Can we make human plague history? A call to action

Plague is a communicable rodent-borne disease caused by Yersinia pestis, a Gram-negative bacillus member of the Enterobacteriaceae family. As a zoonosis, plague is primarily a wildlife disease that occasionally spills over to the human population, resulting in seasonal surges in human cases and localised outbreaks. The predominant clinical form among humans is bubonic plague, which, if untreated, has a lethality of 60%–90% but is readily treatable with antibiotics, reducing the death rate to around 5% if administered shortly after the infection. One to two per cent of all bubonic cases develop into secondary pneumonic plague, which in turn may be transmitted from person to person through respiratory droplets, producing primary pneumonic plague in close contacts. Without antibiotic treatment, pneumonic plague is nearly 100% fatal, but early antibiotic treatment substantially improves survival. Today, Y. pestis is present in at least 26 countries, with more than 30 different flea vectors and over 200 mammal host species. Although human plague cases continue to be reported from Asia and the Americas, most cases currently occur in remote, rural areas of sub-Saharan Africa, mostly in Democratic Republic of Congo and Madagascar (around300–500 per year). However, large-scale transmission may also occur. During the 14th century, the Black Death, caused by Y. pestis, is estimated to have killed 30%–40% of the European population. It is important to emphasise that human plague is mostly a poverty-related disease. Therefore, given that population density and the absolute number of people living in extreme poverty are both increasing in sub-Saharan Africa, there is no likelihood of plague being eliminated as a public health threat in the foreseeable future. However, the WHO does not consider plague to be either a neglected tropical disease or a ‘priority pathogen’ that poses a public health risk because of its epidemic potential. In September 2017, an unprecedented urban outbreak of pneumonic plague was declared in Madagascar, striking primarily its capital Antananarivo and the major seaport of Toamasina. This episode once again brought international attention to plague, reminding us of the capacity for human plague to spread in urban settings and cause substantial societal and economic disruption. This should raise alarm bells that a research agenda is needed

Human plague: An old scourge that needs new answers

Yersinia pestis, the bacterial causative agent of plague, remains an important threat to human health. Plague is a rodent-borne disease that has historically shown an outstanding ability to colonize and persist across different species, habitats, and environments while provoking sporadic cases, outbreaks, and deadly global epidemics among humans. Between September and November 2017, an outbreak of urban pneumonic plague was declared in Madagascar, which refocused the attention of the scientific community on this ancient human scourge. Given recent trends and plague’s resilience to control in the wild, its high fatality rate in humans without early treatment, and its capacity to disrupt social and healthcare systems, human plague should be considered as a neglected threat. A workshop was held in Paris in July 2018 to review current knowledge about plague and to identify the scientific research priorities to eradicate plague as a human threat. It was concluded that an urgent commitment is needed to develop and fund a strong research agenda aiming to fill the current knowledge gaps structured around 4 main axes: (i) an improved understanding of the ecological interactions among the reservoir, vector, pathogen, and environment; (ii) human and societal responses; (iii) improved diagnostic tools and case management; and (iv) vaccine development. These axes should be cross-cutting, translational, and focused on delivering context-specific strategies. Results of this research should feed a global control and prevention strategy within a “One Health” approach

Cytosystematics, sex chromosome translocations and speciation in African mole-rats (Bathyergidae: Rodentia)

Thesis (PhD (Botany and Zoology))--University of Stellenbosch, 2008.The Bathyergidae are subterranean rodents endemic to Africa south of the Sahara. They are characterised by divergent diploid numbers that range from 2n=40 in Fukomys mechowi to 2n=78 in F. damarensis. In spite of this variation there is limited understanding of the events that shaped the extant karyotypes and in an attempt to address this, and to shed light on the mode and tempo of chromosomal evolution in the African mole-rats, a detailed analysis of both the autosomal and sex chromosome components of the genome was undertaken. In addition to G- and Cbanding, Heterocephalus glaber (2n=60) flow-sorted painting probes were used to conduct cross-species chromosome painting among bathyergids. This allowed the detection of a balanced sex chromosome-autosome translocation in F. mechowi that involved a complex series of rearrangements requiring fractionation of four H. glaber autosomes and the subsequent translocation of segments to sex chromosomes and to the autosomal partners. The fixation of this rare rearrangement has probably been favoured by the presence of an intercalary heterochromatic block (IHB) that was detected at the boundary with the translocated autosomal segment. Male meiosis in Cryptomys, the Fukomys sister clade, was investigated by immunostaining of the SCP1 and SCP3 proteins involved in the formation of the synaptonemal complex. This allowed confirmation of a Y-autosome translocation that is shared by C. hottentotus subspecies. We discuss reduced recombination between Y and X2 that seems to be heterochromatin dependent in the C hottentotus lineage, and the implications this holds for the evolution of a meiotic sex chromosome chain such as has been observed in platypus. By extending cross-species chromosome painting to Bathyergus janetta, F. damarensis, F. darlingi and Heliophobius argenteocinereus, homologous chromosomal regions across a total of 11 species/subspecies and an outgroup were examined using cladistic and bioinformatics approaches. The results show that Bathyergus, Georychus and Cryptomys are karyotypically highly conserved in comparison to Heterocephalus, Heliophobius and Fukomys. Fukomys in particular is characterised by a large number of rearrangements that contrast sharply with the conservative Cryptomys. The occurrence and fixation of rearrangements in these species has probably been facilitated by vicariance in combination with life history traits that are particular to these mammals

Antagonist Xist and Tsix co-transcription during mouse oogenesis and maternal Xist expression during pre-implantation development calls into question the nature of the maternal imprint on the X chromosome

International audienceDuring the first divisions of the female mouse embryo, the paternal X-chromosome is coated by Xist non-coding RNA and gradually silenced. This imprinted X-inactivation principally results from the apposition, during oocyte growth, of an imprint on the X-inactivation master control region: the X-inactivation center (Xic). This maternal imprint of yet unknown nature is thought to prevent Xist upregulation from the maternal X (XM) during early female development. In order to provide further insight into the XM imprinting mechanism, we applied single-cell approaches to oocytes and pre-implantation embryos at different stages of development to analyze the expression of candidate genes within the Xic. We show that, unlike the situation pertaining in most other cellular contexts, in early-growing oocytes, Xist and Tsix sense and antisense transcription occur simultaneously from the same chromosome. Additionally, during early development, Xist appears to be transiently transcribed from the XM in some blastomeres of late 2-cell embryos concomitant with the general activation of the genome indicating that XM imprinting does not completely suppress maternal Xist transcription during embryo cleavage stages. These unexpected transcriptional regulations of the Xist locus call for a re-evaluation of the early functioning of the maternal imprint on the X-chromosome and suggest that Xist/Tsix antagonist transcriptional activities may participate in imprinting the maternal locus as described at other loci subject to parental imprinting

Lineage-specific regulation of imprinted X inactivation in extraembryonic endoderm stem cells.

International audienceBACKGROUND: Silencing of the paternal X chromosome (Xp), a phenomenon known as imprinted X-chromosome inactivation (I-XCI), characterises, amongst mouse extraembryonic lineages, the primitive endoderm and the extraembryonic endoderm (XEN) stem cells derived from it. RESULTS: Using a combination of chromatin immunoprecipitation characterisation of histone modifications and single-cell expression studies, we show that whilst the Xp in XEN cells, like the inactive X chromosome in other cell types, globally accumulates the repressive histone mark H3K27me3, a large number of Xp genes locally lack H3K27me3 and escape from I-XCI. In most cases this escape is specific to the XEN cell lineage. Importantly, the degree of escape and the genes concerned remain unchanged upon XEN conversion into visceral endoderm, suggesting stringent control of I-XCI in XEN derivatives. Surprisingly, chemical inhibition of EZH2, a member of the Polycomb repressive complex 2 (PRC2), and subsequent loss of H3K27me3 on the Xp, do not drastically perturb the pattern of silencing of Xp genes in XEN cells. CONCLUSIONS: The observations that we report here suggest that the maintenance of gene expression profiles of the inactive Xp in XEN cells involves a tissue-specific mechanism that acts partly independently of PRC2 catalytic activity

Antagonist <i>Xist</i> and <i>Tsix</i> co-transcription during mouse oogenesis and maternal <i>Xist</i> expression during pre-implantation development calls into question the nature of the maternal imprint on the X chromosome

<div><p>During the first divisions of the female mouse embryo, the paternal X-chromosome is coated by <i>Xist</i> non-coding RNA and gradually silenced. This imprinted X-inactivation principally results from the apposition, during oocyte growth, of an imprint on the X-inactivation master control region: the X-inactivation center (<i>Xic</i>). This maternal imprint of yet unknown nature is thought to prevent <i>Xist</i> upregulation from the maternal X (X^M) during early female development. In order to provide further insight into the X^M imprinting mechanism, we applied single-cell approaches to oocytes and pre-implantation embryos at different stages of development to analyze the expression of candidate genes within the <i>Xic</i>. We show that, unlike the situation pertaining in most other cellular contexts, in early-growing oocytes, <i>Xist</i> and <i>Tsix</i> sense and antisense transcription occur simultaneously from the same chromosome. Additionally, during early development, <i>Xist</i> appears to be transiently transcribed from the X^M in some blastomeres of late 2-cell embryos concomitant with the general activation of the genome indicating that X^M imprinting does not completely suppress maternal <i>Xist</i> transcription during embryo cleavage stages. These unexpected transcriptional regulations of the <i>Xist</i> locus call for a re-evaluation of the early functioning of the maternal imprint on the X-chromosome and suggest that <i>Xist</i>/<i>Tsix</i> antagonist transcriptional activities may participate in imprinting the maternal locus as described at other loci subject to parental imprinting.</p></div

Sperm-inherited organelle clearance in C-elegans relies on LC3-dependent autophagosome targeting to the pericentrosomal area

International audienceMacroautophagic degradation of sperm-inherited organelles prevents paternal mitochondrial DNA transmission in C. elegans. The recruitment of autophagy markers around sperm mitochondria has also been observed in mouse and fly embryos but their role in degradation is debated. Both worm Atg8 ubiquitin-like proteins, LGG1/GABARAP and LGG-2/LC3, are recruited around sperm organelles after fertilization. Whereas LGG-1 depletion affects autophagosome function, stabilizes the substrates and is lethal, we demonstrate that LGG-2 is dispensable for autophagosome formation but participates in their microtubule-dependent transport toward the pericentrosomal area prior to acidification. In the absence of LGG-2, autophagosomes and their substrates remain clustered at the cell cortex, away from the centrosomes and their associated lysosomes. Thus, the clearance of sperm organelles is delayed and their segregation between blastomeres prevented. This allowed us to reveal a role of the RAB5/RAB-7 GTPases in autophagosome formation. In conclusion, the major contribution of LGG-2 in sperm-inherited organelle clearance resides in its capacity to mediate the retrograde transport of autophagosomes rather than their fusion with acidic compartments: a potential key function of LC3 in controlling the fate of sperm mitochondria in other species

Spontaneous Reactivation of Clusters of X-Linked Genes Is Associated with the Plasticity of X-Inactivation in Mouse Trophoblast Stem Cells

International audienceRandom epigenetic silencing of the X-chromosome in somatic tissues of female mammals equalizes the dosage of X-linked genes between the sexes. Unlike this form of X-inactivation that is essentially irreversible, the imprinted inactivation of the paternal X, which characterizes mouse extra-embryonic tissues, appears highly unstable in the trophoblast giant cells of the placenta. Here, we wished to determine whether such instability is already present in placental progenitor cells prior to differentiation toward lineage-specific cell types. To this end, we analyzed the behavior of a GFP transgene on the paternal X both in vivo and in trophoblast stem (TS) cells derived from the trophectoderm of XX(GFP) blastocysts. Using single-cell studies, we show that not only the GFP transgene but also a large number of endogenous genes on the paternal X are subject to orchestrated cycles of reactivation/de novo inactivation in placental progenitor cells. This reversal of silencing is associated with local losses of histone H3 lysine 27 trimethylation extending over several adjacent genes and with the topological relocation of the hypomethylated loci outside of the nuclear compartment of the inactive X. The "reactivated" state is maintained through several cell divisions. Our study suggests that this type of "metastable epigenetic" states may underlie the plasticity of TS cells and predispose specific genes to relaxed regulation in specific subtypes of placental cells

Chromosome evolution in the subtribe Bovina (Mammalia, Bovidae): the karyotype of the Cambodian banteng (Bos javanicus birmanicus) suggests that Robertsonian translocations are related to interspecific hybridization

Three subspecies of banteng (Bos javanicus) have been described: B. j. javanicus in Java, B. j. lowi in Borneo, and B. j. birmanicus in Cambodia, Lao PDR, Myanmar, Thailand and Vietnam. In this paper we provide the first description of the karyotype of the Cambodian banteng. The chromosomal complement of B. j. birmanicus differs from that of B. j. javanicus, which was previously found to be similar to that of cattle, Bos taurus (2n = 60). The Cambodian banteng karyotype has a diploid number of 2n = 56 (FN = 62) and the karyotype consists of 26 pairs of acrocentric chromosomes and two pairs of submetacentric chromosomes. Comparisons with other species of the subtribe Bovina show that the two pairs of bi-armed chromosomes resulted from two centric fusions involving the equivalent of cattle chromosomes 1 and 29, and 2 and 28, respectively. Cross-species fluorescence in-situ hybridization (FISH) with B. taurus whole chromosome paints and satellite DNA I probes was used to identify the chromosomes involved in the translocations, and their orientation. We suggest that Robertsonian translocations (1;29) and (2;28) have been fixed in the common ancestor of Cambodian banteng as a consequence of hybridization with the kouprey (Bos sauveli) during the Pleistocene epoch