Critical Roles for LIGHT and Its Receptors in Generating T Cell-Mediated Immunity during Leishmania donovani Infection

LIGHT (TNFSF14) is a member of the TNF superfamily involved in inflammation and defence against infection. LIGHT signals via two cell-bound receptors; herpes virus entry mediator (HVEM) and lymphotoxin-beta receptor (LTβR). We found that LIGHT is critical for control of hepatic parasite growth in mice with visceral leishmaniasis (VL) caused by infection with the protozoan parasite Leishmania donovani. LIGHT-HVEM signalling is essential for early dendritic cell IL-12/IL-23p40 production, and the generation of IFNγ- and TNF-producing T cells that control hepatic infection. However, we also discovered that LIGHT-LTβR interactions suppress anti-parasitic immunity in the liver in the first 7 days of infection by mechanisms that restrict both CD4+ T cell function and TNF-dependent microbicidal mechanisms. Thus, we have identified distinct roles for LIGHT in infection, and show that manipulation of interactions between LIGHT and its receptors may be used for therapeutic advantage

Oligomeric states in sodium ion-dependent regulation of cyanobacterial histidine kinase-2

IMI thanks Queen Mary University of London for a graduate teaching studentship. LW thanks the China Scholarship Council (CSC) and Queen Mary University of London for financial support. SP held a Leverhulme Trust early-career post-doctoral research fellowship. JN is grateful for the continued support of the JST CREST Grant Number JPMJCR13M4, Japan. JFA acknowledges the support of research grant F/07 476/AQ and fellowship EM-2015-068 of the Leverhulme Trust

Structure of the Extracellular Portion of CD46 Provides Insights into Its Interactions with Complement Proteins and Pathogens

The human membrane cofactor protein (MCP, CD46) is a central component of the innate immune system. CD46 protects autologous cells from complement attack by binding to complement proteins C3b and C4b and serving as a cofactor for their cleavage. Recent data show that CD46 also plays a role in mediating acquired immune responses, and in triggering autophagy. In addition to these physiologic functions, a significant number of pathogens, including select adenoviruses, measles virus, human herpes virus 6 (HHV-6), Streptococci, and Neisseria, use CD46 as a cell attachment receptor. We have determined the crystal structure of the extracellular region of CD46 in complex with the human adenovirus type 11 fiber knob. Extracellular CD46 comprises four short consensus repeats (SCR1-SCR4) that form an elongated structure resembling a hockey stick, with a long shaft and a short blade. Domains SCR1, SCR2 and SCR3 are arranged in a nearly linear fashion. Unexpectedly, however, the structure reveals a profound bend between domains SCR3 and SCR4, which has implications for the interactions with ligands as well as the orientation of the protein at the cell surface. This bend can be attributed to an insertion of five hydrophobic residues in a SCR3 surface loop. Residues in this loop have been implicated in interactions with complement, indicating that the bend participates in binding to C3b and C4b. The structure provides an accurate framework for mapping all known ligand binding sites onto the surface of CD46, thereby advancing an understanding of how CD46 acts as a receptor for pathogens and physiologic ligands of the immune system

Malic Enzyme and Malolactic Enzyme Pathways Are Functionally Linked but Independently Regulated in Lactobacillus casei BL23

Lactobacillus casei is the only lactic acid bacterium in which two pathways for l-malate degradation have been described: the malolactic enzyme (MLE) and the malic enzyme (ME) pathways. Whereas the ME pathway enables L. casei to grow on l-malate, MLE does not support growth. The mle gene cluster consists of three genes encoding MLE (mleS), the putative l-malate transporter MleT, and the putative regulator MleR. The mae gene cluster consists of four genes encoding ME (maeE), the putative transporter MaeP, and the two-component system MaeKR. Since both pathways compete for the same substrate, we sought to determine whether they are coordinately regulated and their role in l-malate utilization as a carbon source. Transcriptional analyses revealed that the mle and mae genes are independently regulated and showed that MleR acts as an activator and requires internalization of l-malate to induce the expression of mle genes. Notwithstanding, both l-malate transporters were required for maximal l-malate uptake, although only an mleT mutation caused a growth defect on l-malate, indicating its crucial role in l-malate metabolism. However, inactivation of MLE resulted in higher growth rates and higher final optical densities on l-malate. The limited growth on l-malate of the wild-type strain was correlated to a rapid degradation of the available l-malate to l-lactate, which cannot be further metabolized. Taken together, our results indicate that L. casei l-malate metabolism is not optimized for utilization of l-malate as a carbon source but for deacidification of the medium by conversion of l-malate into l-lactate via MLE

Cast production and NIR spectral signatures of Aporrectodea caliginosa fed soil with different amounts of half-decomposed Populus nigra litter

Sub-adult individuals of Aporrectodea caliginosa were incubated for 16 weeks under laboratory cultures in a soil treated with 0%, 10% or 50% of a Populus nigra half-decomposed leaves, respectively. Growth was maximum in the 50% organic matter treatment and cocoon production occurred. Average soil ingestion rates decreased from 1.56 g/g(-1) fresh weight of worm per day(-1) in control soil to 1.17 and 0.5 g, respectively, in treatments with 10% and 50% half-decomposed litter. Surface casts never comprised more than 10% of total cast production. Near-infrared spectrometry (NIRS)signatures of digested and non-ingested soil significantly differed and showed a rather constant effect of digestion, independent of the organic matter content (p < 0.01). These results confirm the value of NIRS spectral signatures as indicators of the origin of soil aggregates and biological processes involved in soil aggregation

Domain shuffling in a sensor protein contributed to the evolution of insect pathogenicity in plant-beneficial Pseudomonas protegens.

Pseudomonas protegens is a biocontrol rhizobacterium with a plant-beneficial and an insect pathogenic lifestyle, but it is not understood how the organism switches between the two states. Here, we focus on understanding the function and possible evolution of a molecular sensor that enables P. protegens to detect the insect environment and produce a potent insecticidal toxin specifically during insect infection but not on roots. By using quantitative single cell microscopy and mutant analysis, we provide evidence that the sensor histidine kinase FitF is a key regulator of insecticidal toxin production. Our experimental data and bioinformatic analyses indicate that FitF shares a sensing domain with DctB, a histidine kinase regulating carbon uptake in Proteobacteria. This suggested that FitF has acquired its specificity through domain shuffling from a common ancestor. We constructed a chimeric DctB-FitF protein and showed that it is indeed functional in regulating toxin expression in P. protegens. The shuffling event and subsequent adaptive modifications of the recruited sensor domain were critical for the microorganism to express its potent insect toxin in the observed host-specific manner. Inhibition of the FitF sensor during root colonization could explain the mechanism by which P. protegens differentiates between the plant and insect host. Our study establishes FitF of P. protegens as a prime model for molecular evolution of sensor proteins and bacterial pathogenicity