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1.
Nat Chem Biol ; 19(9): 1091-1096, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37322159

RESUMEN

As antimicrobial resistance threatens our ability to treat common bacterial infections, new antibiotics with limited cross-resistance are urgently needed. In this regard, natural products that target the bacterial ribosome have the potential to be developed into potent drugs through structure-guided design, provided their mechanisms of action are well understood. Here we use inverse toeprinting coupled to next-generation sequencing to show that the aromatic polyketide tetracenomycin X primarily inhibits peptide bond formation between an incoming aminoacyl-tRNA and a terminal Gln-Lys (QK) motif in the nascent polypeptide. Using cryogenic electron microscopy, we reveal that translation inhibition at QK motifs occurs via an unusual mechanism involving sequestration of the 3' adenosine of peptidyl-tRNALys in the drug-occupied nascent polypeptide exit tunnel of the ribosome. Our study provides mechanistic insights into the mode of action of tetracenomycin X on the bacterial ribosome and suggests a path forward for the development of novel aromatic polyketide antibiotics.


Asunto(s)
Antibacterianos , Policétidos , Antibacterianos/farmacología , Antibacterianos/química , Péptidos/farmacología , Péptidos/química , Policétidos/farmacología , Biosíntesis de Proteínas
2.
PLoS Pathog ; 17(8): e1009427, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34370799

RESUMEN

Impaired type I interferons (IFNs) production or signaling have been associated with severe COVID-19, further promoting the evaluation of recombinant type I IFNs as therapeutics against SARS-CoV-2 infection. In the Syrian hamster model, we show that intranasal administration of IFN-α starting one day pre-infection or one day post-infection limited weight loss and decreased viral lung titers. By contrast, intranasal administration of IFN-α starting at the onset of symptoms three days post-infection had no impact on the clinical course of SARS-CoV-2 infection. Our results provide evidence that early type I IFN treatment is beneficial, while late interventions are ineffective, although not associated with signs of enhanced disease.


Asunto(s)
Antivirales/administración & dosificación , Tratamiento Farmacológico de COVID-19 , Interferón Tipo I/administración & dosificación , Administración Intranasal , Animales , Chlorocebus aethiops , Cricetinae , Modelos Animales de Enfermedad , Mesocricetus , SARS-CoV-2
3.
J Gen Virol ; 102(3)2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33612147

RESUMEN

Understanding the pathogenesis of the SARS-CoV-2 infection is key to developing preventive and therapeutic strategies against COVID-19, in the case of severe illness but also when the disease is mild. The use of appropriate experimental animal models remains central in the in vivo exploration of the physiopathology of infection and antiviral strategies. This study describes SARS-CoV-2 intranasal infection in ferrets and hamsters with low doses of low-passage SARS-CoV-2 clinical French isolate UCN19, describing infection levels, excretion, immune responses and pathological patterns in both animal species. Individual infection with 103 p.f.u. SARS-CoV-2 induced a more severe disease in hamsters than in ferrets. Viral RNA was detected in the lungs of hamsters but not of ferrets and in the brain (olfactory bulb and/or medulla oblongata) of both species. Overall, the clinical disease remained mild, with serological responses detected from 7 days and 10 days post-inoculation in hamsters and ferrets respectively. The virus became undetectable and pathology resolved within 14 days. The kinetics and levels of infection can be used in ferrets and hamsters as experimental models for understanding the pathogenicity of SARS-CoV-2, and testing the protective effect of drugs.


Asunto(s)
Anticuerpos Antivirales/inmunología , COVID-19/virología , Cricetinae , Modelos Animales de Enfermedad , Hurones , Animales , Encéfalo/virología , COVID-19/inmunología , COVID-19/patología , COVID-19/fisiopatología , Progresión de la Enfermedad , Inmunoglobulina G/inmunología , Pulmón/patología , Pulmón/virología , Nariz , Reacción en Cadena en Tiempo Real de la Polimerasa , SARS-CoV-2/genética , SARS-CoV-2/inmunología , SARS-CoV-2/aislamiento & purificación , SARS-CoV-2/patogenicidad , Carga Viral/genética
4.
PLoS Pathog ; 15(6): e1007799, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-31220188

RESUMEN

The development of high-throughput genome sequencing enables accurate measurements of levels of sub-consensus intra-host virus genetic diversity and analysis of the role played by natural selection during cross-species transmission. We analysed the natural and experimental evolution of rabies virus (RABV), an important example of a virus that is able to make multiple host jumps. In particular, we (i) analyzed RABV evolution during experimental host switching with the goal of identifying possible genetic markers of host adaptation, (ii) compared the mutational changes observed during passage with those observed in natura, and (iii) determined whether the colonization of new hosts or tissues requires adaptive evolution in the virus. To address these aims, animal infection models (dog and fox) and primary cell culture models (embryo brain cells of dog and fox) were developed and viral variation was studied in detail through deep genome sequencing. Our analysis revealed a strong unidirectional host evolutionary effect, as dog-adapted rabies virus was able to replicate in fox and fox cells relatively easily, while dogs or neuronal dog cells were not easily susceptible to fox adapted-RABV. This suggests that dog RABV may be able to adapt to some hosts more easily than other host variants, or that when RABV switched from dogs to red foxes it lost its ability to adapt easily to other species. Although no difference in patterns of mutation variation between different host organs was observed, mutations were common following both in vitro and in vivo passage. However, only a small number of these mutations also appeared in natura, suggesting that adaptation during successful cross-species virus transmission is a complex, multifactorial evolutionary process.


Asunto(s)
Enfermedades de los Perros , Evolución Molecular , Interacciones Huésped-Parásitos/inmunología , Virus de la Rabia/fisiología , Rabia , Animales , Línea Celular , Enfermedades de los Perros/genética , Enfermedades de los Perros/inmunología , Perros , Femenino , Zorros/genética , Zorros/inmunología , Zorros/virología , Secuenciación de Nucleótidos de Alto Rendimiento , Interacciones Huésped-Parásitos/genética , Masculino , Mutación , Rabia/genética , Rabia/inmunología
5.
J Exp Biol ; 224(Pt 5)2021 03 05.
Artículo en Inglés | MEDLINE | ID: mdl-33619173

RESUMEN

The jaw system in canids is essential for defence and prey acquisition. However, how it varies in wild species in comparison with domestic species remains poorly understood, yet is of interest in terms of understanding the impact of artificial selection. Here, we explored the variability and interrelationships between the upper and lower jaws, muscle architecture and bite force in the red fox (Vulpes vulpes). We performed dissections and used 3D geometric morphometric approaches to quantify jaw shape in 68 foxes. We used a static lever model and bite force estimates were compared with in vivo measurements of 10 silver foxes. Our results show strong relationships exist between cranial and mandible shape, and between cranial or mandible shape on the one hand and muscles or estimated bite force on the other hand, confirming the strong integration of the bony and muscular components of the jaw system. These strong relationships are strongly driven by size. The functional links between shape and estimated bite force are stronger for the mandible, which probably reflects its greater specialisation towards biting. We then compared our results with data previously obtained for dogs (Canis lupus familiaris) to investigate the effect of domestication. Foxes and dogs differ in skull shape and muscle physiological cross-sectional area (PCSA). They show a similar amount of morphological variation in muscle PCSA, but foxes show lower variation in cranial and mandible shape. Interestingly, the patterns of covariation are not stronger in foxes than in dogs, suggesting that domestication did not lead to a disruption of the functional links of the jaw system.


Asunto(s)
Fuerza de la Mordida , Zorros , Animales , Perros , Maxilares , Músculos Masticadores , Músculos
6.
Soins Psychiatr ; 42(335): 38-42, 2021.
Artículo en Francés | MEDLINE | ID: mdl-34266549

RESUMEN

The treatment of post-traumatic stress disorder is one of the priorities of the armed forces' health service, but there are few measures for families, who are nevertheless the first to be affected. At the Robert-Picqué army training hospital in Bordeaux, an information and exchange day for carers was set up in 2018. It takes place once every term. Here is a look at how it works, its benefits and its limitations.


Asunto(s)
Personal Militar , Trastornos por Estrés Postraumático , Cuidadores , Humanos
7.
Brain Behav Immun ; 89: 579-586, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32629042

RESUMEN

Anosmia is one of the most prevalent symptoms of SARS-CoV-2 infection during the COVID-19 pandemic. However, the cellular mechanism behind the sudden loss of smell has not yet been investigated. The initial step of odour detection takes place in the pseudostratified olfactory epithelium (OE) mainly composed of olfactory sensory neurons surrounded by supporting cells known as sustentacular cells. The olfactory neurons project their axons to the olfactory bulb in the central nervous system offering a potential pathway for pathogens to enter the central nervous system by bypassing the blood brain barrier. In the present study, we explored the impact of SARS-CoV-2 infection on the olfactory system in golden Syrian hamsters. We observed massive damage of the OE as early as 2 days post nasal instillation of SARS-CoV-2, resulting in a major loss of cilia necessary for odour detection. These damages were associated with infection of a large proportion of sustentacular cells but not of olfactory neurons, and we did not detect any presence of the virus in the olfactory bulbs. We observed massive infiltration of immune cells in the OE and lamina propria of infected animals, which may contribute to the desquamation of the OE. The OE was partially restored 14 days post infection. Anosmia observed in COVID-19 patient is therefore likely to be linked to a massive and fast desquamation of the OE following sustentacular cells infection with SARS-CoV-2 and subsequent recruitment of immune cells in the OE and lamina propria.


Asunto(s)
Infecciones por Coronavirus/patología , Bulbo Olfatorio/patología , Mucosa Olfatoria/patología , Neumonía Viral/patología , Animales , Betacoronavirus , COVID-19 , Cilios/patología , Infecciones por Coronavirus/fisiopatología , Mesocricetus , Trastornos del Olfato/patología , Trastornos del Olfato/fisiopatología , Bulbo Olfatorio/virología , Mucosa Olfatoria/virología , Neuronas Receptoras Olfatorias/patología , Neuronas Receptoras Olfatorias/virología , Pandemias , Neumonía Viral/fisiopatología , SARS-CoV-2
8.
J Exp Biol ; 223(Pt 16)2020 08 17.
Artículo en Inglés | MEDLINE | ID: mdl-32587065

RESUMEN

Previous studies based on two-dimensional methods have suggested that the great morphological variability of cranial shape in domestic dogs has impacted bite performance. Here, we used a three-dimensional biomechanical model based on dissection data to estimate the bite force of 47 dogs of various breeds at several bite points and gape angles. In vivo bite force for three Belgian shepherd dogs was used to validate our model. We then used three-dimensional geometric morphometrics to investigate the drivers of bite force variation and to describe the relationships between the overall shape of the jaws and bite force. The model output shows that bite force is rather variable in dogs and that dogs bite harder on the molar teeth and at lower gape angles. Half of the bite force is determined by the temporal muscle. Bite force also increased with size, and brachycephalic dogs showed higher bite forces for their size than mesocephalic dogs. We obtained significant covariation between the shape of the upper or lower jaw and absolute or residual bite force. Our results demonstrate that domestication has not resulted in a disruption of the functional links in the jaw system in dogs and that mandible shape is a good predictor of bite force.


Asunto(s)
Fuerza de la Mordida , Maxilares , Animales , Fenómenos Biomecánicos , Perros , Mandíbula , Músculos Masticadores , Diente Molar , Cráneo
9.
BMC Vet Res ; 15(1): 295, 2019 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-31412882

RESUMEN

In recent years, outbreaks caused by multi-host pathogens (MHP) have posed a serious challenge to public and animal health authorities. The frequent implication of wildlife in such disease systems and a lack of guidelines for mitigating these diseases within wild animal populations partially explain why the outbreaks are particularly challenging. To face these challenges, the French Ministry of Agriculture launched a multi-disciplinary group of experts that set out to discuss the main wildlife specific concepts in the management of MHP disease outbreaks and how to integrate wildlife in the disease management process.This position paper structures the primary specific concepts of wildlife disease management, as identified by the working group. It is designed to lay out these concepts for a wide audience of public and/or animal health officers who are not necessarily familiar with wildlife diseases. The group's discussions generated a possible roadmap for the management of MHP diseases. This roadmap is presented as a cycle for which the main successive step are: step 1-descriptive studies and monitoring; step 2-risk assessment; step 3-management goals; step 4-management actions and step 5-assessment of the management plan. In order to help choose the most adapted management actions for all involved epidemiological units, we integrated a decision-making framework (presented as a spreadsheet). This tool and the corresponding guidelines for disease management are designed to be used by public and health authorities when facing MHP disease outbreaks. These proposals are meant as an initial step towards a harmonized transboundary outbreak response framework that integrates current scientific understanding adapted to practical intervention.


Asunto(s)
Animales Salvajes , Especificidad del Huésped , Animales , Brotes de Enfermedades , Medición de Riesgo
10.
BMC Vet Res ; 15(1): 445, 2019 Dec 06.
Artículo en Inglés | MEDLINE | ID: mdl-31810466

RESUMEN

BACKGROUND: Oral vaccination with Mycobacterium bovis Bacille of Calmette and Guerin (BCG) has provided protection against M. bovis to badgers both experimentally and in the field. There is also evidence suggesting that the persistence of live BCG within the host is important for maintaining protection against TB. Here we investigated the capacity of badger inductive mucosal sites to absorb and maintain live BCG. The targeted mucosae were the oropharyngeal cavity (tonsils and sublingual area) and the small intestine (ileum). RESULTS: We showed that significant quantities of live BCG persisted within badger in tissues of vaccinated badgers for at least 8 weeks following oral vaccination with only very mild pathological features and induced the circulation of IFNγ-producing mononuclear cells. The uptake of live BCG by tonsils and drainage to retro-pharyngeal lymph nodes was repeatable in the animal group vaccinated by oropharyngeal instillation whereas those vaccinated directly in the ileum displayed a lower frequency of BCG detection in the enteric wall or draining mesenteric lymph nodes. No faecal excretion of live BCG was observed, including when BCG was delivered directly in the ileum. CONCLUSIONS: The apparent local loss of BCG viability suggests an unfavorable gastro-enteric environment for BCG in badgers, which should be taken in consideration when developing an oral vaccine for use in this species.


Asunto(s)
Administración Oral , Vacuna BCG/administración & dosificación , Mustelidae/microbiología , Mycobacterium bovis/aislamiento & purificación , Animales , Vacuna BCG/inmunología , Preparaciones de Acción Retardada , Heces/microbiología , Femenino , Íleon/microbiología , Interferón gamma/metabolismo , Ganglios Linfáticos/microbiología , Mycobacterium bovis/inmunología , Tuberculosis/microbiología , Tuberculosis/prevención & control , Tuberculosis/veterinaria , Vacunación/veterinaria
11.
mBio ; 15(4): e0320023, 2024 Apr 10.
Artículo en Inglés | MEDLINE | ID: mdl-38421162

RESUMEN

The mechanisms underpinning the replication of genomic DNA have recently been challenged in Archaea. Indeed, the lack of origin of replication has no deleterious effect on growth, suggesting that replication initiation relies on homologous recombination. Recombination-dependent replication (RDR) appears to be based on the recombinase RadA, which is of absolute requirement when no initiation origins are detected. The origin of this flexibility in the initiation of replication and the extent to which it is used in nature are yet to be understood. Here, we followed the process of DNA replication throughout the growth stages of Thermococcus barophilus. We combined deep sequencing and genetics to elucidate the dynamics of oriC utilization according to growth phases. We discovered that in T. barophilus, the use of oriC diminishes from the lag to the middle of the log phase, and subsequently increases gradually upon entering the stationary phase. Although oriC demonstrates no indispensability, RadA does exhibit essentiality. Notably, a knockdown mutant strain provides confirmation of the pivotal role of RadA in RDR for the first time. Thus, we demonstrate the existence of a tight combination between oriC utilization and homologous recombination to initiate DNA replication along the growth phases. Overall, this study demonstrates how diverse physiological states can influence the initiation of DNA replication, offering insights into how environmental sensing might impact this fundamental mechanism of life. IMPORTANCE: Replication of DNA is highly important in all organisms. It initiates at a specific locus called ori, which serves as the binding site for scaffold proteins-either Cdc6 or DnaA-depending on the domain of life. However, recent studies have shown that the Archaea, Haloferax volcanii and Thermococcus kodakarensis could subsist without ori. Recombination-dependent replication (RDR), via the recombinase RadA, is the mechanism that uses homologous recombination to initiate DNA replication. The extent to which ori's use is necessary in natural growth remains to be characterized. In this study, using Thermococcus barophilus, we demonstrated that DNA replication initiation relies on both oriC and RDR throughout its physiological growth, each to varying degrees depending on the phase. Notably, a knockdown RadA mutant confirmed the prominent use of RDR during the log phase. Moreover, the study of ploidy in oriC and radA mutant strains showed that the number of chromosomes per cell is a critical proxy for ensuring proper growth and cell survival.


Asunto(s)
Thermococcus , Thermococcus/genética , Replicación del ADN , Recombinación Homóloga , ADN , Recombinasas/genética , Origen de Réplica , Proteínas Bacterianas/genética
12.
Nat Commun ; 14(1): 3891, 2023 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-37393329

RESUMEN

Antibiotic resistance ABC-Fs (ARE ABC-Fs) are translation factors that provide resistance against clinically important ribosome-targeting antibiotics which are proliferating among pathogens. Here, we combine genetic and structural approaches to determine the regulation of streptococcal ARE ABC-F gene msrD in response to macrolide exposure. We show that binding of cladinose-containing macrolides to the ribosome prompts insertion of the leader peptide MsrDL into a crevice of the ribosomal exit tunnel, which is conserved throughout bacteria and eukaryotes. This leads to a local rearrangement of the 23 S rRNA that prevents peptide bond formation and accommodation of release factors. The stalled ribosome obstructs the formation of a Rho-independent terminator structure that prevents msrD transcriptional attenuation. Erythromycin induction of msrD expression via MsrDL, is suppressed by ectopic expression of mrsD, but not by mutants which do not provide antibiotic resistance, showing correlation between MsrD function in antibiotic resistance and its action on this stalled complex.


Asunto(s)
Enfermedades del Nervio Abducens , Antibacterianos , Humanos , Antibacterianos/farmacología , Farmacorresistencia Bacteriana/genética , Macrólidos/farmacología , Acomodación Ocular
13.
bioRxiv ; 2023 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-36778275

RESUMEN

Soon after the beginning of the COVID-19 pandemic in early 2020, the Betacoronavirus SARS-CoV-2 infection of several mink farms breeding American minks ( Neovison vison ) for fur was detected in several countries of Europe. The risk of a new reservoir formation and of a reverse zoonosis from minks was then a major concern. The aim of this study was to investigate the four French mink farms for the circulation of SARS-CoV-2 at the end of 2020. The investigations took place during the slaughtering period thus facilitating different types of sampling (swabs and blood). In one of the four mink farms, 96.6% of serum samples were positive in SARS-CoV-2 ELISA coated with purified N protein recombinant antigen and 54 out of 162 (33%) pharyngo-tracheal swabs were positive by RT-qPCR. The genetic variability among 12 SARS-CoV-2 genomes sequenced in this farm indicated the co-circulation of several lineages at the time of sampling. All SARS-CoV-2 genomes detected were nested within the 20A clade (Nextclade), together with SARS-CoV-2 genomes from humans sampled at the same period. The percentage of SARS-CoV-2 seropositivity by ELISA varied between 0.5 and 1.2% in the three other farms. Interestingly, among these three farms, 11 pharyngo-tracheal swabs and 3 fecal pools from two farms were positive by end-point RT-PCR for an Alphacoronavirus highly similar to a mink coronavirus sequence observed in Danish farms in 2015. In addition, a mink Caliciviridae was identified in one of the two positive farms for Alphacoronavirus . The clinical impact of these unapparent viral infections is not known. The co-infection of SARS-CoV-2 with other viruses in mink farms could contribute to explain the diversity of clinical symptoms noted in different infected farms in Europe. In addition, the co-circulation of an Alphacoronavirus and SARS-CoV-2 within a mink farm would increase potentially the risk of viral recombination between alpha and betacoronaviruses already suggested in wild and domestic animals, as well as in humans. Author summary: France is not a country of major mink fur production. Following the SARS-CoV-2 contamination of mink farms in Denmark and the Netherlands, the question arose for the four French farms.The investigation conducted at the same time in the four farms revealed the contamination of one of them by a variant different from the one circulating at the same time in Denmark and the Netherlands mink farms. Investigation of three other farms free of SARS-CoV-2 contamination revealed the circulation of other viruses including a mink Alphacoronavirus and Caliciviridae , which could modify the symptomatology of SARS-CoV-2 infection in minks.

14.
PLoS One ; 18(8): e0290444, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37624818

RESUMEN

Soon after the beginning of the COVID-19 pandemic in early 2020, the Betacoronavirus SARS-CoV-2 infection of several mink farms breeding American minks (Neovison vison) for fur was detected in various European countries. The risk of a new reservoir being formed and of a reverse zoonosis from minks quickly became a major concern. The aim of this study was to investigate the four French mink farms to see whether SARS-CoV-2 was circulating there in late 2020. The investigations took place during the slaughtering period, thus facilitating different types of sampling (swabs and blood). On one of the four mink farms, 96.6% of serum samples were positive when tested with a SARS-CoV-2 ELISA coated with purified N protein recombinant antigen, and 54 out of 162 (33%) pharyngo-tracheal swabs were positive by RT-qPCR. The genetic variability among 12 SARS-CoV-2 genomes sequenced from this farm indicated the co-circulation of several lineages at the time of sampling. All the SARS-CoV-2 genomes detected were nested within the 20A clade (Nextclade), together with SARS-CoV-2 genomes from humans sampled during the same period. The percentage of SARS-CoV-2 seropositivity by ELISA varied between 0.3 and 1.1% on the other three farms. Interestingly, among these three farms, 11 pharyngo-tracheal swabs and 3 fecal pools from two farms were positive by end-point RT-PCR for an Alphacoronavirus very similar to a mink coronavirus sequence observed on Danish farms in 2015. In addition, a mink Caliciviridae was identified on one of the two farms positive for Alphacoronavirus. The clinical impact of these inapparent viral infections is not known. The co-infection of SARS-CoV-2 with other viruses on mink farms could help explain the diversity of clinical symptoms noted on different infected farms in Europe. In addition, the co-circulation of an Alphacoronavirus and SARS-CoV-2 on a mink farm would potentially increase the risk of viral recombination between alpha and betacoronaviruses as already suggested in wild and domestic animals, as well as in humans.


Asunto(s)
Alphacoronavirus , COVID-19 , Animales , Humanos , COVID-19/epidemiología , COVID-19/veterinaria , SARS-CoV-2/genética , Visón , Granjas , Pandemias , Francia , Infecciones Asintomáticas
15.
Front Immunol ; 14: 1188605, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37409116

RESUMEN

Spike-based COVID-19 vaccines induce potent neutralizing antibodies but their efficacy against SARS-CoV-2 variants decreases. OVX033 is a recombinant protein composed of the full-length nucleocapsid (N) protein of SARS-CoV-2 genetically fused to oligoDOM®, a self-assembling domain which improves antigen immunogenicity. OVX033 including N as an antigenic target is proposed as new vaccine candidate providing broad-spectrum protection against sarbecoviruses. OVX033 demonstrated its ability to trigger cross-reactive T cell responses and cross-protection against three variants of SARS-CoV-2 (B.1 Europe, Delta B.1.617.2, and Omicron B.1.1.529) in a hamster challenge model, as evidenced by lower weight loss, lower lung viral loads, and reduced lung histopathological lesions.


Asunto(s)
COVID-19 , Vacunas , Animales , Cricetinae , Humanos , SARS-CoV-2 , Vacunas contra la COVID-19 , COVID-19/prevención & control , Nucleocápside
16.
Viruses ; 14(8)2022 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-36016399

RESUMEN

OBJECTIVE: There is extensive evidence that SARS-CoV-2 replicates in the gastrointestinal tract. However, the infectivity of virions in feces is poorly documented. Although the primary mode of transmission is airborne, the risk of transmission from contaminated feces remains to be assessed. DESIGN: The persistence of SARS-CoV-2 (infectivity and RNA) in human and animal feces was evaluated by virus isolation on cell culture and RT-qPCR, respectively. The exposure of golden Syrian hamsters to experimentally contaminated feces through intranasal inoculation has also been tested to assess the fecal-oral transmission route. RESULTS: For periods that are compatible with average intestinal transit, the SARS-CoV-2 genome was noticeably stable in human and animal feces, contrary to the virus infectivity that was reduced in a time- and temperature-dependent manner. In human stools, this reduction was variable depending on the donors. Viral RNA was excreted in the feces of infected hamsters, but exposure of naïve hamsters to feces of infected animals did not lead to any productive infection. Conversely, hamsters could be experimentally infected following exposure to spiked fresh feces. CONCLUSION: Infection following exposure to naturally contaminated feces has been suspected but has not been established so far. The present work demonstrates that SARS-CoV-2 rapidly lost infectivity in spiked or naturally infected feces. Although the possibility of persistent viral particles in human or animal feces cannot be fully ruled out, SARS-CoV-2 transmission after exposure to contaminated feces is unlikely.


Asunto(s)
COVID-19 , SARS-CoV-2 , Animales , Cricetinae , Heces , Humanos , Mesocricetus , ARN Viral
17.
ISME J ; 15(12): 3423-3436, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34088977

RESUMEN

Removal of reducing equivalents is an essential catabolic process for all microorganisms to maintain their internal redox balance. The electron disposal by chemoorganotrophic Thermococcales generates H2 by proton reduction or H2S in presence of S0. Although in the absence of S0 growth of these (hyper)thermopiles was previously described to be H2-limited, it remains unclear how Thermococcales could be present in H2-rich S0-depleted habitats. Here, we report that 12 of the 47 strains tested, distributed among all three orders of Thermococcales, could grow without S0 at 0.8 mM dissolved H2 and that tolerance to H2 was always associated with formate production. Two conserved gene clusters coding for a formate hydrogenlyase (FHL) and a putative formate dehydrogenase-NAD(P)H-oxidoreductase were only present in H2-dependent formate producers, and were both systematically associated with a formate dehydrogenase and a formate transporter. As the reaction involved in this alternative pathway for disposal of reducing equivalents was close to thermodynamic equilibrium, it was strongly controlled by the substrates-products concentration ratio even in the presence of S0. Moreover, experimental data and thermodynamic modelling also demonstrated that H2-dependent CO2 reduction to formate could occur within a large temperature range in contrasted hydrothermal systems, suggesting it could also provide an adaptive advantage.


Asunto(s)
Hidrogenasas , Thermococcales , Formiatos , Hidrógeno/metabolismo , Hidrogenasas/metabolismo , Proteínas de Transporte de Membrana , Oxidación-Reducción , Azufre/metabolismo , Thermococcales/metabolismo
18.
Nat Commun ; 12(1): 4466, 2021 07 22.
Artículo en Inglés | MEDLINE | ID: mdl-34294725

RESUMEN

Macrolides and ketolides comprise a family of clinically important antibiotics that inhibit protein synthesis by binding within the exit tunnel of the bacterial ribosome. While these antibiotics are known to interrupt translation at specific sequence motifs, with ketolides predominantly stalling at Arg/Lys-X-Arg/Lys motifs and macrolides displaying a broader specificity, a structural basis for their context-specific action has been lacking. Here, we present structures of ribosomes arrested during the synthesis of an Arg-Leu-Arg sequence by the macrolide erythromycin (ERY) and the ketolide telithromycin (TEL). Together with deep mutagenesis and molecular dynamics simulations, the structures reveal how ERY and TEL interplay with the Arg-Leu-Arg motif to induce translational arrest and illuminate the basis for the less stringent sequence-specific action of ERY over TEL. Because programmed stalling at the Arg/Lys-X-Arg/Lys motifs is used to activate expression of antibiotic resistance genes, our study also provides important insights for future development of improved macrolide antibiotics.


Asunto(s)
Antibacterianos/farmacología , Cetólidos/farmacología , Macrólidos/farmacología , Inhibidores de la Síntesis de la Proteína/farmacología , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Antibacterianos/química , Bacillus subtilis/efectos de los fármacos , Bacillus subtilis/enzimología , Bacillus subtilis/genética , Sitios de Unión/genética , Microscopía por Crioelectrón , Farmacorresistencia Microbiana/genética , Eritromicina/química , Eritromicina/farmacología , Genes Bacterianos , Cetólidos/química , Cetólidos/farmacocinética , Macrólidos/química , Metiltransferasas/química , Metiltransferasas/genética , Metiltransferasas/metabolismo , Simulación de Dinámica Molecular , Mutagénesis Insercional , Biosíntesis de Proteínas/efectos de los fármacos , Inhibidores de la Síntesis de la Proteína/química , Ribosomas/efectos de los fármacos
19.
Animal ; 15(6): 100241, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-34091225

RESUMEN

The ongoing coronavirus disease 19s pandemic has yet again demonstrated the importance of the human-animal interface in the emergence of zoonotic diseases, and in particular the role of wildlife and livestock species as potential hosts and virus reservoirs. As most diseases emerge out of the human-animal interface, a better understanding of the specific drivers and mechanisms involved is crucial to prepare for future disease outbreaks. Interactions between wildlife and livestock systems contribute to the emergence of zoonotic diseases, especially in the face of globalization, habitat fragmentation and destruction and climate change. As several groups of viruses and bacteria are more likely to emerge, we focus on pathogenic viruses of the Bunyavirales, Coronaviridae, Flaviviridae, Orthomyxoviridae, and Paramyxoviridae, as well as bacterial species including Mycobacterium sp., Brucella sp., Bacillus anthracis and Coxiella burnetii. Noteworthy, it was difficult to predict the drivers of disease emergence in the past, even for well-known pathogens. Thus, an improved surveillance in hotspot areas and the availability of fast, effective, and adaptable control measures would definitely contribute to preparedness. We here propose strategies to mitigate the risk of emergence and/or re-emergence of prioritized pathogens to prevent future epidemics.


Asunto(s)
Animales Salvajes , COVID-19 , Animales , COVID-19/veterinaria , Humanos , Ganado , SARS-CoV-2 , Zoonosis
20.
Pathogens ; 10(9)2021 Sep 09.
Artículo en Inglés | MEDLINE | ID: mdl-34578197

RESUMEN

In Europe, Puumala virus (PUUV) transmitted by the bank vole (Myodes glareolus) is the causative agent of nephropathia epidemica (NE), a mild form of haemorrhagic fever with renal syndrome. In France, very little is known about the spatial and temporal variability of the virus circulating within bank vole populations. The present study involved monitoring of bank vole population dynamics and PUUV microdiversity over a ten-year period (2000-2009) in two forests of the Ardennes region: Elan and Croix-Scaille. Ardennes region is characterised by different environmental conditions associated with different NE epidemiology. Bank vole density and population parameters were estimated using the capture/marking/recapture method, and blood samples were collected to monitor the overall seroprevalence of PUUV in rodent populations. Phylogenetic analyses of fifty-five sequences were performed to illustrate the genetic diversity of PUUV variants between forests. The pattern of the two forests differed clearly. In the Elan forest, the rodent survival was higher, and this limited turn-over resulted in a lower seroprevalence and diversity of PUUV sequences than in the Croix-Scaille forest. Uncovering the links between host dynamics and virus microevolution is improving our understanding of PUUV distribution in rodents and the NE risk.

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