Global increases in coral disease prevalence have been linked to ocean warming through changes in coral‐associated bacterial communities, pathogen virulence and immune system function. However, the ...interactive effects of temperature and pathogens on the coral holobiont are poorly understood. Here, we assessed three compartments of the holobiont (host, Symbiodinium and bacterial community) of the coral Montipora aequituberculata challenged with the pathogen Vibrio coralliilyticus and the commensal bacterium Oceanospirillales sp. under ambient (27°C) and elevated (29.5 and 32°C) seawater temperatures. Few visual signs of bleaching and disease development were apparent in any of the treatments, but responses were detected in the holobiont compartments. V. coralliilyticus acted synergistically and negatively impacted the photochemical efficiency of Symbiodinium at 32°C, while Oceanospirillales had no significant effect on photosynthetic efficiency. The coral, however, exhibited a minor response to the bacterial challenges, with the response towards V. coralliilyticus being significantly more pronounced, and involving the prophenoloxidase‐activating system and multiple immune system‐related genes. Elevated seawater temperatures did not induce shifts in the coral‐associated bacterial community, but caused significant gene expression modulation in both Symbiodinium and the coral host. While Symbiodinium exhibited an antiviral response and upregulated stress response genes, M. aequituberculata showed regulation of genes involved in stress and innate immune response processes, including immune and cytokine receptor signalling, the complement system, immune cell activation and phagocytosis, as well as molecular chaperones. These observations show that M. aequituberculata is capable of maintaining a stable bacterial community under elevated seawater temperatures and thereby contributes to preventing disease development.
Plants are important in urban environments for removing pathogens and improving water quality. Seagrass meadows are the most widespread coastal ecosystem on the planet. Although these plants are ...known to be associated with natural biocide production, they have not been evaluated for their ability to remove microbiological contamination. Using amplicon sequencing of the 16S ribosomal RNA gene, we found that when seagrass meadows are present, there was a 50% reduction in the relative abundance of potential bacterial pathogens capable of causing disease in humans and marine organisms. Moreover, field surveys of more than 8000 reef-building corals located adjacent to seagrass meadows showed twofold reductions in disease levels compared to corals at paired sites without adjacent seagrass meadows. These results highlight the importance of seagrass ecosystems to the health of humans and other organisms.
Immune abnormalities have been described in some individuals with autism spectrum disorders (ASDs) as well as their family members. However, few studies have directly investigated the role of ...prenatal cytokine and chemokine profiles on neurodevelopmental outcomes in humans. In the current study, we characterized mid-gestational serum profiles of 22 cytokines and chemokines in mothers of children with ASD (N=415), developmental delay (DD) without ASD (N=188), and general population (GP) controls (N=428) using a bead-based multiplex technology. The ASD group was further divided into those with intellectual disabilities (developmental/cognitive and adaptive composite score<70) (ASD+ID, N=184) and those without (composite score⩾70) (ASD-noID, N=201). Levels of cytokines and chemokines were compared between groups using multivariate logistic regression analyses, adjusting for maternal age, ethnicity, birth country and weight, as well as infant gender, birth year and birth month. Mothers of children with ASD+ID had significantly elevated mid-gestational levels of numerous cytokines and chemokines, such as granulocyte macrophage colony-stimulating factor, interferon-γ, interleukin-1α (IL-1α) and IL-6, compared with mothers of children with either ASD-noID, those with DD, or GP controls. Conversely, mothers of children with either ASD-noID or with DD had significantly lower levels of the chemokines IL-8 and monocyte chemotactic protein-1 compared with mothers of GP controls. This observed immunologic distinction between mothers of children with ASD+ID from mothers of children with ASD-noID or DD suggests that the intellectual disability associated with ASD might be etiologically distinct from DD without ASD. These findings contribute to the ongoing efforts toward identification of early biological markers specific to subphenotypes of ASD.
Gorgonians are important habitat-providing species in the Mediterranean Sea, but their populations are declining due to microbial diseases and repeated mass mortality events caused by summer heat ...waves. Elevated seawater temperatures may impact the stress tolerance and disease resistance of gorgonians and lead to disturbances in their microbiota. However, our knowledge of the biological response of the gorgonian holobiont (
the host and its microbiota) to thermal stress remains limited. Here, we investigated how the holobiont of two gorgonian species (
and
) are affected throughout a 7-week thermal stress event by following both the corals' physiology and the composition of their bacterial communities. We found that
was more sensitive to elevated seawater temperatures than
, showing a greater loss in energy reserves, reduced feeding ability, and partial mortality. This lower thermotolerance may be linked to the ∼20× lower antioxidant defense capacity in
compared with
. In the first 4 weeks of thermal stress, we also observed minor shifts in the microbiota of both species, suggesting that the microbiota likely plays a limited role in thermal acclimation of the holobiont. However, major stochastic changes occurred later on in some colonies, which were of a transient nature in
, but were linked to partial colony mortality in
. Overall, our results show significant, but differential, effects of thermal stress on the holobionts of both
and
and predict potentially severe impacts on gorgonian populations under future climate scenarios.
In the Mediterranean Sea, the tree-shaped gorgonian corals form large forests that provide a place to live for many species. Because of this important ecological role, it is crucial to understand how common habitat-forming gorgonians, like
and
, are affected by high seawater temperatures that are expected in the future due to climate change. We found that both species lost biomass, but
was more affected, being also unable to feed and showing signs of mortality. The microbiota of both gorgonians also changed substantively under high temperatures. Although this could be linked to partial colony mortality in
, the changes were temporary in
The overall higher resistance of
may be related to its much higher antioxidant defense levels than
Climate change may thus have severe impacts on gorgonian populations and the habitats they provide.
Increasing physical damage on coral reefs from predation, storms and anthropogenic disturbances highlights the need to understand the impact of injury on the coral immune system. In this study, we ...examined the regulation of the coral immune response over 10 days following physical trauma artificially inflicted on in situ colonies of the coral Acropora aspera, simultaneously with bacterial colonization of the lesions. Corals responded to injury by increasing the expression of immune system‐related genes involved in the Toll‐like and NOD‐like receptor signalling pathways and the lectin–complement system in three phases (<2, 4 and 10 days post‐injury). Phenoloxidase activity was also significantly upregulated in two phases (<3 and 10 days post‐injury), as were levels of non‐fluorescent chromoprotein. In addition, green fluorescent protein expression was upregulated in response to injury from 4 days post‐injury, while cyan fluorescent protein expression was reduced. No shifts in the composition of coral‐associated bacterial communities were evident following injury based on 16S rRNA gene amplicon pyrosequencing. Bacteria‐specific fluorescence in situ hybridization also showed no evidence of bacterial colonization of the wound or regenerating tissues. Coral tissues showed near‐complete regeneration of lesions within 10 days. This study demonstrates that corals exhibit immune responses that support rapid recovery following physical injury, maintain coral microbial homeostasis and prevent bacterial infestation that may compromise coral fitness.
Octocorals are one of the most ubiquitous benthic organisms in marine ecosystems from the shallow tropics to the Antarctic deep sea, providing habitat for numerous organisms as well as ecosystem ...services for humans. In contrast to the holobionts of reef-building scleractinian corals, the holobionts of octocorals have received relatively little attention, despite the devastating effects of disease outbreaks on many populations. Recent advances have shown that octocorals possess remarkably stable bacterial communities on geographical and temporal scales as well as under environmental stress. This may be the result of their high capacity to regulate their microbiome through the production of antimicrobial and quorum-sensing interfering compounds. Despite decades of research relating to octocoral-microbe interactions, a synthesis of this expanding field has not been conducted to date. We therefore provide an urgently needed review on our current knowledge about octocoral holobionts. Specifically, we briefly introduce the ecological role of octocorals and the concept of holobiont before providing detailed overviews of (I) the symbiosis between octocorals and the algal symbiont Symbiodinium; (II) the main fungal, viral, and bacterial taxa associated with octocorals; (III) the dominance of the microbial assemblages by a few microbial species, the stability of these associations, and their evolutionary history with the host organism; (IV) octocoral diseases; (V) how octocorals use their immune system to fight pathogens; (VI) microbiome regulation by the octocoral and its associated microbes; and (VII) the discovery of natural products with microbiome regulatory activities. Finally, we present our perspectives on how the field of octocoral research should move forward, and the recognition that these organisms may be suitable model organisms to study coral-microbe symbioses.
The deregulation of the epidermal growth factor receptor (EGFR) has a significant role in the progression of tumors. Despite the development of a number of EGFR-targeting agents that can arrest tumor ...growth, their success in the clinic is limited in several tumor types, particularly in the highly malignant glioblastoma multiforme (GBM). In this study, we generated and characterized EGFR-specific nanobodies (ENb) and imageable and proapoptotic ENb immunoconjugates released from stem cells (SC) to ultimately develop a unique EGFR-targeted therapy for GBM. We show that ENbs released from SCs specifically localize to tumors, inhibit EGFR signaling resulting in reduced GBM growth and invasiveness in vitro and in vivo in both established and primary GBM cell lines. We also show that ENb primes GBM cells for proapoptotic tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Furthermore, SC-delivered immunoconjugates of ENb and TRAIL target a wide spectrum of GBM cell types with varying degrees of TRAIL resistance and significantly reduce GBM growth and invasion in both established and primary invasive GBM in mice. This study demonstrates the efficacy of SC-based EGFR targeted therapy in GBMs and provides a unique approach with clinical implications.
Autism spectrum disorders (ASDs) are neurodevelopmental in origin, affecting an estimated 1 in 88 children in the United States. We previously described ASD-specific maternal autoantibodies that ...recognize fetal brain antigens. Herein, we demonstrate that lactate dehydrogenase A and B (LDH), cypin, stress-induced phosphoprotein 1 (STIP1), collapsin response mediator proteins 1 and 2 (CRMP1, CRMP2) and Y-box-binding protein to comprise the seven primary antigens of maternal autoantibody-related (MAR) autism. Exclusive reactivity to specific antigen combinations was noted in 23% of mothers of ASD children and only 1% of controls. ASD children from mothers with specific reactivity to LDH, STIP1 and CRMP1 and/or cypin (7% vs 0% in controls; P<0.0002; odds ratios of 24.2 (95% confidence interval: 1.45-405)) had elevated stereotypical behaviors compared with ASD children from mothers lacking these antibodies. We describe the first panel of clinically significant biomarkers with over 99% specificity for autism risk thereby advancing our understanding of the etiologic mechanisms and therapeutic possibilities for MAR autism.
Summary
Dinitrogen (N2) fixing bacteria (diazotrophs) are an important source of new nitrogen in oligotrophic environments and represent stable members of the microbiome in tropical corals, while ...information on corals from temperate oligotrophic regions is lacking. Therefore, this study provides new insights into the diversity and activity of diazotrophs associated with the temperate coral Oculina patagonica from the Mediterranean Sea by combining metabarcoding sequencing of amplicons of both the 16S rRNA and nifH genes and 15N2 stable isotope tracer analysis to assess diazotroph‐derived nitrogen (DDN) assimilation by the coral. Results show that the diazotrophic community of O. patagonica is dominated by autotrophic bacteria (i.e. Cyanobacteria and Chlorobia). The majority of DDN was assimilated into the tissue and skeletal matrix, and DDN assimilation significantly increased in bleached corals. Thus, diazotrophs may constitute an additional nitrogen source for the coral host, when nutrient exchange with Symbiodinium is disrupted (e.g. bleaching) and external food supply is limited (e.g. oligotrophic summer season). Furthermore, we hypothesize that DDN can facilitate the fast proliferation of endolithic algae, which provide an alternative carbon source for bleached O. patagonica. Overall, O. patagonica could serve as a good model for investigating the importance of diazotrophs in coral recovery from bleaching.
The poor prognosis of patients with aggressive and invasive cancers combined with toxic effects and short half-life of currently available treatments necessitate development of more effective tumor ...selective therapies. Mesenchymal stem cells (MSCs) are emerging as novel cell-based delivery agents; however, a thorough investigation addressing their therapeutic potential and fate in different cancer models is lacking. In this study, we explored the engineering potential, fate, and therapeutic efficacy of human MSCs in a highly malignant and invasive model of glioblastoma. We show that engineered MSC retain their "stem-like" properties, survive longer in mice with gliomas than in the normal brain, and migrate extensively toward gliomas. We also show that MSCs are resistant to the cytokine tumor necrosis factor apoptosis ligand (TRAIL) and, when engineered to express secreted recombinant TRAIL, induce caspase-mediated apoptosis in established glioma cell lines as well as CD133-positive primary glioma cells in vitro. Using highly malignant and invasive human glioma models and employing real-time imaging with correlative neuropathology, we demonstrate that MSC-delivered recombinant TRAIL has profound anti-tumor effects in vivo. This study demonstrates the efficacy of diagnostic and therapeutic MSC in preclinical glioma models and forms the basis for developing stem cell-based therapies for different cancers.
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