Editorial: Sustained Effects of Early Nutrition on Immune Development and Microbiome-Immune Crosstalk

Non-communicable diseases associated with immune system dysfunction are an increasing challenge for twenty-first century medicine. There is growing evidence that predisposition to many such conditions originate during early-life "programming events." This term refers to critical points of developmental plasticity where changes in environmental factors have long-term effects on physiological development, including the development of the immune system. From birth, the neonatal immune system develops rapidly in response to external stimuli, primarily from the intestinal microbiota and nutrition, and this pattern of development is essential in adult immune functionality and competence. Nutritional components of the early diet including antioxidants, polyunsaturated fatty acids, folate, and other vitamins can directly influence immunity. This is by shifting the structure and/or functions of different immune cell populations and hematopoietic organs, and also by modulating gene expression and various signaling pathways in immune cells that contribute to homeostasis. Non-digestible oligosaccharides and their metabolites can also drive differential immune development indirectly through modification of both the composition and the metabolic activity of the gut microbiota. While current literature indicates the existence of a dynamic interplay between the immune system, nutrition and the intestinal microbiota, the molecular interactions and pathways involved in this cross-talk are complex and poorly characterized

Risk Factors for Human Infection with Puumala Virus, Southwestern Germany

Risk factors are available bank vole habitat, abundant vole food supply, high human population density, and warmer climate

Age-related Changes in the Natural Killer Cell Response to Seasonal Influenza Vaccination are not Influenced by a Synbiotic; a Randomised Controlled Trial

Natural killer (NK) cells are an important component of the immune response to influenza infection, but are subject to alteration during ageing, which may play a role in impaired response to infection and vaccination in older people. Enhancement of NK cell activity could, therefore, present a means to improve the immune response to vaccination in older subjects, and pre- and probiotics offer an opportunity to modulate anti-viral defences via alteration of the gut microbiota. This study investigated the effect of a novel probiotic, Bifidobacterium longum bv. infantis CCUG 52486, combined with a prebiotic, gluco-oligosaccharide (B. longum + Gl-OS), on the NK cell response to seasonal influenza vaccination in young and older subjects in a double-blind, randomized controlled trial. There were significant effects of ageing on NK cell phenotype, the most notable of which were an increase in CD56dim cells, mainly reflected in the CD16+ subset, a decrease in CD56bright cells, mainly reflected in the CD16- subset, and greater expression of the immunosenescence marker, CD57, on NK cell subsets. However, these changes only partially translated to differences in NK cell activity, observed as trends towards reduced NK cell activity in older subjects when analysed on a per cell basis. Influenza vaccination increased the proportion of CD56bright cells and decreased the proportion of CD56dim cells, in young, but not older subjects. Although NK cell activity in response to vaccination was not significantly different between the young and older subjects, low post-vaccination NK cell activity was associated with poor seroconversion in only the older subjects. There was no influence of the synbiotic on NK cell phenotype or activity, either before or after influenza vaccination. In conclusion, ageing is associated with marked alteration of the phenotype of the NK cell population and there was evidence of an impaired NK cell response to influenza vaccination in older subjects. The effects of ageing on NK cell phenotype and activity could not be offset by B. longum + Gl-OS. Clinical trial identifier: clinicaltrials.gov NCT01066377

Altered drug susceptibility during host adaptation of a <i>Plasmodium falciparum</i> strain in a non-human primate model

Infections with Plasmodium falciparum, the most pathogenic of the Plasmodium species affecting man, have been reduced in part due to artemisinin-based combination therapies. However, artemisinin resistant parasites have recently emerged in South-East Asia. Novel intervention strategies are therefore urgently needed to maintain the current momentum for control and elimination of this disease. In the present study we characterize the phenotypic and genetic properties of the multi drug resistant (MDR) P. falciparum Thai C2A parasite strain in the non-human Aotus primate model, and across multiple passages. Aotus infections with C2A failed to clear upon oral artesunate and mefloquine treatment alone or in combination, and ex vivo drug assays demonstrated reduction in drug susceptibility profiles in later Aotus passages. Further analysis revealed mutations in the pfcrt and pfdhfr loci and increased parasite multiplication rate (PMR) across passages, despite elevated pfmdr1 copy number. Altogether our experiments suggest alterations in parasite population structure and increased fitness during Aotus adaptation. We also present data of early treatment failures with an oral artemisinin combination therapy in a pre-artemisinin resistant P. falciparum Thai isolate in this animal model

A Plasmodium falciparum Histone Deacetylase Regulates Antigenic Variation and Gametocyte Conversion

SummaryThe asexual forms of the malaria parasite Plasmodium falciparum are adapted for chronic persistence in human red blood cells, continuously evading host immunity using epigenetically regulated antigenic variation of virulence-associated genes. Parasite survival on a population level also requires differentiation into sexual forms, an obligatory step for further human transmission. We reveal that the essential nuclear gene, P. falciparum histone deacetylase 2 (PfHda2), is a global silencer of virulence gene expression and controls the frequency of switching from the asexual cycle to sexual development. PfHda2 depletion leads to dysregulated expression of both virulence-associated var genes and PfAP2-g, a transcription factor controlling sexual conversion, and is accompanied by increases in gametocytogenesis. Mathematical modeling further indicates that PfHda2 has likely evolved to optimize the parasite’s infectious period by achieving low frequencies of virulence gene expression switching and sexual conversion. This common regulation of cellular transcriptional programs mechanistically links parasite transmissibility and virulence

Potential Biomarkers, Risk Factors and their Associations with IgE-mediated Food Allergy in Early Life: A Narrative Review

Food allergy affects the quality of life of millions of people worldwide and presents a significant psychological and financial burden for both national and international public health. In the past few decades, the prevalence of allergic disease has been on the rise worldwide. Identified risk factors for food allergy include family history, mode of delivery, variations in infant feeding practices, prior diagnosis of other atopic diseases such as eczema, and social economic status. Identifying reliable biomarkers which predict the risk of developing food allergy in early life would be valuable in both preventing morbidity and mortality and by making current interventions available at the earliest opportunity. There is also the potential to identify new therapeutic targets. This narrative review provides details on the genetic, epigenetic, dietary and microbiome influences upon the development of food allergy and synthesizes the currently available data indicating potential biomarkers. While there is a large body of research evidence available within each field of potential risk factors, there are very limited number of studies which span multiple methodological fields, for example including immunology, microbiome, genetic/epigenetic factors and dietary assessment. We recommend that further collaborative research with detailed cohort phenotyping is required to identify biomarkers, and whether these vary between at-risk populations and the wider population. The low incidence of oral food challenge confirmed food allergy in the general population, and the complexities of designing nutritional intervention studies will provide challenges for researchers to address in generating high quality, reliable and reproducible research findings.\nFood allergy affects the quality of life of millions of people worldwide and presents a significant psychological and financial burden for both national and international public health. Identifying reliable biomarkers which predict the risk of developing food allergy would be valuable in both preventing morbidity and mortality and by making current interventions available at the earliest opportunity. This review provides details on the genetic, epigenetic, dietary and microbiome influences upon the development of food allergy. This helps in identifying reliable biomarkers to predict the risk of developing food allergy, which could be valuable in both preventing morbidity and mortality and by making interventions available at the earliest opportunity.</p

Impact of ageing and a synbiotic on the immune response to seasonal influenza vaccination; a randomised controlled trial

Background & Aims Ageing increases risk of respiratory infections and impairs the response to influenza vaccination. Pre- and probiotics offer an opportunity to modulate anti-viral defenses and the response to vaccination via alteration of the gut microbiota. This study investigated the effect of a novel probiotic, Bifidobacterium longum bv. infantis CCUG 52486, combined with a prebiotic, gluco-oligosaccharide, on the B and T cell response to seasonal influenza vaccination in young and older subjects. Methods In a double-blind, randomized controlled trial, 58 young (18-35y) and 54 older (60-85y) subjects were supplemented with the synbiotic for 8 weeks. At 4 weeks they were administered with a seasonal influenza vaccine. B and T cell phenotype and responsiveness to in vitro re-stimulation with the vaccine were assessed at baseline, 4, 6 and 8 weeks. Results B and T cell profiles differed markedly between young and older subjects. Vaccination increased numbers of memory, IgA+ memory, IgG+ memory and total IgG+ B cells in young subjects, but failed to do so in older subjects and did not significantly alter T cell subsets. Seroconversion to the H1N1 subunit in the older subjects was associated with higher post-vaccination numbers of plasma B cells, but seroconversion was less consistently associated with T cell phenotype. B and T cell subsets from both young and older subjects demonstrated a strong antigen-specific recall challenge, and although not influenced by age, responsiveness to the recall challenge was associated with seroconversion. In older subjects, CMV seropositivity was associated with a significantly lower recall response to the vaccine, but the synbiotic did not affect the responsiveness of B or T cells to re-stimulation with influenza vaccine. Conclusions Antigen-specific B and T cell activation following an in vitro recall challenge with the influenza vaccine was influenced by CMV seropositivity, but not by a synbiotic

Diagnostic accuracy of the vegetative and minimally conscious state: Clinical consensus versus standardized neurobehavioral assessment

BACKGROUND: Previously published studies have reported that up to 43% of patients with disorders of consciousness are erroneously assigned a diagnosis of vegetative state (VS). However, no recent studies have investigated the accuracy of this grave clinical diagnosis. In this study, we compared consensus-based diagnoses of VS and MCS to those based on a well-established standardized neurobehavioral rating scale, the JFK Coma Recovery Scale-Revised (CRS-R). METHODS: We prospectively followed 103 patients (55 +/- 19 years) with mixed etiologies and compared the clinical consensus diagnosis provided by the physician on the basis of the medical staff's daily observations to diagnoses derived from CRS-R assessments performed by research staff. All patients were assigned a diagnosis of 'VS', 'MCS' or 'uncertain diagnosis.' RESULTS: Of the 44 patients diagnosed with VS based on the clinical consensus of the medical team, 18 (41%) were found to be in MCS following standardized assessment with the CRS-R. In the 41 patients with a consensus diagnosis of MCS, 4 (10%) had emerged from MCS, according to the CRS-R. We also found that the majority of patients assigned an uncertain diagnosis by clinical consensus (89%) were in MCS based on CRS-R findings. CONCLUSION: Despite the importance of diagnostic accuracy, the rate of misdiagnosis of VS has not substantially changed in the past 15 years. Standardized neurobehavioral assessment is a more sensitive means of establishing differential diagnosis in patients with disorders of consciousness when compared to diagnoses determined by clinical consensus

Evolutionary consequences of feedbacks between within-host competition and disease control

Lay Summary: Competition often occurs among diverse parasites within a single host, but control efforts could change its strength. We examined how the interplay between competition and control could shape the evolution of parasite traits like drug resistance and disease severity