ACS Infectious Diseases最新文献

Leishmania donovani (Ld) promastigotes secrete exosomes that are crucial in host-pathogen interactions and intercellular communication by carrying parasite-specific molecules. Although the composition of cargos in Leishmania exosomes is known, the effects of the unique metabolic repertoire on immunometabolism rewiring of macrophage polarization are poorly understood. Interestingly, we found the enrichment of polyamines (PAs) such as spermidine and putrescine in the Ld-exosomes. Herein, we investigate the critical polycationic molecules and their crucial role in parasite survival. Our study shows that PA inhibition or depletion significantly impairs parasite growth and fitness, particularly in drug-resistant strains. Furthermore, we aimed to elucidate the impact of PAs-enriched Ld-exosomes on host macrophages. The data demonstrated that macrophages efficiently internalized these exosomes, leading to heightened phagocytic activity and infectivity. In addition, internalized Ld-exosomes induced M2 macrophage polarization characterized by elevated Arginase-1 expression and activity. The increased expression of the solute carrier gene (SLC3A2) and elevated intracellular spermidine levels suggest that Ld-exosomes contribute to the host PAs pool and create an anti-inflammatory milieu. These findings highlight the essential role of PAs-enriched Ld-exosomes in parasite survival and establishing a pro-parasitic environment in the host macrophage.

Mycobacterium tuberculosis is the most ancient human tuberculosis pathogen and has been the leading cause of death from bacterial infectious diseases throughout human history. According to the World Health Organization Global Tuberculosis Report, in 2022, 7.5 million new tuberculosis cases were identified, marking the highest number of cases since the World Health Organization initiated its worldwide tuberculosis surveillance program in 1995. The 2019 peak was 7.1 million cases, with 5.8 million cases in 2020 and 6.4 million in 2021. The increase in 2022, which may be attributed to the COVID-19 pandemic complicating tuberculosis case tracing, has raised concerns. To better understand the regulation spectrum of Mycobacterium smegmatis mraZ under hypoxia, we performed a transcriptome analysis of M. smegmatis mutant and wild-type strains using Illumina Agilent 5300 sequencing. The study identified 6898 differentially expressed genes, which were annotated with NCBI nonredundant protein sequences, a manually annotated and reviewed protein sequence database, Pfam, Clusters of Orthologous Groups of Proteins, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes. Several mycobacteria transcriptional regulators, virulence genes, membrane transporters, and cell wall biosynthesis genes were annotated. These data serve as a valuable resource for future investigations and may offer insight into the development of drugs to combat M. tuberculosis infection.

In the chronic phase of Chagas disease (CCD), diagnosis relies on detecting specific IgG antibodies due to the low or absent presence of the parasiteTrypanosoma cruzi in human blood. However, the performance of current serological tests is highly variable, lacking a "gold standard" assay with 100% sensitivity and specificity, which challenges the exploration of new biomarkers. In the present study, we evaluated the diagnostic accuracy of an optimized ELISA using the predicted immunogenic domains (called TcD3 and TcD6) of Tc323, a protein highly conserved among T. cruzi strains but absent in other clinically significant parasites such as Leishmania spp. This study was conducted using plasma or serum samples from CCD individuals with different clinical manifestations and living in endemic regions in Latin America, subjects with unrelated infectious diseases, and noninfected donors. The sensitivity and specificity of recombinant TcD3 were 90.8% and 92.6%, respectively, while rTcD6 displayed values of 93.1% and 93.6% for the same parameters. Area under curve (AUC) values were 0.949 for rTcD3 and 0.954 for rTcD6. The receiver operative characteristic (ROC) curve showed a highly significant difference between CCD individuals and noninfected donors. Cross-reactivity was 10.2% for rTcD3 and 8.2% for rTcD6 in subjects infected with leishmaniasis or with toxoplasmosis. In addition, the reactivity against rTcD3 differed among some geographical areas while no significant difference was found using both domains for the detection of T. cruzi-infected individuals with or without cardiac symptoms. Our findings show that the recombinant antigens rTcD3 and rTcD6 could be used as highly potential biomarkers for the serological diagnosis of CCD.

A quantum system prepared in an initial state that is not an eigenstate of its Hamiltonian will exhibit out-of-equilibrium dynamics. These dynamics can span multiple timescales, from the transient response of local correlations to the long-time equilibration of the system. The possibilities seem vast, depending on the initial state, the nature of the interactions and the observables being measured. Reporting in Nature Physics, Yuchen Li and colleagues have observed that the out-of-equilibrium dynamics of local magnetization correlations measured using solid-state nuclear magnetic resonance (NMR) follow a universal form¹.

The free induction decay signal records the temporal correlations of the local magnetization following the quench. Previous studies had suggested that the signal should follow a universal form, with the correlations decaying either as a simple exponential (exp(–γt)) or as a damped oscillation (cos(ωt)exp(–γt)) (ref. ^3,4). Careful NMR experiments on a wide range of systems, including polycrystalline xenon lattices and calcium fluoride^5,6, confirmed such behaviour. Additionally, a second oscillatory decay mode was observed in calcium fluoride⁷. However, the connection between these universal decays and the parameters of the underlying Hamiltonian remained unclear, limiting the possibility of predicting these universal modes in more general settings.

Pseudomonas aeruginosa is a leading bacterial pathogen that causes persistent infections. One major reason that antibiotics fail to clear such infections is the presence of a dormant subpopulation called persister cells. To eradicate persister cells, it is important to change drug development from traditional strategies that focus on growth inhibition to the search for new leads that can kill dormant cells. In this study, we demonstrate that eravacycline can effectively accumulate in P. aeruginosa persister cells, leading to strong killing during wakeup, including persister cells in both planktonic cultures and biofilms of the wild-type strain and its mucoid mutant. The effects of eravacycline on persister control were further validated in vivo using a lung infection model in mice. Collectively, these results demonstrate the possibility to control persister cells of bacterial pathogens by targeting dormancy.

The Zika virus (ZIKV) has garnered significant public attention, particularly following the outbreak in Brazil, due to its potential to cause severe damage to the central nervous system and its ability to cross the placental barrier, resulting in microcephaly in infants. Despite the urgency, there remains a lack of targeted therapies or vaccines for the prevention or treatment of ZIKV infection and its related diseases. Fangchinoline (FAN), an alkaloid derived from traditional Chinese medicinal herbs, has a range of biological activities. In this study, we employed both in vitro and in vivo infection models to demonstrate the efficacy of FAN in inhibiting ZIKV. Our findings indicate that FAN effectively suppresses the replication of ZIKV viral RNA and protein, thereby validating its anti-ZIKV capabilities in living organisms. Further analysis through dosing time assays and infectious inhibition assays revealed that FAN exerts its antiviral effects by impeding the early stages of infection, specifically by inhibiting the internalization of ZIKV. These results underscore the potential of FAN as a candidate for anti-ZIKV drug development and offer novel insights into drug design strategies that target the virus's internalization process.

Nematic phases, in which electrons in a solid spontaneously break rotational symmetry while preserving translational symmetry, exist in several families of unconventional superconductors. Superconductivity mediated by nematic fluctuations is well established theoretically, but it has yet to be unambiguously identified experimentally. One major challenge is that nematicity is often intertwined with other degrees of freedom, such as magnetism and charge order. The FeSe_1−xS_x family of superconductors provides an opportunity to explore this concept, as it features an isolated nematic phase that can be suppressed by sulfur substitution at a quantum critical point where the nematic fluctuations are the largest. Here we determine the momentum structure of the superconducting gap near the centre of the Brillouin zone in FeSe_0.81S_0.19—close to the quantum critical point—and find that it is anisotropic and nearly nodal. The gap minima occur in a direction that is rotated 45° with respect to the Fe–Fe direction, unlike the usual isotropic gaps due to spin-mediated pairing in other tetragonal Fe-based superconductors. Instead, we find that the gap structure agrees with theoretical predictions for superconductivity mediated by nematic fluctuations, indicating a change in the pairing mechanism across the phase diagram of FeSe_1−xS_x.