Recent scholarship has found evidence that refugee flows may inadvertently contribute to the spread of conflict across borders. Little is known, however, about the spatial diffusion of conflict ...within a state’s borders and what role internal displacement plays in such a dynamic. This question is of relevance because of the particular marginalization of internally displaced persons, which make them at risk of predation and militarization by armed groups. Drawing on a novel global data set on internal displacement, we evaluate this question and find evidence for a similar mechanism leading to conflict spread operating at the domestic level.
The human fetal immune system begins to develop early during gestation; however, factors responsible for fetal immune-priming remain elusive. We explored potential exposure to microbial agents in ...utero and their contribution toward activation of memory T cells in fetal tissues. We profiled microbes across fetal organs using 16S rRNA gene sequencing and detected low but consistent microbial signal in fetal gut, skin, placenta, and lungs in the 2nd trimester of gestation. We identified several live bacterial strains including Staphylococcus and Lactobacillus in fetal tissues, which induced in vitro activation of memory T cells in fetal mesenteric lymph node, supporting the role of microbial exposure in fetal immune-priming. Finally, using SEM and RNA-ISH, we visualized discrete localization of bacteria-like structures and eubacterial-RNA within 14th weeks fetal gut lumen. These findings indicate selective presence of live microbes in fetal organs during the 2nd trimester of gestation and have broader implications toward the establishment of immune competency and priming before birth.
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•Human fetuses in 2nd trimester show T cell diversity with effector-memory phenotype•Fetal organs show diverse bacterial genera that can be cultured and propagated•Bacterial structures with mucin-like threads are visualized in 14-weeks EGA fetal gut•Fetal bacteria induce syngeneic memory T cell activation in fetal mLN T cells
Analysis of human fetal tissues and the placenta in the 2nd trimester of gestation identifies live bacterial strains that are able to induce the activation of memory T cells in the fetal mesenteric lymph node, thus providing insights into early life immunity.
Due to limited mobility, fungi, like most unicellular organisms, have evolved mechanisms to adapt to sudden chemical and/or physical variation in their environment.
is recognized as a model organism ...to study eukaryotic responses to environmental changes, as this human commensal yeast but also opportunistic pathogen responds to numerous environmental cues through switching morphologies from yeast to hyphae growth. This mechanism is largely controlled by two major pathways: cAMP-PKA and MAPK, but each environmental signal is sensed by specific sensors. However, morphological switching is not the only response
exerts in response to environmental cues. Recently, fungal cell wall remodeling in response to host-derived environmental cues has been identified as a way for
to manipulate the innate immune system. The fungal cell wall is composed of a chitin skeleton linked to a network of β-glucan, which anchors proteins and mannans to the fungal cell surface. As localized on the cell surface, these molecules drive interactions with the environment and other cells, particularly with host immune cells.
is recognized by immune cells such as neutrophils and macrophages via pathogen recognition receptors (PRRs) that bind different components of the cell wall. While β-glucan and mannan are proinflammatory molecules, chitin can induce anti-inflammatory responses. Interestingly,
is able to regulate the exposure of these pathogen-associated molecular patterns (PAMPs) according to environmental cues resulting in a modulation of the host immune response. This review describes the mechanisms involved in
response to environmental changes and their effect on immune recognition.
is a commensal yeast of the human gut which is tolerated by the immune system but has the potential to become an opportunistic pathogen. One way in which
achieves this duality is through concealing ...or exposing cell wall pathogen-associated molecular patterns (PAMPs) in response to host-derived environment cues (pH, hypoxia, and lactate). This cell wall remodeling allows
to evade or hyperactivate the host's innate immune responses, leading to disease. Previously, we showed that adaptation of
to acidic environments, conditions encountered during colonization of the female reproductive tract, induces significant cell wall remodeling resulting in the exposure of two key fungal PAMPs (β-glucan and chitin). Here, we report that this pH-dependent cell wall remodeling is time dependent, with the initial change in pH driving cell wall unmasking, which is then remasked at later time points. Remasking of β-glucan was mediated via the cell density-dependent fungal quorum sensing molecule farnesol, while chitin remasking was mediated via a small, heat-stable, nonproteinaceous secreted molecule(s). Transcript profiling identified a core set of 42 genes significantly regulated by pH over time and identified the transcription factor Efg1 as a regulator of chitin exposure through regulation of
This dynamic cell wall remodeling influenced innate immune recognition of
, suggesting that during infection,
can manipulate the host innate immune responses.
is part of the microbiota of the skin and gastrointestinal and reproductive tracts of humans and has coevolved with us for millennia. During that period,
has developed strategies to modulate the host's innate immune responses, by regulating the exposure of key epitopes on the fungal cell surface. Here, we report that exposing
to an acidic environment, similar to the one of the stomach or vagina, increases the detection of the yeast by macrophages. However, this effect is transitory, as
is able to remask these epitopes (glucan and chitin). We found that glucan remasking is controlled by the production of farnesol, a molecule secreted by
in response to high cell densities. However, chitin-remasking mechanisms remain to be identified. By understanding the relationship between environmental sensing and modulation of the host-pathogen interaction, new opportunities for the development of innovative antifungal strategies are possible.
Msb2 is a sensor protein in the plasma membrane of fungi. In the human fungal pathogen C. albicans Msb2 signals via the Cek1 MAP kinase pathway to maintain cell wall integrity and allow filamentous ...growth. Msb2 doubly epitope-tagged in its large extracellular and small cytoplasmic domain was efficiently cleaved during liquid and surface growth and the extracellular domain was almost quantitatively released into the growth medium. Msb2 cleavage was independent of proteases Sap9, Sap10 and Kex2. Secreted Msb2 was highly O-glycosylated by protein mannosyltransferases including Pmt1 resulting in an apparent molecular mass of >400 kDa. Deletion analyses revealed that the transmembrane region is required for Msb2 function, while the large N-terminal and the small cytoplasmic region function to downregulate Msb2 signaling or, respectively, allow its induction by tunicamycin. Purified extracellular Msb2 domain protected fungal and bacterial cells effectively from antimicrobial peptides (AMPs) histatin-5 and LL-37. AMP inactivation was not due to degradation but depended on the quantity and length of the Msb2 glycofragment. C. albicans msb2 mutants were supersensitive to LL-37 but not histatin-5, suggesting that secreted rather than cell-associated Msb2 determines AMP protection. Thus, in addition to its sensor function Msb2 has a second activity because shedding of its glycofragment generates AMP quorum resistance.
The human microbiota provides tonic signals that calibrate the host immune response
, but their identity is unknown. Bacterial peptidoglycan (PGN) subunits are likely candidates since they are ...well-known immunity-enhancing adjuvants, released by most bacteria during growth, and have been found in the blood of healthy people
. We developed a monoclonal antibody (mAb), 2E7, that targets muramyl-L-alanyl-D-isoglutamine (MDP), a conserved and minimal immunostimulatory structure of PGN. Using 2E7-based assays, we detected PGN ubiquitously in human blood at a broad range of concentrations that is relatively stable in each individual. We also detected PGN in the serum of several warm-blooded animals. However, PGN is barely detectable in the serum of germ-free mice, indicating that its origin is the host microbiota. Neutralization of circulating PGN via intraperitoneal administration of 2E7 suppressed the development of autoimmune arthritis and experimental autoimmune encephalomyelitis in mice. Arthritic NOD2
mice lacking the MDP sensor did not respond to 2E7, indicating that 2E7 dampens inflammation by blocking nucleotide-binding oligomerization domain-containing protein 2 (NOD2)-mediated pathways. We propose that circulating PGN acts as a natural immune potentiator that tunes the host immune response; altering its level is a promising therapeutic strategy for immune-mediated diseases.
•We examine the effect of climate variability on irregular migration to the EU.•We find that drought decreases the level of irregular migration.•This effects is observed in particular for agrarian ...countries.
The so-called ‘European Migrant Crisis’ has been blamed on armed conflict and economic misery, particularly in the Middle East and Sub-Saharan Africa. Some have suggested that this process has been exacerbated by climate change and weather events. In this paper, we evaluate these claims, focusing on the role of droughts in influencing irregular migration flows to the European Union. Drawing on temporally disaggregated data on the detection of unauthorized migrants at EU external borders, we examine how weather shocks affect irregular migration. We show that weather events may indeed influence migration. Yet, in contradiction to the findings from recent research, we find no evidence that a drought in a sending country increases unauthorized migration to the EU. If anything, and while not entirely conclusive, the incidence of drought seems rather to exert a negative, albeit moderate, impact on the size of migration flows, in particular for countries dependent on agriculture. Conversely, higher levels of rainfall increase migration. We interpret this as evidence that international migration is cost-prohibitive, and that adverse weather shocks reinforce existing financial barriers to migration.
Sequencing-based microbiome profiling aims at detecting and quantifying individual members of a microbial community in a culture-independent manner. While amplicon-based sequencing (ABS) of bacterial ...or fungal ribosomal DNA is the most widely used technology due to its low cost, it suffers from PCR amplification biases that hinder accurate representation of microbial population structures. Shotgun metagenomics (SMG) conversely allows unbiased microbiome profiling but requires high sequencing depth. Here we report the development of a meta-total RNA sequencing (MeTRS) method based on shotgun sequencing of total RNA and benchmark it on a human stool sample spiked in with known abundances of bacterial and fungal cells. MeTRS displayed the highest overall sensitivity and linearity for both bacteria and fungi, the greatest reproducibility compared to SMG and ABS, while requiring a ~20-fold lower sequencing depth than SMG. We therefore present MeTRS as a valuable alternative to existing technologies for large-scale profiling of complex microbiomes.
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