Vitamin D Regulation of Immune Function.

PURPOSE OF REVIEW: To review the mechanisms by which vitamin D and its metabolites regulate the immune system to facilitate the ability of the body to prevent and/or treat SARS-CoV2 and other respiratory infections and encourage further research into the role that vitamin D supplementation plays in preventing/treating such infections. RECENT FINDINGS: Vitamin D deficiency is associated with an increased risk of SARS-CoV2 and other respiratory infections. Clinical trials in general demonstrate that correction of vitamin D deficiency reduces the risk of hospitalization, ICU admission, and death from SARS-CoV2 infection. The airway epithelium and alveolar macrophages express the enzyme, CYP27B1, that produces the active metabolite of vitamin D, 1,25(OH)2D, and the vitamin D receptor, VDR. Vitamin D and its metabolites promote the innate immune response, which provides the first line of defense against viral and bacterial infections while restricting the adaptive immune response, which if unchecked promotes the inflammatory response leading to the acute respiratory distress syndrome and death. The rationale for treating vitamin D deficiency to reduce the risk of SARS-CoV2 infection and supplementing patients with vitamin D early in the course of SARS-CoV2 infection rests primarily on the ability of vitamin D metabolites to promote an effective immune response to the infection.

Zinc Supplementation Modulates NETs Release and Neutrophils' Degranulation.

Zinc plays an important physiological role in the entire body, especially in the immune system. It is one of the most abundant microelements in our organism and an essential component of enzymes and antibacterial proteins. Zinc levels were reported to be correlated with the intensity of innate immunity responses, especially those triggered by neutrophils. However, as the results are fragmentary, the phenomenon is still not fully understood and requires further research. In this study, we aimed to perform a comprehensive assessment and study the impact of zinc on several basic neutrophils' functions in various experimental setups. Human and murine neutrophils were preincubated in vitro with zinc, and then phagocytosis, oxidative burst, degranulation and release of neutrophil extracellular traps (NETs) were analyzed. Moreover, a murine model of zinc deficiency and zinc supplementation was introduced in the study and the functions of isolated cells were thoroughly studied. We showed that zinc inhibits NETs release as well as degranulation in both human and murine neutrophils. Our study revealed that zinc decreases NETs release by inhibiting citrullination of histone H3. On the other hand, studies performed in zinc-deficient mice demonstrated that low zinc levels result in increased release of NETs and enhanced neutrophils degranulation. Overall, it was shown that zinc affects neutrophils' functions in vivo and in vitro. Proper zinc level is necessary to maintain efficient functioning of the innate immune response.

Innate immune activation by conditioned medium of cancer cells following combined phototherapy with photosensitizer-loaded gold nanorods.

Nanoparticle-based phototherapy has evolved to include immunotherapy as an effective treatment combination for cancers through inducing anti-cancer immune activation leading to downstream adaptive responses and immune protection. However, most cancer phototherapy studies that claimed anti-cancer immunogenic effects often included exogenous immunostimulants to potentiate immune responses and did not clearly establish their effects on immune cells. In this study, we showed that combined photodynamic (PDT) and photothermal therapy (PTT) using gold nanorods (NRs) loaded with the photosensitizer chlorin e6 (Ce6) on endogenously formed mouse serum (MS) protein coronas (i.e., NR-MS-Ce6) on EMT6 murine mammary carcinoma cells could potentiate the activation of both J774A.1 macrophages and DC2.4 dendritic cells. The activation of these innate immune cells by the conditioned media from cancer cells treated with combined PDT + PTT was cell-type and number dependent. While treated B16-OVA murine melanoma cells induced lower activation levels for both immune cell types compared to EMT6, they caused higher pro-inflammatory cytokine secretion levels. Our study suggests the importance of immunological investigations to complement any nanoparticle-based therapeutic interventions to better evaluate their efficacy. This could be achieved through a simple approach to screen for the first line of immune responses arising from these therapies prior to in vivo studies.

Peripheral Immunosenescence and Central Neuroinflammation: A Dangerous Liaison - A Dietary Approach.

BACKGROUND & OBJECTIVES: In old people, both innate and adaptive immune responses are impaired, thus leading to a condition of systemic inflamm-ageing, even including the involvement of the central nervous system (CNS). AIMS: Here, main mechanisms of the immune ageing and neuro-inflammation will be discussed along with the dietary approaches for the modulation of age related diseases. DISCUSSION: Neuroinflammation is caused by the passage of inflammatory mediators through the brain blood barrier to CNS. Then, in the brain, antigenic stimulation of microglia and/or its activation by peripheral cytokines lead to a robust production of free radicals with another wave of proinflammatory cytokines which, in turn, causes massive neuronal damage. Also, infiltrating T cells [T helper (h) and T cytotoxic cells] contribute to neuronal damage. Additionally, a peripheral imbalance between inflammatory Th17 cells and anti-inflammatory T regulatory cells seems to be prevalent in the aged brain, thus leading to a proinflammatory profile. Alzheimer's disease, Parkinson's disease and multiple sclerosis will be described as typical neurodegenerative diseases. Finally, modulation of the immune response thanks to the anti-oxidant and anti-inflammatory effects exerted by dietary products and nutraceuticals in ageing will be discussed. Special emphasis will be placed on polyunsaturated fatty acids, polyphenols, micronutrients and pre-probiotics and synbiotics. CONCLUSION: Ageing is characterized by an imbalance subversion of the immune system with a condition of inflamm-ageing. Neuroinflammation and neurodegenerative diseases seem to be a central manifestation of a peripheral perturbation of the immune machinery. Dietary products and nutraceuticals may lead to a down-regulation of the oxidative and pro-inflammatory profile in ageing.

A combined in vivo and in vitro approach to evaluate the influence of linseed oil or sesame oil and their combination on innate immune competence and eicosanoid metabolism processes in common carp (Cyprinus carpio).

This study aimed to evaluate the influence of dietary pure linseed oil or sesame oil or a mixture on innate immune competence and eicosanoid metabolism in common carp (Cyprinus carpio). Carp of 100.4 ±â€¯4.7 g were fed to satiation twice daily for 6 weeks with four diets prepared from three lipid sources (CLO; LO; SO; SLO). On day 42, plasma was sampled for immune parameter analyses, and kidney and liver tissues were dissected for gene expression analysis. On day 45, HKL and PBMCs from remaining fish were isolated and exposed to E. coli LPS at a dose of 10 µg/mL for 24 h. Results show that the SLO diet enhanced feed utilisation (P = 0.01), while no negative effects on growth or survival were observed in plant oil-fed fish compared to those fed a fish-oil based diet. Plant oil diets did not alter lysozyme and peroxidase activities or gene expression levels. Moreover, the diets did not affect the expression levels of some genes involved in eicosanoid metabolism processes (pla, pge2, lox5). Lys expression in HKL in vitro following exposure to LPS was up-regulated in LO-fed fish, while expression levels of pge2 were higher in SLO fish than in other groups (P < 0.05). The highest value for peroxidase activity in HKL exposed to LPS was found in the SLO-fed group (P < 0.05). In conclusion, our results indicate that dietary plant oils did not induce any negative effects on fish growth, survival, and immune competence status. Moreover, a dietary combination of SO and LO improved the feed utilisation efficiency and seemed more effective in inducing a better immunomodulatory response to LPS through a more active eicosanoid metabolism process.

A versatile imaging platform with fluorescence and CT imaging capabilities that detects myeloperoxidase activity and inflammation at different scales.

Aberrant innate immune response drives the pathophysiology of many diseases. Myeloperoxidase (MPO) is a highly oxidative enzyme secreted by activated myeloid pro-inflammatory immune cells such as neutrophils and macrophages, and is a key mediator of the damaging innate immune response. Current technologies for detecting MPO activity in living organisms are sparse and suffer from any combination of low specificity, low tissue penetration, or low spatial resolution. We describe a versatile imaging platform to detect MPO activity using an activatable construct conjugated to a biotin moiety (MPO-activatable biotinylated sensor, MABS) that allows monitoring the innate immune response and its modulation at different scales and settings. Methods: We designed and synthesized MABS that contains MPO-specific and biotin moieties, and validated its specificity and sensitivity combining with streptavidin-labeled fluorescent agent and gold nanoparticles imaging in vitro and in vivo in multiple mouse models of inflammation and infection, including Matrigel implant, dermatitis, cellulitis, cerebritis and complete Fraud's adjuvant (CFA)-induced inflammation. Results: MABS MPO imaging non-invasively detected varying MPO concentrations, MPO inhibition, and MPO deficiency in vivo with high sensitivity and specificity. MABS can be used to obtain not only a fluorescence imaging agent, but also a CT imaging agent, conferring molecular activity information to a structural imaging modality. Importantly, using this method on tissue-sections, we found that MPO enzymatic activity does not always co-localize with MPO protein detected with conventional techniques (e.g., immunohistochemistry), underscoring the importance of monitoring enzymatic activity. Conclusion: By choosing from different available secondary probes, MABS can be used to create systems suitable to investigate and image MPO activity at different scales and settings.

Oncolytic bacteria: past, present and future.

More than a century ago, independent groups raised the possibility of using bacteria to selectively infect tumours. Such treatment induces an immune reaction that can cause tumour rejection and protect the patient against further recurrences. One of the first holistic approximations to use bacteria in cancer treatment was performed by William Coley, considered the father of immune-therapy, at the end of XIX century. Since then, many groups have used different bacteria to test their antitumour activity in animal models and patients. The basis for this reactivity implies that innate immune responses activated upon bacteria recognition, also react against the tumour. Different publications have addressed several aspects of oncolytic bacteria. In the present review, we will focus on revisiting the historical aspects using bacteria as oncolytic agents and how they led to the current clinical trials. In addition, we address the molecules present in oncolytic bacteria that induce specific toxic effects against the tumors as well as the activation of host immune responses in order to trigger antitumour immunity. Finally, we discuss future perspectives that could be considered in the different fields implicated in the implementation of this kind of therapy in order to improve the current use of bacteria as oncolytic agents.

Near-Infrared Fluorescent Endoscopic Image-Guided Photothermal Ablation Therapy of Colorectal Cancer Using Dual-Modal Gold Nanorods Targeting Tumor-Infiltrating Innate Immune Cells in a Transgenic TS4 CRE/APC loxΔ468 Mouse Model.

Colorectal cancer (CRC) is diagnosed with colonoscopy and treated with focal therapies. CRC is a good candidate for nanoparticle-mediated photothermal ablation (PTA) therapy. Herein, we developed a near-infrared fluorescent (NIRF) endoscopic image-guided PTA approach using a nanoparticle capable of simultaneously diagnosing and treating CRC. Dual-modal NIR heating and fluorescent gold nanorods (dual-modal GNRs) were synthesized by conjugation of GNRs to an NIRF probe. To validate the translational potential of our approach, a well-characterized transgenic TS4 CRE/APC loxΔ468 colon cancer mouse model was used to carry out NIRF image-guided PTA using our dual-modal GNRs under clinically relevant conditions. Intravenously infused dual-modal GNRs were effectively targeted at colon polyps by immunogenic capturing of the GNRs within tumor-infiltrating innate immune cells. NIRF endoscopic image-guided PTA using the GNRs permitted successful detection and ablation of inflammatory colon polyps. NIRF endoscopy image-guided PTA using dual-modal GNRs can be utilized for diagnosis and treatment of CRC and various inflammatory diseases.

[Aging of the immune system: From fundamental to clinical data]. / Le vieillissement du système immunitaire : du fondamental à la clinique.

Major progress in preventing, delaying or curing various pathologies normally encountered in old age results in a continuous improvement in life expectancy. However, understanding the underlying cause of the disparate comorbidities occurrence with aging remains a priority in order to propose adapted care for the older population. In one hand, aging profoundly impairs the immune system; it is characterized by many changes in haematopoiesis, adaptive and innate systems, and is associated with pro-inflammatory environment. In another hand, stressful events (acute or chronic) can also impact the immune system through the secretion of hormones, which are also altered with aging. Blooming evidences from psychoneuroimmunology field suggest that, in acute medical conditions, elderly people are not equal in their responses to stressors depending on many extrinsic and intrinsic parameters. These factors could interfere with elderly's ability to mount an effective immune response. The objective of this review is to provide an overview of the literature (from fundamental to clinical observations) to draw a global picture of immunosenescence. Understanding this process could enable us to target fundamental age-related pathways and thus open new avenues in improving both lifespan and health span.

Effect of N-carbamoylglutamate supplementation on the growth performance, antioxidant status and immune response of mirror carp (Cyprinus carpio) fed an arginine-deficient diet.

The present study was conducted to determine the effect of dietary N-carbamoylglutamate (NCG) supplementation on the growth performance, antioxidant capability and immune responses of mirror carp (Cyprinus carpio) fed an arginine (Arg)-deficient diet. A total of 630 mirror carp (41.65 ±â€¯0.14 g) were fed diets (Arg 1.24% of the diet) that were supplemented with 0.50% Arg (control diet) or graded levels of NCG at 0 (Arg deficiency diet), 0.04%, 0.08%, 0.12%, 0.16% and 0.20% for 8 weeks. The results showed that, compared with the control diet, the Arg-deficient diet supplementation with 0 NCG (1) decreased the final body weight (FWB), the weight gain rate (WGR) or the protein efficiency ratio (PER) and increased the feed conversion ratio (FCR); (2) decreased the concentration of Arg and nitric oxide (NO) and the activity of total nitric oxide synthetase (T-NOS) in the plasma; (3) decreased the activities of superoxide dismutase (SOD) in the proximal intestine (PI), catalase (CAT) in the PI and distal intestine (DI), and glutathione peroxidase (GPx) in PI and mid-intestine (MI) and increased the concentration of malondialdehyde (MDA) in the PI, MI and DI; and (4) decreased the activity of lysozyme in the plasma, increased the relative mRNA expression of tumor necrosis factor-α (TNF-α), interleukin1ß (IL-1ß) and interleukin 8 (IL-8) in the PI, MI and DI, and decreased the relative mRNA expression of interleukin 10 (IL-10) in the PI and MI, and transforming growth factor ß2 (TGF-ß2) in the PI, MI and DI. Compared with the Arg deficient-diet supplementation with 0 NCG, (1) 0.12% or 0.16% NCG increased the FBW, WGR and PER, and 0.16% NCG increased the FCR; (2) 0.08%-0.20% NCG increased the concentration of Arg, NO and the activity of T-NOS; (3) 0.08% NCG increased the activities of SOD in the PI and MI, and 0.12% NCG increased activities of CAT and GPx in the PI, MI and DI; and (4) 0.04%-0.20% NCG increased the activity of lysozyme, 0.04%-0.20% NCG decreased the relative mRNA expression of TNF-α, IL-1ß and IL-8 in the PI and MI, and 0.04%-0.20% NCG increased the relative mRNA expression of IL-10 and TGF-ß2 in the PI and MI. The present results indicated that dietary 0.12% or 0.16% NCG improved the growth performance, feed utilization, intestinal antioxidant capacity and immune response of mirror carp fed an Arg-deficient diet.

Nanoparticle Delivery of RIG-I Agonist Enables Effective and Safe Adjuvant Therapy in Pancreatic Cancer.

Local immunomodulation can be a promising strategy to augment the efficacy and decrease off-target toxicities associated with cancer treatment. Pancreatic cancer is resistant to immunotherapies due to the immunosuppressive tumor microenvironment. Herein, we investigated a therapeutic approach involving delivery of a short interfering double-stranded RNA (dsRNA), specific to Bcl2, with 5' triphosphate ends, by lipid calcium phosphate nanoparticles, in an orthotopic allograft KPC model of pancreatic cancer. Retinoic acid-inducible gene I (RIG-I)-like receptors can bind to 5' triphosphate dsRNA (ppp dsRNA), a pathogen-associated molecular pattern, producing type I interferon, while Bcl2 silencing can drive apoptosis of cancer cells. Our approach demonstrated a robust enrichment of tumor tissue with therapeutic nanoparticles and enabled a significant tumor growth inhibition, prolonging median overall survival. Nanoparticles encapsulating dual-therapeutic ppp dsRNA allowed strong induction in levels of pro-inflammatory Th1 cytokines, further increasing proportions of CD8+ T cells over regulatory T cells, M1 over M2 macrophages, and decreased levels of immunosuppressive B regulatory and plasma cells in the tumor microenvironment. Thus, these results provide a new immunotherapy approach for pancreatic cancer.

Human stem cell-derived hepatocyte-like cells support Zika virus replication and provide a relevant model to assess the efficacy of potential antivirals.

Zika virus (ZIKV) infection during pregnancy has been extensively linked to microcephaly in newborns. High levels of ZIKV RNA were, however, also detected in mice and non-human primates in organs other than the brain, such as the liver. As ZIKV is a flavivirus closely related to the dengue and yellow fever virus, which are known to cause hepatitis, we here examined whether human hepatocytes are susceptible to ZIKV infection. We demonstrated that both human pluripotent stem cell (hPSC)-derived hepatocyte-like cells (HLCs) and the Huh7 hepatoma cell line support the complete ZIKV replication cycle. Of three antiviral molecules that inhibit ZIKV infection in Vero cells, only 7-deaza-2'-C-methyladenosine (7DMA) inhibited ZIKV replication in hPSC-HLCs, while all drugs inhibited ZIKV infection in Huh7 cells. ZIKV-infected hPSC-HLCs but not Huh7 cells mounted an innate immune and NFκß response, which may explain the more extensive cytopathic effect observed in Huh7 cells. In conclusion, ZIKV productively infects human hepatocytes in vitro. However, significant differences in the innate immune response against ZIKV and antiviral drug sensitivity were observed when comparing hPSC-HLCs and hepatoma cells, highlighting the need to assess ZIKV infection as well as antiviral activity not only in hepatoma cells, but also in more physiologically relevant systems.

Effects of Lactococcus lactis subsp. lactis I2 with ß-Glucooligosaccharides on Growth, Innate Immunity and Streptococcosis Resistance in Olive Flounder (Paralichthys olivaceus).

To identify and quantify the effects of a combination of dietary 1 × 108 CFU/g Lactococcus lactis subsp. lactis I2 (LI2) and 0.1% ß-glucooligosaccharides (BGO) on the growth and immunity of olive flounder (Paralichthys olivaceus), a feeding experiment was conducted. Flounder (14 ± 0.5 g) were divided into two groups and fed control and synbiotic feeds for 8 weeks. Investigations were carried out on growth and feed utilization, innate immunity, serum biochemical parameters, intestinal lactic acid bacterial (LAB) viability, microvillus length, and changes in the expression levels of genes encoding pro-inflammatory cytokines (tumor necrosis factor [TNF]-α, interleukin [IL]-1ß, and IL-6). Results demonstrated the synbiotic diet had significantly better (p < 0.05) responses in terms of weight gain and specific growth rate, three innate immune parameters (respiratory burst, serum lysozyme, and superoxide dismutase), intestinal LAB viability, and the relative TNF-α expression level (p < 0.05). Moreover, after challenge with Streptococcus iniae (1 × 108 CFU/ml), the synbiotically fed group exhibited significantly higher (p < 0.05) protection against streptococcosis, validating the observed changes in immune parameters and induction of the cytokine-encoding gene. Therefore, according to the results of the present study, synbiotic feed (LI2 + BGO) increased growth, modulated innate immune parameters and protected olive flounder against streptococcosis.

Consumption of conjugated linoleic acid (CLA)-supplemented diet during colitis development ameliorates gut inflammation without causing steatosis in mice.

Dietary supplementation with conjugated linoleic acid (CLA) has been proposed for weight management and to prevent gut inflammation. However, some animal studies suggest that supplementation with CLA leads to the development of nonalcoholic fatty liver disease. The aims of this study were to test the efficiency of CLA in preventing dextran sulfate sodium (DSS)-induced colitis, to analyze the effects of CLA in the liver function, and to access putative liver alterations upon CLA supplementation during colitis. So, C57BL/6 mice were supplemented for 3 weeks with either control diet (AIN-G) or 1% CLA-supplemented diet. CLA content in the diet and in the liver of mice fed CLA containing diet were accessed by gas chromatography. On the first day of the third week of dietary treatment, mice received ad libitum a 1.5%-2.5% DSS solution for 7 days. Disease activity index score was evaluated; colon and liver samples were stained by hematoxylin and eosin for histopathology analysis and lamina propria cells were extracted to access the profile of innate cell infiltrate. Metabolic alterations before and after colitis induction were accessed by an open calorimetric circuit. Serum glucose, cholesterol, triglycerides and alanine aminotransaminase were measured; the content of fat in liver and feces was also accessed. CLA prevented weight loss, histopathologic and macroscopic signs of colitis, and inflammatory infiltration. Mice fed CLA-supplemented without colitis induction diet developed steatosis, which was prevented in mice with colitis probably due to the higher lipid consumption as energy during gut inflammation. This result suggests that CLA is safe for use during gut inflammation but not at steady-state conditions.

Novel C-type lectin from razor clam Sinonovacula constricta agglutinates bacteria and erythrocytes in a Ca2+-dependent manner.

Among its other physiological roles, C-type lectins functioned as pattern recognition receptors (PRR) in innate immunity received much attention. In the present study, a novel C-type lectin was identified and characterized from the invertebrate razor clam Sinonovacula constrict and designated as ScCTL. The complete cDNA sequence of ScCTL was 828 bp in length and coded a secreted polypeptide of 158 amino acids with a typical CRD domain. Multiple sequence alignments combined with phylogenetic analysis both collectively confirmed that ScCTL was a novel member belong to lectin family. Spatial expression distribution analysis revealed that ScCTL was extensively expressed in all of the examined tissues, and the highest expression was detected in the hepatopancreas. After 1 × 107 CFU/mL Vibrio parahaemolyticus challenge by immersion infection, the ScCTL transcript in hepatopancreas and gill were markedly upregulated and arrived the maximum levels at 24 or 12 h after challenge, respectively. Recombinant ScCTL could agglutinate not only all tested bacteria but sheep and mouse erythrocyte in the presence of Ca2+. All of our studies suggested that ScCTL performed important roles in protecting cells from pathogenic infection in S. constrict.

An origin of the immunogenicity of in vitro transcribed RNA.

The emergence of RNA-based therapeutics demands robust and economical methods to produce RNA with few byproducts from aberrant activity. While in vitro transcription using the bacteriophage T7 RNA polymerase is one such popular method, its transcripts are known to display an immune-stimulatory activity that is often undesirable and uncontrollable. We here showed that the immune-stimulatory activity of T7 transcript is contributed by its aberrant activity to initiate transcription from a promoter-less DNA end. This activity results in the production of an antisense RNA that is fully complementary to the intended sense RNA product, and consequently a long double-stranded RNA (dsRNA) that can robustly stimulate a cytosolic pattern recognition receptor, MDA5. This promoter-independent transcriptional activity of the T7 RNA polymerase was observed for a wide range of DNA sequences and lengths, but can be suppressed by altering the transcription reaction with modified nucleotides or by reducing the Mg2+ concentration. The current work thus not only offers a previously unappreciated mechanism by which T7 transcripts stimulate the innate immune system, but also shows that the immune-stimulatory activity can be readily regulated.

Personalized vaccinology: A review.

At the current time, the field of vaccinology remains empirical in many respects. Vaccine development, vaccine immunogenicity, and vaccine efficacy have, for the most part, historically been driven by an empiric "isolate-inactivate-inject" paradigm. In turn, a population-level public health paradigm of "the same dose for everyone for every disease" model has been the normative thinking in regard to prevention of vaccine-preventable infectious diseases. In addition, up until recently, no vaccines had been designed specifically to overcome the immunosenescence of aging, consistent with a post-WWII mentality of developing vaccines and vaccine programs for children. It is now recognized that the current lack of knowledge concerning how immune responses to vaccines are generated is a critical barrier to understanding poor vaccine responses in the elderly and in immunoimmaturity, discovery of new correlates of vaccine immunogenicity (vaccine response biomarkers), and a directed approach to new vaccine development. The new fields of vaccinomics and adversomics provide models that permit global profiling of the innate, humoral, and cellular immune responses integrated at a systems biology level. This has advanced the science beyond that of reductionist scientific approaches by revealing novel interactions between and within the immune system and other biological systems (beyond transcriptional level), which are critical to developing "downstream" adaptive humoral and cellular responses to infectious pathogens and vaccines. Others have applied systems level approaches to the study of antibody responses (a.k.a. "systems serology"), [1] high-dimensional cell subset immunophenotyping through CyTOF, [2,3] and vaccine induced metabolic changes [4]. In turn, this knowledge is being utilized to better understand the following: identifying who is at risk for which infections; the level of risk that exists regarding poor immunogenicity and/or serious adverse events; and the type or dose of vaccine needed to fully protect an individual. In toto, such approaches allow for a personalized approach to the practice of vaccinology, analogous to the substantial inroads that individualized medicine is playing in other fields of human health and medicine. Herein we briefly review the field of vaccinomics, adversomics, and personalized vaccinology.

Will Systems Biology Deliver Its Promise and Contribute to the Development of New or Improved Vaccines? Systems Biology Views of Vaccine Innate and Adaptive Immunity.

During the last decade, several high-throughput technologies have been applied to gather deeper understanding on the biological events elicited by vaccination. The main goal of systems biology is to integrate different sources of data and extract biologically meaningful information. This holistic approach has provided new insights on the impact that the innate immune status has on vaccine responsiveness. Other factors like chronic infections, age, microbiome, and metabolism can influence the outcome of vaccination, and systems biology offers unique opportunities to expand our understanding of their role on the immune response. However, a few challenges that still need to be overcome will be discussed.

Effects of dietary hawthorn extract on growth performance, immune responses, growth- and immune-related genes expression of juvenile golden pompano (Trachinotus ovatus) and its susceptibility to Vibrio harveyi infection.

The present study was conducted to investigate the effects of dietary hawthorn extract (HTE) supplementation on growth performance, immune responses, hepatic antioxidant abilities, growth- and immune-related and heat shock protein genes expression and resistance to the pathogen Vibrio harveyi in Trachinotus ovatus. A basal diet supplemented with HTE at 0 (Diet 1), 0.50 (Diet 2), 1.00 (Diet 3), 2.00 (Diet 4), 4.00 (Diet 5) and 10.00 (Diet 6) g kg-1 were fed to golden pompano for 8 weeks. The highest final body weight, weight gain rate, specific growth rate, feed efficiency ratio and protein efficiency rate were observed in fish fed Diet 2 (P < 0.05). Dietary HTE significantly increased plasma complement 3, complement 4 and immunoglobulin M content (P < 0.05). Hepatic antioxidant enzymes (SOD, T-AOC, CAT, GPx, GR) significantly increased (P < 0.05), whereas MDA content decreased first and then increased in fish fed HTE supplement. After challenge with Vibrio harveyi, significant higher post-challenge survival was observed in fish fed Diet 2 and Diet 3 than the control group (P < 0.05). Transcription levels of growth-related genes (IGF-I and IGF-II) were significantly up-regulated in fish fed HTE supplement (P < 0.05), whereas HSP70 and HSP90 mRNA levels were significantly down-regulated (P < 0.05). With respect to immune-related genes, such as tumour necrosis factor-alpha (TNF-α), interleukin-8 (IL-8) and inhibitor protein κBα (IκB-α), upregulation was observed in the liver of fish fed with the diet supplemented with HTE. In contrast, the expression of antioxidant enzyme genes (CAT, GPx, MnSOD and Keap1) and cytokines (IL-10, TGF-ß1 and TOR) was downregulated. These results indicated that golden pompano fed a diet supplemented with 0.50 g kg-1 HTE could significantly promote growth performance and growth-related genes expression, strengthen immunity, and improve hepatic antioxidative abilities and resistance to Vibrio harveyi infection.