Biology subjects

Despres, P.

Publications and source records attributed to Despres, P..

5 recordsLinked to original sources

bioRxiv2024

FungAMR: A comprehensive portrait of antimicrobial resistance mutations in fungi

Antimicrobial resistance (AMR) is a global threat. To optimize the use of our antifungal arsenal, we need rapid detection and monitoring tools that rely on high-quality AMR mutation data. Here, we performed a thorough manual curation of published AMR mutations in fungal pathogens to produce the FungAMR reference dataset. A total of 501 papers were curated, leading to 35,792 mutation entries all classified with the degree of evidence that supports their role in resistance. FungAMR covers 95 species, 246 genes and 208 drugs. We combined variant effect predictors with FungAMR resistance mutations and showed that these tools could be used to help predict the potential impact of mutations on AMR. Additionally, a comparative analysis among species revealed a high level of convergence in the molecular basis of resistance, highlighting some potentially universal resistance mutations. The analysis also showed that a significant number of resistance mutations lead to cross-resistance within antifungals of a class, as well as between classes for certain mutated genes. The acquisition of fungal resistance in the clinic and the field is an urging concern. Finally, we provide a computational tool, ChroQueTas, that leverages FungAMR to screen fungal genomes for AMR mutations. These resources are anticipated to have great utility for researchers in the fight against antifungal resistance.

microbiology↗

bioRxiv2024

A recombinant CHIKV-NLuc virus identifies chondrocytes as target of Chikungunya virus in a immunocompetent mouse model

First isolated in 1953 in Tanzania, the arthritogenic Chikungunya virus (CHIKV) re-emerged globally in 2005, leading to widespread outbreaks. Unlike other arboviruses, CHIKV predominantly induces symptomatic infections (72-96%), marked by fever, myalgia, polyarthralgia, and rash. Although rarely fatal, atypical forms such as encephalopathies can occur. Notably, 75.4% of patients experience persistent arthralgias for up to three years after the acute phase. Understanding CHIKVs pathophysiology in the joints is challenging due to the difficulties to obtain biological samples. The study employs a mouse model infected with a reporter virus expressing a Nano Luciferase to investigate the diseases transition to chronic arthritis. The murine model reveals viral replication in metatarsi joints, particularly in chondrocytes, confirmed in primary human chondrocytes undergoing viral-induced apoptosis. Ex vivo analysis confirmed viral replication in leg bones and articular cartilages, with histological evidence of focal erosive lesions and periarticular inflammation. The study further utilizes an in vivo imaging mouse model to monitor viral replication over time. Human chondrocytes prove susceptible to CHIKV infection, exhibiting active viral replication, bioluminescence activity, and increased viral production. CHIKV induced apoptosis, the upregulation of markers associated with cartilage remodeling and altered the cytokine production. This comprehensive study, utilizing advanced techniques and models, provides insights into CHIKVs ability to infect articular cartilages, shedding light on the mechanisms of chronic arthritis following infection.

microbiology↗

bioRxiv2024

The NS1 protein of contemporary West African Zika virus is efficient to increase cellular permissiveness to virus replication

Mosquito-borne Zika virus (ZIKV; orthoflavivirus, Flaviviridae) has become a global health problem due to expansion of the geographic distribution of Asian Lineage virus. Contemporary ZIKV strains of African lineage have recently gained increased attention due to their epidemic potential and their capacity to be highly teratogenic in humans. The ZIKV non-structural NS1 protein from recent West African strains Africa was been studied where with view of its importance in the pathogenicity. NS1 protein from contemporary West African ZIKV (NS1CWA) and historical African ZIKV strain MR766 (NS1MR766) differ by seven amino-acid substitutions. Expression of recombinant NS1 proteins showed differences in the subcellular distribution between NS1CWA and NS1MR766 in HEK-293T cells. There was an increased secretion efficiency of soluble NS1CWA compared to NS1MR766. The replication of a chimeric MR766/NS1CWA virus was studied in Vero and A549 cells. Insertion of NS1CWA into MR766 enhances virus replication in both cell lines leading to more pronounced cell death. This correlated with lower up-regulation of IFN-{beta} and interferon-stimulated gene mRNA in A549 cells infected by MR766/NS1CWA virus. Our data raise the question on the importance of NS1 protein in the pathogenicity of contemporary ZIKV from West Africa, and point to differences within viral strains belonging to the same African lineage. AUTHOR SUMMARYMosquito-borne Zika virus (ZIKV) of African lineage has the potential to cause epidemic along with a high risk of fetal pathogenicity. Too little is still known on the features of contemporary ZIKV from West Africa. We find there is a remarkable conservation of NS1 amino-acid residues between ZIKV strains recently isolated in Senegal and Guinea. Analysis of recombinant ZIKV NS1 protein revealed efficient secretion of contemporary African NS1 protein from human cells. Using infectious molecular clone of African ZIKV, we showed that contemporary West Africa NS1 protein influences virus replication and innate immune activation. The NS1 protein has been proposed as playing a major role in the pathogenicity of contemporary ZIKV from West Africa.

microbiology↗

bioRxiv2024

The replication properties of a contemporary Zika virus from West Africa depends on NS1/NS4B proteins

Zika virus (ZIKV) have become a global health problem over the past decade due to the extension of the geographic distribution of ZIKV of Asian genotype. Epidemics of Asian ZIKV have been associated with developmental disorders in humans. ZIKV of African lineage would have an epidemic potential associated to fetal pathogenicity requiring a greater attention towards the most recently isolated viral strains from West Africa. In the present study, an infectious molecular clone GUINEA-18 has been obtained from viral strain ZIKV-15555 that had been sequenced from an individual infected by ZIKV in Guinea in 2018. A molecular clone-based comparative study between GUINEA-18 and viral clone MR766MC from historical African ZIKV strain MR766 revealed a lower replication rate for GUINEA-18 associated to a weaker cytotoxicity and reduced innate immune system activation in Vero E6, A549 and HCM3 cell lines. Analysis of chimeric viruses between MR766MC and GUINEA-18 stressed the importance NS1/NS4B proteins with a particular focus for NS4B on GUINEA-18 replication properties. ZIKV has developed strategies to prevent cytoplasmic stress granule formation which occurs in response to virus infection. Study of G3BP protein showed that GUINEA-18 but not MR766MC was efficient to inhibit stress granule assembly in A549 cells subjected to a physiological stressor. GUINEA-18 depends on NS1/NS4B proteins for suppressing stress granule response to environmental stress. The involvement of GUINEA-18 NS1/NS4B proteins on virus replication capability and host-cell responses to ZIKV infection raises the question of the importance of nonstructural proteins in the pathogenicity of contemporary viral strains from West Africa. AUTHOR SUMMARYMost of studies having for objectives to understand the biology of Zika virus (ZIKV) were carried out using epidemic viral strains of Asian lineage. It is now admitted that ZIKV of African genotype would have also a great epidemic potential associated a high risk of fetal pathogenicity. Today, it is urgent to improve our knowledge on recently isolated ZIKV strains in West Africa. In our study, we used the sequence of viral strain from an individual infected by ZIKV in Guinea in 2018 to generate an infectious molecular clone. Analysis of viral clone highlighted the preponderant role of NS1/NS4B proteins in virus replication strategy and cell interactions with a particular focus on ZIKV-specific stress granule formation blockade. We believe that our data will improve our knowledge on the biology of contemporary West Africa ZIKV opening perspectives towards a better understanding on the pathogenicity of African viral strains.

microbiology↗

bioRxiv2023

The hydrophobic nature of dengue 2 M residue 36 influences E protein and ApoptoM peptide

The recent epidemics of dengue in South West Indian Ocean coincided with the emergence of Cosmopolitan dengue virus type 2, including viral strains DES-14 in Tanzania and then RUN-18 in La Reunion. The initial step of dengue virus assembly is the formation of heterodimers between prM and E proteins where prM acts as a chaperone for E. During dengue virus maturation, prM is cleaved into membrane protein M which embeds a pro-apoptotic peptide consisting of residues 31/41 and referred as ApoptoM. An infrequent valine at position M-36 was found in DES-14 whereas RUN-18 bears a common isoleucine. Here, we investigated whether Ile-to-Val substitution at position M-36 may have an impact on RUN-18 E expression and cell-death promoting capability of RUN-18 ApoptoM. Using recombinant RUN-18 envelope proteins expressed in human epithelial A549 cells, we showed that Ile-to-Val but not Ile-to-Ala substitution affects the behavior E protein reducing the cytotoxicity of prM and E proteins. The substitution of isoleucine by valine at position M-36 leads to increase the apoptosis-inducing activity of ApoptoM. Our data highlight that hydrophobic nature of amino-acid residue in position 36 of dengue virus M protein influences E protein expression and death-promoting activity of ApoptoM opens up important perspectives in the development of effective live-attenuated DENV vaccines.

microbiology↗