Cestode infections in non-human primates suggest the existence of zoonotic cycles in the area surrounding the Strasbourg primatology center

Background: Several cases of infections due to Echinococcus multilocularis, Taenia martis and Taenia crassiceps were recently described in various species of captive non-human primates (NHPs) harbored in the Strasbourg Primate Center (SPC). Furthermore, one of the first cases of human cysticercosis due to T. martis was described in the Strasbourg region. These data suggest the existence of zoonotic cycles of tapeworm infections in the direct environment of the SPC. The aim of our study was to assess the prevalence of larval cestode infections among intermediate and definitive hosts in the close neighborhood of the center. We analyzed carnivore mammal fecal samples as well as rodent carcasses, collected inside or near the SPC, using PCR. Furthermore, we performed serology for Echinococcus spp. and Taenia spp. on NHP sera. Results: We found that 14.5% (95% CI [8.6; 20.4]) of 138 carnivore feces were positive for E. multilocularis-DNA, as well as 25% (95% CI [5.5; 57.2]) of 12 rodent carcasses, and 5.1% (95% CI [1.4; 8.7]) for T. martis or T. crassiceps. Of all NHPs tested, 10.1% (95% CI [3.8; 16.4]) were seropositive for Echinococcus spp. and 8.2% (95% CI [1.3; 15.1]) for Taenia spp. Conclusions: Our data support the existence of zoonotic cycles of larval cestode infections in the direct environment of the primatology center affecting NHPs harbored in the SPC, potentially threatening the human population living in this area. Since this zoonotic risk is borne by local wildlife, and given the severity of these infections, it seems necessary to put in place measures to protect captive NHPs, and further studies to better assess the risk to human populations

Apoptosis, G1 Phase Stall, and Premature Differentiation Account for Low Chimeric Competence of Human and Rhesus Monkey Naive Pluripotent Stem Cells

After reprogramming to naive pluripotency, human pluripotent stem cells (PSCs) still exhibit very low ability to make interspecies chimeras. Whether this is because they are inherently devoid of the attributes of chimeric competency or because naive PSCs cannot colonize embryos from distant species remains to be elucidated. Here, we have used different types of mouse, human, and rhesus monkey naive PSCs and analyzed their ability to colonize rabbit and cynomolgus monkey embryos. Mouse embryonic stem cells (ESCs) remained mitotically active and efficiently colonized host embryos. In contrast, primate naive PSCs colonized host embryos with much lower efficiency. Unlike mouse ESCs, they slowed DNA replication after dissociation and, after injection into host embryos, they stalled in the G1 phase and differentiated prematurely, regardless of host species. We conclude that human and non-human primate naive PSCs do not efficiently make chimeras because they are inherently unfit to remain mitotically active during colonization

Frontal Cortical Functional Connectivity Is Impacted by Anaesthesia in Macaques

International audienceA critical aspect of neuroscience is to establish whether and how brain networks evolved across primates. To date, most comparative studies have used resting-state functional magnetic resonance imaging (rs-fMRI) in anaesthetized nonhuman primates and in awake humans. However, anaesthesia strongly affects rs-fMRI signals. The present study investigated the impact of the awareness state (anaesthesia vs. awake) within the same group of macaque monkeys on the rs-fMRI functional connectivity organization of a wellcharacterized network in the human brain, the cingulo-frontal lateral network. Results in awake macaques show that rostral seeds in the cingulate sulcus exhibited stronger correlation strength with rostral compared to caudal lateral frontal cortical areas, while more caudal seeds displayed stronger correlation strength with caudal compared to anterior lateral frontal cortical areas. Critically, this inverse rostro-caudal functional gradient was abolished under anaesthesia. This study demonstrated a similar functional connectivity (FC) organization of the cingulo-frontal cortical network in awake macaque to that previously uncovered in the human brain pointing toward a preserved FC organization from macaque to human. However, it can only be observed in awake state suggesting that this network is sensitive to anaesthesia and warranting significant caution when comparing FC patterns across species under different states

Cestode infections in non-human primates suggest the existence of zoonotic cycles in the area surrounding the Strasbourg primatology center

International audienceBackground: Several cases of infections due to Echinococcus multilocularis, Taenia martis and Taenia crassiceps were recently described in various species of captive non-human primates (NHPs) harbored in the Strasbourg Primate Center (SPC). Furthermore, one of the first cases of human cysticercosis due to T. martis was described in the Strasbourg region. These data suggest the existence of zoonotic cycles of tapeworm infections in the direct environment of the SPC. The aim of our study was to assess the prevalence of larval cestode infections among intermediate and definitive hosts in the close neighborhood of the center. We analyzed carnivore mammal fecal samples as well as rodent carcasses, collected inside or near the SPC, using PCR. Furthermore, we performed serology for Echinococcus spp. and Taenia spp. on NHP sera. Results: We found that 14.5% (95% CI [8.6; 20.4]) of 138 carnivore feces were positive for E. multilocularis-DNA, as well as 25% (95% CI [5.5; 57.2]) of 12 rodent carcasses , and 5.1% (95% CI [1.4; 8.7]) for T. martis or T. crassiceps. Of all NHPs tested, 10.1% (95% CI [3.8; 16.4]) were seropositive for Echinococcus spp. and 8.2% (95% CI [1.3; 15.1]) for Taenia spp. Conclusions: Our data support the existence of zoonotic cycles of larval cestode infections in the direct environment of the primatology center affecting NHPs harbored in the SPC, potentially threatening the human population living in this area. Since this zoonotic risk is borne by local wildlife, and given the severity of these infections, it seems necessary to put in place measures to protect captive NHPs, and further studies to better assess the risk to human populations. Ré sumé-Des cestodoses chez des primates non humains suggèrent l'existence de cycles zoonotiques dans la région du centre de primatologie de Strasbourg. Contexte : Plusieurs cas de cestodoses larvaires dues à Echinococcus multilocularis, Taenia martis et T. crassiceps ont été récemment décrits chez des primates non-humains (PNH) captifs appartenant à diverses espèces, hébergés au Centre de Primatologie de Strasbourg (CdP). De plus, un des premiers cas humains de cysticercose due à T. martis a été décrit dans la région de Strasbourg. Ces données suggèrent l'émergence d'un nouveau foyer parasitaire dans l'environnement direct du CdP. Le but de notre étude était d'évaluer la prévalence des cestodoses larvaires chez les hôtes intermédiaires et définitifs de ces parasites dans le proche voisinage du CdP. Nous avons analysé des échantillons de selles de mammifères carnivores, ainsi que des carcasses de rongeurs, collectés à l'intérieur ou aux alentours du CdP. De plus, nous avons réalisé des sérologies pour Echinococcus spp. et Taenia spp. sur des sérums de PNH. Résultats : Nous avons trouvé que 14,5 % (IC95 % [8,6 ; 20,4]) des 138 selles de carnivores étaient positives pour E. multilocularis, ainsi que 25 % (IC95 % [5,5 ; 57,2]) des 12 carcasses de rongeur, et 5,1 % (IC95 % [1,4 ; 8,7]) pour T. martis ou T. crassiceps. De tous les PNH testés, 10,1 % (IC95 % [3,8 ; 16,4]) étaient positifs pour Echinococcus spp. et 8,2 % (IC95 % [1,3 ; 15,1]) pour Taenia spp. Conclusions : Nos données suggèrent l'existence de cycles zoonotiques de cestodoses larvaires dans l'environnement direct du centre de primatologie, affectant les PNH This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. OPEN ACCESS RESEARCH ARTICLE hébergés au CdP et menaçant potentiellement les populations humaines vivant dans cette zone. Ce risque zoonotique étant porté par la faune sauvage locale, et comptes tenus de la sévérité de ces infections, il semble nécessaire de mettre en place des mesures afin de protéger les PNH captifs, et de plus larges études afin d'évaluer le risque pour les populations humaines environnantes

Pathogenesis of recent Lassa virus isolates from lineages II and VII in cynomolgus monkeys

We thank P. Regnard, P.H. Moreau, and L. Fellmann (SILABE, Strasbourg) for medical care given to the monkeys. We thank S. Mundweiller, S. Godard, E. Moissonnier, D. Thomas, S. Mely, B. Labrosse, D. Pannetier, and C. Leculier (P4 INSERM–Jean Merieux, US003, INSERM) for assistance in conducting the BSL-4 experiments. We thank M-A Dillies (HUB, Institut Pasteur) for helpful discussions. We thank G. Fourcaud and B. Lafoux (UBIVE, CIRI, Institut Pasteur) for technical help. We also thank L. Branco (Zalgen Labs) for providing recombinant proteins. We are grateful to the Coalition for Epidemic Preparedness and Innovations (R. Hatchett, G. Thiry, and M. Saville) and C. Gerke (Department of Innovation Development, Institut Pasteur) for invaluable support.International audienceThe area of Lassa virus (LASV) circulation is expanding, with the emergence of highly pathogenic new LASV lineages. Benin recently became an endemic country for LASV and has seen the emergence of a new LASV lineage (VII). The first two outbreaks in 2014 and 2016 showed a relatively high mortality rate compared to other outbreaks. We infected cynomolgus monkeys with two strains belonging to lineage II and lineage VII that were isolated from deceased patients during the 2016 outbreak in Benin. The lineage VII strain (L7) caused uniform mortality. Death was associated with uncontrolled viral replication, unbalanced inflammatory responses characterized by increased concentrations of pro- and anti-inflammatory mediators, and the absence of efficient immune responses, resembling the pathogenesis associated with the prototypic Josiah strain in monkeys. The lineage II strain (L2) showed apparently lower virulence than its counterpart, with a prolonged time to death and a lower mortality rate. Prolonged survival was associated with better control of viral replication, a moderate inflammatory response, and efficient T-cell responses. Transcriptomic analyses also highlighted important differences in the immune responses associated with the outcome. Both strains caused strong inflammation in several organs. Notably, meningitis and encephalitis were observed in the cerebral cortex and cerebellum in all monkeys, independently of the outcome. Due to their apparently high pathogenicity, emerging strains from lineage VII should be considered in preclinical vaccine testing. Lineage II would also be beneficial in pathogenesis studies to study the entire spectrum of Lassa fever severity

A single-shot Lassa vaccine induces long-term immunity and protects cynomolgus monkeys against heterologous strains

Acknowledgments: We thank P. Regnard (Silabe, Strasbourg) for medical care given to the monkeys. We thank S. Mundweiller, S. Godard, E. Moissonnier, D. Thomas, S. Mély, B. Labrosse, D. Pannetier, and C. Léculier (P4 INSERM–Jean Mérieux, US003, INSERM) for assistance in conducting the BSL-4 experiments. We are grateful to G. Fourcaud and B. Lafoux (Institut Pasteur, CIRI, Lyon) for technical help with histological studies. We thank S. Becker for providing us with the Josiah strain and T. G. Ksiasek, P. E. Rollin, and P. Jahrling for the LASV monoclonal antibodies. We also thank L. Branco (Zalgen Labs) for providing recombinant proteins. We are grateful to THEMIS Bioscience GmbH, a wholly owned subsidiary of Merck & Co. Inc. (E. Tauber, A. Kort, K. Ramsauer, S. Schrauf, Y. Tomberger, and R. Tschismarov), to the Coalition for Epidemic Preparedness and Innovations (R. Hatchett, G. Thiry, and M. Saville), and to C. Gerke (Department of Innovation Development, Institut Pasteur) for invaluable supportInternational audienceA safe and protective Lassa virus vaccine is crucially needed in Western Africa to stem the recurrent outbreaks of Lassa virus infections in Nigeria and the emergence of Lassa virus in previously unaffected countries, such as Benin and Togo. Major challenges in developing a Lassa virus vaccine include the high diversity of circulating strains and their reemergence from 1 year to another. To address each of these challenges, we immunized cynomolgus monkeys with a measles virus vector expressing the Lassa virus glycoprotein and nucleoprotein of the prototypic Lassa virus strain Josiah (MeV-NP). To evaluate vaccine efficacy against heterologous strains of Lassa virus, we challenged the monkeys a month later with heterologous strains from lineage II or lineage VII, finding that the vaccine was protective against these strains. A second cohort of monkeys was challenged 1 year later with the homologous Josiah strain, finding that a single dose of MeV-NP was sufficient to protect all vaccinated monkeys. These studies demonstrate that MeV-NP can generate both long-lasting immune responses and responses that are able to protect against diverse strains of Lassa virus

Hemostasis defects underlying the hemorrhagic syndrome caused by Mammarenaviruses in a cynomolgus macaque model

Viral hemorrhagic fevers (HF) are a group of acute febrile diseases with high mortality rates. While hemostatic dysfunction appears to be a major determinant of the severity of the disease, it is still unclear what pathogenic mechanisms lead to it. In clinical studies, arenaviruses such as Lassa, Machupo and Guanarito viruses caused HF that vary in symptoms and biological alterations. In this study we aimed to characterize the hemostatic dysfunction induced by arenaviral HF to determine its implication in the severity of the disease and to elucidate the origin of this syndrome. We found that lethal infection with Machupo, Guanarito and Lassa viruses is associated with cutaneo-mucosal, cerebral, digestive and pulmonary hemorrhages. The affected animals developed a severe alteration of the coagulation system, which was concomitant with acute hepatitis, minor deficit of hepatic factor synthesis, presence of a plasmatic inhibitor of coagulation and dysfunction of the fibrinolytic system. Despite signs of increased vascular permeability, endothelial cell infection was not a determinant factor of the hemorrhagic syndrome. There were also alterations of the primary hemostasis during lethal infection, with moderate to severe thrombocytopenia and platelet dysfunction. Finally, we show that lethal infection is accompanied by a reduced hematopoietic potential of the bone marrow. This study provides an unprecedented characterization of the hemostasis defects induced by several highly pathogenic Arenaviruses