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Flagellin aerosol administration improves the efficacy of antibiotic treatment in Actinobacillus pleuropneumoniae infected pigs
No full textInternational audienceAbstract Swine infections with Actinobacillus pleuropneumoniae ( App ), the causative agent of porcine pleuropneumonia, lead to significant production losses. Surviving pigs may harbor antibiotic-resistant bacteria, highlighting the need for alternatives to reduce antimicrobial use. Stimulation of respiratory innate immunity via Toll-like receptor 5 (TLR5) agonists such as FLAMOD (a recombinant flagellin), has emerged as a promising strategy for combating bacterial lung infections. In a recent study, aerosolized administration of FLAMOD was found to elicit respiratory immune responses in pigs. This study assessed FLAMOD’s protective effects against App , either as a prophylactic intervention or as an adjunct to antibiotic therapy. Prophylactic administration of aerosolized FLAMOD via nebulization before App challenge failed to confer protection. However, in a therapeutic setting, where pigs were infected with App and treated with either a subtherapeutic dose of penicillin G (PenG) alone or a combination of PenG and aerosolized FLAMOD. Notably, the FLAMOD and PenG combination significantly improved bacterial clearance from the lungs. Moreover, FLAMOD-PenG treated pigs exhibited a trend toward increased weight gain and fewer lung lesions compared to those receiving PenG alone. These findings provide proof for the concept that FLAMOD enhances antibiotic efficacy, potentially lowering the required antibiotic dose and contributing to antimicrobial resistance mitigation in pigs
Targeting TRPV6/CXCR4 complexes prevents castration-resistant prostate cancer metastasis to the bone
No full textInternational audienceBone metastasis most commonly occurs in castration-resistant prostate cancer (CRPC). The TRPV6 calcium channel is absent in healthy prostate tissue, but its expression increases considerably during cancer progression. We hypothesized that cancer cells induce TRPV6 expression de novo to directly benefit from tightly regulated calcium intake via TRPV6 while providing cancer cells with a selective advantage for metastasis in the calcium-abundant niche, such as bone. Using a cohort of prostate cancer tissue biopsies from patients with a clinical history of at least 10 years after biopsy, we report that TRPV6 expression directly correlates with CRPC tumor aggressiveness and increased risk of metastasis development. The TRPV6 channel is involved in the acquisition of both mesenchymal and invasive phenotypes through increased phosphorylation of CaMK2 followed by the translocation of the transcription factor NF-κB to the nucleus and the expression of EMT markers, MMPs, and transcription factors such as Twist, Snail, and Slug. Moreover, TRPV6 expression was accompanied by increased formation of CXCR4/TRPV6 complexes. In vivo, mice bearing trpv6+/+ tumors presented increased metastasis, notably bone metastasis, whereas trpv6−/− mice developed no metastasis. Targeting TRPV6 with a monoclonal antibody resulted in a significant reduction in the metastatic burden and an increase in overall survival. When AMD3100, a selective inhibitor of the CXCR4 receptor, was combined with AMD3100, a synergistic effect on the suppression of metastasis development was achieved. Thus, the suppression of CRPC metastasis to bone can be achieved via simultaneous targeting of TRPV6/CXCR4, demonstrating that combined therapy is a proof-of-concept approach in vivo
Weekly Screening of Circulating Mucorales DNA and early treatment in Severely Burned Patients Improves Survival: Real-Life Bi-center Experience in France.
No full textInternational audienceBackgoundInvasive fungal diseases, among which includes invasive wound mucormycosis (IWM), are associated with poor outcomes in severely burned patients (SBPs). In recent years, quantitative real-time polymerase chain reaction (PCR) in serum to detect circulating Mucorales DNA (cmDNA) has shown promise for early diagnosis, reducing treatment duration and improving survival. Similarly, recent studies suggest that cmDNA detection enabled earlier diagnosis of IWM in SBPs. This retrospective study aimed to assess the impact of cmDNA-based diagnosis compared to conventional fungal culture on all-cause mortality at 30 and 100 days in SBPs.MethodsWe retrospectively analyzed medical records of SBPs with proven or probable IWM over 2 periods, before and after the systematic implementation of cmDNA detection across 2 centers.ResultsA total of 37 IWM patients were included. No significant differences were observed in clinical characteristics, treatment regimens, or disease severity between both groups. Our findings indicate that systematic cmDNA detection allowed earlier diagnosis of IWM with a median of −8 days [−16; −4] than mycological culture. The 100-day mortality was reduced from 63.6% to 30.8% (P = .071), and significantly reduced when considering only patients with total body surface area (TBSA) ≥ 30% (P = .047), in the cmDNA group. This earlier detection was associated with early initiation of liposomal amphotericin B-based therapy combined with surgery and may have contributed to the improved outcome.ConclusionscmDNA screening in targeted high-risk SBPs allows for earlier initiation of specific treatment and appears to improve the prognosis of IWM
Evaluating the technical feasibility of serological testing and treatment for Plasmodium vivax in mobile at-risk of malaria Cambodian populations
No full textInternational audienceBackgroundCambodia is targeting malaria elimination by 2025, aligning with the WHO's Mekong Malaria Elimination program. While elimination of Plasmodium falciparum is nearly achieved, Plasmodium vivax elimination presents challenges inherent to this species due to the occurrence of dormant parasite stages, known as hypnozoites. A new approach has been proposed to serologically identify individuals likely carrying hypnozoites that should receive appropriate antimalarial treatment: P. vivax serological testing and treatment (PvSeroTAT). This study aims to determine the technical feasibility of a PvSeroTAT approach in malaria endemic communities with highly mobile populations in Eastern Cambodia.MethodsFrom October 24th 2021 to February 26th 2023, two successive rounds of PvSeroTAT were conducted in adult and adolescent males in three villages of Mondolkiri, Eastern Cambodia. At each round, capillary blood samples were collected from consenting participants to be used for P. vivax serology and G6PD activity determination. Seropositive participants, who were G6PD normal, were then recontacted to be provided an anti-hypnozoite primaquine regimen following Cambodian treatment guidelines (0.25 mg/kg for 14 days). Cross-sectional surveys to evaluate P. vivax prevalence were conducted before, during and after the PvSeroTAT interventions in the same three villages and in three additional neighboring control villages where interventions were not implemented.FindingsParticipation was high, with 96% (456/477) of eligible individuals enrolled in at least one round of PvSeroTAT. However, only 63% of participants enrolled in the first PvSeroTAT round agreed to participate in the second round. In the first and second round of PvSeroTAT, 31% (101/327) and 30% (98/334) of enrolled participants, respectively, were seropositive and among those, 82% (163/199) were eligible for primaquine treatment. All 163 seropositive eligible individuals could be recontacted and offered a primaquine treatment, this occurred within 10 days for 96% of individuals (157/163). P. vivax prevalence decreased in all villages, including the control ones, after the first round of PvSeroTAT from 7.7% to 2.7% overall.InterpretationThe participation rates and overall technical feasibility of PvSeroTAT in highly mobile individuals living within communities in malaria endemic areas of Cambodia were very promising. PvSeroTAT with a lab-based assay is feasible in Cambodia even if it is logistically more challenging than using point-of-care assays. Further studies to understand community perspectives about test and treat approaches in the absence of clinical symptoms will be important for the development of tailored community education and awareness material to improve participation in multiple rounds of test and treat interventions
rhPTH(1-84) for hypoparathyroidism: a randomized study of patient-reported outcomes.
No full textInternational audienceObjective: To assess the impact of recombinant human parathyroid hormone (1-84) [rhPTH(1-84)] compared with placebo, in combination with conventional therapy with vitamin D and/or calcium supplements, on health-related quality of life (HRQoL) in patients with symptomatic chronic hypoparathyroidism (cHypoPT).Design: Randomized, double-blind, placebo-controlled, phase 3b-4 study (ClinicalTrials.gov ID: NCT03324880).Methods: Eligible patients with symptomatic cHypoPT were randomized to receive subcutaneous rhPTH(1-84) 25-100 µg/day or placebo. The primary endpoint was the change from baseline to week 26 in Hypoparathyroidism Symptom Diary (HypoPT-SD) symptom subscale score. Key secondary endpoints were changes from baseline to week 26 in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue and in 36-item Short Form Health Survey physical component summary (SF-36v2 PCS).Results: In total, 93 patients were randomized to receive treatment: 45 received rhPTH(1-84) and 48 received placebo. Change from baseline to week 26 in HypoPT-SD symptom subscale score was significantly greater (improved) in the rhPTH(1-84) group than in the placebo group (difference in least-squares mean changes, -0.53; 95% confidence interval, -0.90 to -0.15, P = .003). Key secondary endpoints, changes between baseline and week 26 in the FACIT-Fatigue and SF-36v2 PCS scores were also significantly greater (improved) in the rhPTH(1-84) group than in the placebo group. The safety profile of rhPTH(1-84) was consistent with previous findings, and no new safety signals were identified.Conclusions: rhPTH(1-84) alongside conventional therapy improved symptom burden (as measured by the HypoPT-SD) and HRQoL to a greater extent than conventional therapy alone in patients with symptomatic cHypoPT
Gene deletion as a possible strategy adopted by New World Leishmania infantum to maximize geographic dispersion
No full textCorrection sur le rôle des auteurs ici : 10.1371/journal.ppat.1013452International audienceBackground The present study investigates implications of a sub-chromosomal deletion in Leishmania infantum strains, the causative agent of American Visceral Leishmaniasis (AVL). Primarily found in New World strains, the deletion leads to the absence of the ecto-3’-nucleotidase/nuclease enzyme, impacting parasite virulence, pathogenicity, and drug susceptibility. The factors favoring prevalence and the widespread geographic distribution of these deleted mutant parasites (DEL) in the NW (NW) are discussed under the generated data. Methods We conducted phenotypic assessments of the sub-chromosomal deletion through in vitro assays with axenic parasites and experimental infections in both in vitro and in vivo models of vertebrate and invertebrate hosts using geographically diverse mutant field isolates. Results Despite reduced pathogenicity, the DEL strains efficiently infect vertebrate hosts and exhibit relevant differences, including enhanced metacyclogenesis and colonization rates in sand flies, potentially facilitating transmission. This combination may represent a more effective way to maintain and disperse the transmission cycle of DEL strains. Conclusions Phenotypic assessments reveal altered parasite fitness, with potential enhanced transmissibility at the population level. Reduced susceptibility of DEL strains to miltefosine, a key drug in VL treatment, further complicates control efforts. The study underscores the importance of typing parasite genomes for surveillance and control, advocating for the sub-chromosomal deletion as a molecular marker in AVL management
Phages with a broad host range are common across ecosystems
No full textInternational audiencePhages are diverse and abundant within microbial communities, where they play major roles in their evolution and adaptation. Phage replication - and multiplication - is generally thought to be restricted within a single or narrow host range. Here we use published and newly generated proximity ligation-based metagenomic Hi-C (metaHiC) data from various environments to explore virus-host interactions. We reconstructed 4,975 microbial and 6,572 phage genomes of medium quality or higher. MetaHiC yielded a contact network between genomes and enabled assignment of approximately half of phage genomes to their hosts, revealing that a substantial proportion of these phages interact with multiple species and this, in environments as diverse as oceanic water column or the human gut. This observation challenges the traditional view of a narrow host spectrum of phages by unveiling that multi-host associations are common across ecosystems, with implications how they might impact ecology and evolution and phage therapy approaches
Temporal Patterns of Haplotypic and Allelic Diversity Reflect the Changing Selection Landscape of the Malaria Parasite Plasmodium falciparum
No full textInternational audienceThe malaria parasite Plasmodium falciparum regularly confronts orchestrated changes in frontline drug treatment that drastically alter its selection landscape. When this has occurred, the parasite has successfully adapted to new drugs through novel resistance mutations. These novel mutations, however, emerge in a genetic background already shaped by prior drug selection. In some instances, selection imposed by different drugs targets the same loci in either synergistic or antagonistic ways, which may leave genomic signatures that are hard to attribute to a specific agent. Here, we use two approaches for detecting sequential bouts of drug adaptation: haplotype-based selection testing and temporal changes in allele frequencies. Using a set of longitudinal samples from French Guiana, we determine that since the official introduction of artemisinin combination therapy in 2007 there have been rapid hard selective sweeps at both known and novel loci. At four high-profile genes with demonstrated involvement in drug resistance (pfcrt, pfmdr1, pfaat1, and pfgch1), we see selection signals both before and after drug regime change; however, selection favored different haplotypes in the two time periods. Similarly, allele frequency analysis identified coding variants whose frequency trajectory changed signs under the new drug pressure. These selected alleles were enriched for genes implicated in artemisinin or partner-drug resistance in other global populations. Overall, these results suggest that drug resistance in P. falciparum is governed by known alleles of large effect along with a polygenic architecture of potentially more subtle variants, any of which can experience fitness reversals under distinct drug regimes
Unraveling the role of rat and flea population dynamics on the seasonality of plague epidemics in Madagascar
No full textInternational audiencePlague continues to pose a public health problem in multiple regions of the world, including Madagascar, where it is characterized by a pronounced seasonal pattern. The drivers of plague seasonality remain poorly understood. Using a deterministic compartmental model, calibrated to rat and flea capture data, serological data collected in active rural foci, and human plague surveillance data, we analyzed the effects of seasonal rat and flea population dynamics on plague transmission. The models that incorporated seasonal fluctuations in rat and flea populations provided better predictive performances than those that did not. We found that a simpler mass-action model also performed well. Driven by these seasonal changes, the effective reproduction number (Re) between rats peaks at 1.45 [95% credible interval (CI): 1.41, 1.48] in October and falls to 0.6 (95% CI: 0.57, 0.63) in March. We estimated that 0.5% (95% CI: 0.2%, 0.9%) of rats are infected annually, indicating that plague is not the main driver of rat population changes. Using our model, we evaluated intervention strategies and found that targeting both rats and their fleas at the start of the epidemic season (July–September) was the most effective approach for reducing human plague cases. Such an approach contrasts with the reactive strategy currently employed in Madagascar. Our findings highlight the role of flea and rat populations in plague seasonality and identify strategies that could be deployed in Madagascar to better control plague epidemics
