the brain, ferritin expression was also increased in infection. These findings demonstrate the evolutionary conservation of transferrin and ferritin dual functions in vertebrates, being involved in both the immune response and iron metabolism.

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Available from: Pedro Rodrigues, Dec 21, 2015
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    • "Ferritin is ubiquitously distributed throughout the biota from microbes to humans, and ferritin genes encoding distinct subunits have been identified in a diverse group of invertebrate and vertebrate species, including fish. For instance, the ferritin H gene has been reported from Ictalurus punctatus[16], Scophthalmus maximus[17], Dicentrarchus labrax[13], Salmo salar[5,18], and Oplegnathus fasciatus[19]. Meanwhile, the ferritin M gene has been characterized from several marine teleost species, including Cynoglossus semilaevis[20], Pseudosciaena crocea[21], Sciaenops ocellatus[22], S. maximus[10], S. salar[5], and O. fasciatus[6]. "
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    ABSTRACT: Ferritins play an indispensable role in iron homeostasis through their iron-withholding function in living beings. In the current study, cDNA sequences of three distinct ferritin subunits, including a ferritin H, a ferritin M, and a ferritin L, were identified from big belly seahorse, Hippocampus abdominalis, and molecularly characterized. Complete coding sequences (CDS) of seahorse ferritin H (HaFerH), ferritin M (HaFerM), and ferritin L (HaFerL) subunits were comprised of 531, 528, and 522 base pairs (bp), respectively, which encode polypeptides of 177, 176, and 174 amino acids, respectively, with molecular masses of ∼20-21 kDa. Our in silico analyses demonstrate that these three ferritin subunits exhibit the typical characteristics of ferritin superfamily members including iron regulatory elements, domain signatures, and reactive centers. The coding sequences of HaFerH, M, and L were cloned and the corresponding proteins were overexpressed in a bacterial system. Recombinantly expressed HaFer proteins demonstrated detectable in vivo iron sequestrating (ferroxidase) activity, consistent with their putative iron binding capability. Quantification of the basal expression of these three HaFer sequences in selected tissues demonstrated a gene-specific ubiquitous spatial distribution pattern, with HaFerM abundantly detected in the liver and HaFerH and HaFerL predominantly expressed in blood. Interestingly, the basal expression of all three ferritin genes was found to be significantly modulated against pathogenic stress mounted by lipopolysaccharides (LPS), poly I:C, Streptococcus iniae, and Edwardsiella tarda. Collectively, our findings suggest that the three HaFer subunits may be involved in iron (II) homeostasis in big belly seahorse and that they are important in its host defense mechanisms.
    Full-text · Article · Dec 2015 · Fish & Shellfish Immunology
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    • "The hypoferremia and the hepcidin up-regulation were also detected after 24 h in Phdp-infected fish, but after 72 h the liver hepcidin returned to the control level, as reported in sea bream (Pellizzari et al., 2013), whereas the hypoferremia persisted. In such a sense, further investigations are necessary to understand the pathogenic mechanisms of iron uptake by Phdp, also considering the role of specific sea bass strategies to limit iron availability during infections, such as the modulation of ferritin and transferrin (Neves et al., 2009). In sea bass, the hepcidin gene was characterized for the first time by Rodrigues et al. (2006), which indicated its dual function, as antimicrobial peptide and iron metabolism regulator during Phdp infection . "
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    ABSTRACT: Sea bass were experimentally infected with Listonella anguillarum or Photobacterium damselae subsp. piscicida (Phdp). At 24 and 72 hours post-infection, the expression analysis of immune-relevant genes (IL-1β, IL-6, IL-8, Hepcidin), the transcriptional level and detection of HSP70, and the quantification of serum iron were investigated in association with the histological analysis and the bacterial recognition in tissues by immunohistochemistry. At 15 days post-infection, the specific antibody response was detected in surviving fish, as well as the transcriptional levels of TcR and BcR sequences. Both experimental infections were characterized by a similar acute response, whereas different histological and imunohistochemistry evidences were observed. In particular, the early reaction appeared suitable for the clearance of L. anguillarum, thus limiting the histological lesions, the bacterial dissemination and the further development of acquired immunity in surviving fish. On the contrary, the innate response appeared not enough to resolve the Phdp infection, which was characterized by tissue damage, bacterial widespread and substantial detection of specific humoral immunity in surviving fish, also associated to lymphocytes clonal expansion. Besides the opportunistic conditions involved in fish vibriosis and pasteurellosis, the comparison between these experimental infection models seems to suggest that the rate of development of the acquired immunity is strictly linked to the activation of the host innate response combined to the degree of bacterial virulence.
    Full-text · Article · Oct 2014 · Veterinary Immunology and Immunopathology
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    • "On the other hand, M2 showed contrasting expression in both tissues – a slight decrease in the liver but a significant increase in kidney. This observation was particularly interesting as to our knowledge; previous studies in vertebrate ferritin have consistently reported increased ferritin expression during an APR [50], [51]. The different expression patterns displayed between the ferritin chains (H- and M-chains) as well as the individual isoforms (M1 and M2) appear to suggest the possibility of more distinctive and complex roles for ferritin during an immune response than previously assumed. "
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    ABSTRACT: Ferritin is a highly-conserved iron-storage protein that has also been identified as an acute phase protein within the innate immune system. The iron-storage function is mediated through complementary roles played by heavy (H)-chain subunit as well as the light (L) in mammals or middle (M)-chain in teleosts, respectively. In this study, we report the identification of five ferritin subunits (H1, H2, M1, M2, M3) in the Atlantic salmon that were supported by the presence of iron-regulatory regions, gene structure, conserved domains and phylogenetic analysis. Tissue distribution analysis across eight different tissues showed that each of these isoforms is differentially expressed. We also examined the expression of the ferritin isoforms in the liver and kidney of juvenile Atlantic salmon that was challenged with Aeromonas salmonicida as well as in muscle cell culture stimulated with interleukin-1β. We found that each isoform displayed unique expression profiles, and in certain conditions the expressions between the isoforms were completely diametrical to each other. Our study is the first report of multiple ferritin isoforms from both the H- and M-chains in a vertebrate species, as well as ferritin isoforms that showed decreased expression in response to infection. Taken together, the results of our study suggest the possibility of functional differences between the H- and M-chain isoforms in terms of tissue localisation, transcriptional response to bacterial exposure and stimulation by specific immune factors.
    Full-text · Article · Jul 2014 · PLoS ONE
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