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BackgroundClostridioides difficile is the leading cause of hospital-acquired gastrointestinal infection, in part due to the existence of binary toxin (CDT)-expressing hypervirulent strains. Although the effects of the CDT holotoxin on disease pathogenesis have been previously studied, we sought to investigate the role of the individual components of CDT during in vivo infection.MethodsTo determine the contribution of the separate components of CDT during infection, we developed strains of C difficile expressing either CDTa or CDTb individually. We then infected both mice and hamsters with these novel mutant strains and monitored them for development of severe illness.ResultsAlthough expression of CDTb without CDTa did not induce significant disease in a mouse model of C difficile infection, we found that complementation of a CDT-deficient C difficile strain with CDTb alone restored virulence in a hamster model of C difficile infection.ConclusionsOverall, this study demonstrates that the binding component of C difficile binary toxin, CDTb, contributes to virulence in a hamster model of infection.

Clostridioides difficile infection (CDI) represents a significant burden on the health care system, one that is exacerbated by the emergence of binary toxin (CDT)-producing hypervirulent C. difficile strains. Previous work from our laboratory has shown that Toll-like receptor 2 (TLR2) recognizes CDT to induce inflammation. Here we explore the interactions of CDT with TLR2 and the impact on host immunity during CDI. We found that the TLR2/6 heterodimer, not TLR2/1, is responsible for CDT recognition, and that gene pathways including nuclear factor-κB and MAPK downstream of TLR2/6 are upregulated in mice with intact TLR2/6 signaling during CDI.

Clostridioides difficile is the leading cause of hospital-acquired gastrointestinal infection, in part due to the existence of binary toxin (CDT)-expressing hypervirulent strains. We have previously shown that CDT interacts with the TLR2/6 heterodimer to induce inflammation, and in this study we further explore this interaction as well as the contribution of the separate components of CDT, CDTa and CDTb. We found that the binding component, CDTb, is capable of inducing inflammation. Additionally, complementation of a CDT-deficient C. difficile strain with CDTb alone restored virulence in a hamster model of C. difficile infection. Overall, this study demonstrates that the binding component of C. difficile binary toxin contributes to virulence during infection.

The main objective of this paper to show the potential of multitemporal Sentinel-1 (S-1) and Sentinel-2 (S-2) for detection of water hyacinth in Indian wetlands. Water hyacinth (Pontederia crassipes, also called Eichhornia crassipes) is one of the most destructive invasive weed species in many lakes and river systems worldwide, causing significant adverse economic and ecological impacts. We use the expectation maximization (EM) as a benchmark machine learning algorithm and compare its results with three supervised machine learning classifiers, Support Vector Machine (SVM), Random Forest (RF), and k-Nearest Neighbour (kNN), using both synthetic aperture radar (SAR) and optical data to distinguish between clean and infested waters.

Plastics within the ocean have been found to be colonised by microorganisms that, as a by-product of their metabolism, produce surfactants. Short capillary waves on the sea surface can get dampened due to the increased surface elasticity of these surfactants. Radar satellites are sensitive to surface roughness and can therefore detect the dampening of these waves. This research investigates areas inside the Atlantic, Pacific and Indian Ocean gyres using ESA Sentinel-1 and DLR TerraSAR-X data. We found out that we can observe several surfactant instances in the gyres and these are not correlated to medium or high level of chlorophyll. We can exclude that they have origin in biogenic slicks. Among other possible unknown origins, we hypothesise that these surfactants are produced from plastic concentrations within the ocean.

Toll-like receptor 2 (TLR2) recognizes and responds to threats early on in bacterial infections and can influence the downstream immune response to the host’s benefit or detriment. Therapeutically modulating TLR2 signaling represents an under-utilized opportunity to moderate the immune response to infection to promote improved outcome for the host.

Water Hyacinth is an aquatic macrophyte and highly invasive species, indigenous to Amazonia, Brazil and tropical South America. It was first introduced to India in 1896 and has now become and environmental and social nuisance throughout the country in community ponds, freshwater lakes, irrigation channels, rivers and most other surface waterbodies. Considering the adverse impact the infesting weed has, a constant monitoring is needed to aid policy makers involved in remedial measures. Due to the synoptic coverage provided by satellite imaging and other remote sensing practices, it is convenient to find a solution using this type of data. This paper looks at the use of Synthetic Aperture Radar (SAR) Sentinel-1 to detect water hyacinth at an early stage of its life-cycle. While SAR has been used prominently to monitor wetlands, the technique is yet to be fully exploited for monitoring water hyacinth and we seek to fill this knowledge gap. We compare different change detection methodologies based on dual po-larimetric data. We also demonstrate how Sentinel-1 can be used to monitor this type of aquatic weeds in our study areas, which is Vembanad Lake in Kuttanad, Kerala.

Clostridioides difficile infection (CDI) represents a significant burden on the health care system, one that is exacerbated by the emergence of binary toxin (CDT)-producing hypervirulent C. difficile strains. Previous work from our lab has shown that TLR2 recognizes CDT to induce inflammation. Here we explore the interactions of CDT with TLR2 and the impact on host immunity during CDI. We found that the TLR2/6 heterodimer, not TLR2/1, is responsible for CDT recognition, and that gene pathways including NF-κB and MAPK downstream of TLR2/6 are upregulated in mice with intact TLR2/6 signaling during CDI.

The gut microbiome provides resistance to infection. However, the mechanisms for this are poorly understood. Colonization with the intestinal bacteriumClostridium scindensprovided protection from the parasiteEntamoeba histolyticavia innate immunity. Introduction ofC. scindensinto the gut microbiota epigenetically altered and expanded bone marrow granulocyte-monocyte-progenitors (GMPs) and provided neutrophil-mediated protection against subsequent challenge withE. histolytica. Adoptive transfer of bone-marrow fromC. scindenscolonized-mice into naïve-mice protected against ameba infection and increased intestinal neutrophils. Because of the known ability ofC. scindensto metabolize the bile salt cholate, we measured deoxycholate and discovered that it was increased in the sera ofC. scindenscolonized mice, as well as in children protected from amebiasis. Administration of deoxycholate alone (in the absence ofC. scindens) increased the epigenetic mediator JMJD3 and GMPs and provided protection from amebiasis. In conclusion the microbiota was shown to communicate to the bone marrow via microbially-metabolized bile salts to train innate immune memory to provide antigen-nonspecific protection from subsequent infection. This represents a novel mechanism by which the microbiome protects from disease.One Sentence SummaryIntroduction of the human commensal bacteriaClostridium scindensinto the intestinal microbiota epigenetically alters bone marrow and protects from future parasite infection.

Clostridium difficile (C. difficile) incidence has tripled over the past 15 years and is attributed to the emergence of hypervirulent strains. While it is clear that C. difficile toxins cause damaging colonic inflammation, the immune mechanisms protecting from tissue damage require further investigation. Through a transcriptome analysis, we identify IL-33 as an immune target upregulated in response to hypervirulent C. difficile. We demonstrate that IL-33 prevents C. difficile-associated mortality and epithelial disruption independently of bacterial burden or toxin expression. IL-33 drives colonic group 2 innate lymphoid cell (ILC2) activation during infection and IL-33 activated ILC2s are sufficient to prevent disease. Furthermore, intestinal IL-33 expression is regulated by the microbiota as fecal microbiota transplantation (FMT) rescues antibiotic-associated depletion of IL-33. Lastly, dysregulated IL-33 signaling via the decoy receptor, sST2, predicts C. difficile-associated mortality in human patients. Thus, IL-33 signaling to ILC2s is an important mechanism of defense from C. difficile colitis., Here, Frisbee et al. show that hypervirulent Clostridium difficile induces IL-33 expression in the gut and IL-33 reduces mortality and morbidity via group 2 innate lymphoid cells. Furthermore, serum levels of the soluble IL-33 decoy receptor, sST2, are associated with enhanced disease severity in human C. difficile patients.

Clostridiodes difficile infection (CDI) is the leading cause of hospital-acquired gastrointestinal infections in the U.S. While the immune response to C. difficile is not well understood, it has been shown that severe disease is accompanied by high levels of infiltrating immune cells and pro-inflammatory cytokine production. This study tests the roles of two type 2 cytokines, IL-4 and IL-5, in mediating protection in a murine model of disease. Administration of IL-5 protected from mortality due to CDI, and both IL-4 and IL-5 were protective against severe disease symptoms. Together, the results from this study increase our understanding of how type 2 immune signaling processes are protective from severe C. difficile infection.

Compounds that target isoprenoid biosynthesis in Plasmodium falciparum could be a welcome addition to malaria chemotherapy, since the methylerythritol phosphate (MEP) pathway used by the parasite is not present in humans. We previously reported that MMV008138 targets the apicoplast of P. falciparum and that its target in the MEP pathway differs from that of Fosmidomycin. In this Letter, we determine that the active stereoisomer of MMV008138 is 4a , which is (1 R ,3 S )-configured. 2′,4′-Disubstitution of the D ring was also found to be crucial for inhibition of the parasite growth. Limited variation of the C3-carboxylic acid substituent was carried out, and methylamide derivative 8a was found to be more potent than 4a ; other amides, acylhydrazines, and esters were less potent. Finally, lead compounds 4a , 4e , 4f , 4h , 8a , and 8e did not inhibit growth of Escherichia coli , suggesting that protozoan-selective inhibition of the MEP pathway of P. falciparum can be achieved.

Malaria continues to be one of the deadliest diseases worldwide, and the emergence of drug resistance parasites is a constant threat. Plasmodium parasites utilize the methylerythritol phosphate (MEP) pathway to synthesize isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), which are essential for parasite growth. Previously, we and others identified that the Malaria Box compound MMV008138 targets the apicoplast and that parasite growth inhibition by this compound can be reversed by supplementation of IPP. Further work has revealed that MMV008138 targets the enzyme 2-C-methyl-D-erythritol 4-phosphate cytidylyltransferase (IspD) in the MEP pathway, which converts MEP and cytidine triphosphate (CTP) to cytidinediphosphate methylerythritol (CDP-ME) and pyrophosphate. In this work, we sought to gain insight into the structure–activity relationships by probing the ability of MMV008138 analogs to inhibit Pf IspD recombinant enzyme. Here, we report Pf IspD inhibition data for fosmidomycin (FOS) and 19 previously disclosed analogs and report parasite growth and Pf IspD inhibition data for 27 new analogs of MMV008138. In addition, we show that MMV008138 does not target the recently characterized human IspD, reinforcing MMV008138 as a prototype of a new class of species-selective IspD-targeting antimalarial agents.