Therapeutic potential of isoallolithocholic acid in methicillin-resistant Staphylococcus Aureus peritoneal infection
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Resistance to linezolid in Staphylococcus aureus by mutation, modification, and acquisition of genes
Linezolid binds to the 50S subunit of the bacterial ribosome, inhibiting bacterial protein synthesis by preventing the formation of the initiation complex. Oxazolidinone antimicrobial drugs represent the last line of defense in treating Staphylococcus aureus infections; thus, resistance to linezolid in S. aureus warrants high priority. This article examines the major mechanisms of resistance to linezolid in S. aureus, which include: mutations in the domain V of 23S rRNA (primarily G2576); chromosomal mutations in the rplC, rplD, and rplV genes (encoding the ribosomal uL3, uL4, and uL22 proteins, respectively); the exogenous acquisition of the methylase encoded by the chloramphenicol-florfenicol resistance (cfr) gene; the endogenous methylation or demethylation of 23S rRNA; the acquisition of optrA and poxtA resistance genes; and the existence of the LmrS multidrug efflux pump. In conclusion, these mechanisms mediate resistance through mutations or modifications to the bacterial target, thereby reducing the affinity of linezolid for the peptidyl transferase center (PTC) binding site or by preventing the binding of linezolid to the PTC through a ribosomal protective effect. The existence of additional, unexplained resistance mechanisms requires further investigation and verification.
Severity of neonatal influenza infection is driven by type I interferon and oxidative stress
Neonates exhibit increased susceptibility to respiratory viral infections, attributed to inflammation at the developing pulmonary air-blood interface. IFN I are antiviral cytokines critical to control viral replication, but also promote inflammation. Previously, we established a neonatal murine influenza virus (IV) model, which demonstrates increased mortality. Here, we sought to determine the role of IFN I in this increased mortality. We found that three-day-old IFNAR-deficient mice are highly protected from IV-induced mortality. In addition, exposure to IFNβ 24 h post IV infection accelerated death in WT neonatal animals but did not impact adult mortality. In contrast, IFN IIIs are protective to neonatal mice. IFNβ induced an oxidative stress imbalance specifically in primary neonatal IV-infected pulmonary type II epithelial cells (TIIEC), not in adult TIIECs. Moreover, neonates did not have an infection-induced increase in antioxidants, including a key antioxidant, superoxide dismutase 3, as compared to adults. Importantly, antioxidant treatment rescued IV-infected neonatal mice, but had no impact on adult morbidity. We propose that IFN I exacerbate an oxidative stress imbalance in the neonate because of IFN I-induced pulmonary TIIEC ROS production coupled with developmentally regulated, defective antioxidant production in response to IV infection. This age-specific imbalance contributes to mortality after respiratory infections in this vulnerable population.
Peroxisome proliferator-activated receptor alpha is an essential factor in enhanced macrophage immune function induced by angiotensin-converting enzyme
Increased expression of angiotensin-converting enzyme (ACE) by myeloid lineage cells strongly increases the immune activity of these cells, as observed in ACE10/10 mice, which exhibit a marked increase in antitumor and antibactericidal immunity. We report that peroxisome proliferator-activated receptor alpha (PPARα), a transcription factor that regulates genes critical for lipid metabolism, is a key molecule in the enhanced macrophage function induced by ACE. Here, we used a Cre–LoxP approach with LysM-Cre to create a modified ACE10/10 mouse line in which macrophages continue to generate abundant ACE but in which monocyte and macrophage PPARα expression is selectively suppressed. These mice, termed A10-PPARα-Cre, have significantly increased growth of B16-F10 tumors compared with ACE10/10 mice with Cre expression. PPARα depletion impaired cytokine production and antigen-presenting activity in ACE-expressing macrophages, resulting in reduced tumor antigen-specific CD8+ T-cell generation. Additionally, the elevated bactericidal resistance typical of ACE10/10 mice was significantly reduced in A10-PPARα-Cre mice, such that these mice resembled WT mice in their resistance to methicillin-resistant Staphylococcus aureus (MRSA) infection. THP-1 cells expressing increased ACE (termed THP-1-ACE) constitute a human macrophage model with increased PPARα that shows enhanced cytotoxicity against tumor cells and better phagocytosis and killing of MRSA. RNA silencing of PPARα in THP-1-ACE cells reduced both tumor cell death and bacterial phagocytosis and clearance. In contrast, the in vivo administration of pemafibrate, a specific agonist of PPARα, to WT and A10-PPARα-Cre mice reduced B16-F10 tumor growth by 24.5% and 25.8%, respectively, but pemafibrate reduced tumors by 57.8% in ACE10/10 mice. With pemafibrate, the number of antitumor CD8+ T cells was significantly lower in A10-PPARα-Cre mice than in ACE10/10 mice. We conclude that PPARα is important in the immune system of myeloid cells, including wild-type cells, and that its increased expression by ACE-expressing macrophages in ACE10/10 mice is indispensable for ACE-dependent functional upregulation of macrophages in both mice and human cells.
The comprehensive SARS-CoV-2 ‘hijackome’ knowledge base
The continuous evolution of SARS-CoV-2 has led to the emergence of several variants of concern (VOCs) that significantly affect global health. This study aims to investigate how these VOCs affect host cells at proteome level to better understand the mechanisms of disease. To achieve this, we first analyzed the (phospho)proteome changes of host cells infected with Alpha, Beta, Delta, and Omicron BA.1 and BA.5 variants over time frames extending from 1 to 36 h post infection. Our results revealed distinct temporal patterns of protein expression across the VOCs, with notable differences in the (phospho)proteome dynamics that suggest variant-specific adaptations. Specifically, we observed enhanced expression and activation of key components within crucial cellular pathways such as the RHO GTPase cycle, RNA splicing, and endoplasmic reticulum-associated degradation (ERAD)-related processes. We further utilized proximity biotinylation mass spectrometry (BioID-MS) to investigate how specific mutation of these VOCs influence viral–host protein interactions. Our comprehensive interactomics dataset uncovers distinct interaction profiles for each variant, illustrating how specific mutations can change viral protein functionality. Overall, our extensive analysis provides a detailed proteomic profile of host cells for each variant, offering valuable insights into how specific mutations may influence viral protein functionality and impact therapeutic target identification. These insights are crucial for the potential use and design of new antiviral substances, aiming to enhance the efficacy of treatments against evolving SARS-CoV-2 variants.
Ginsenoside Rg3 enriches SCFA-producing commensal bacteria to confer protection against enteric viral infection via the cGAS-STING-type I IFN axis
The microbiota-associated factors that influence host susceptibility and immunity to enteric viral infections remain poorly defined. We identified that the herbal monomer ginsenoside Rg3 (Rg3) can shape the gut microbiota composition, enriching robust short-chain fatty acid (SCFA)-producing Blautia spp. Colonization by representative Blautia coccoides and Blautia obeum could protect germ-free or vancomycin (Van)-treated mice from enteric virus infection, inducing type I interferon (IFN-I) responses in macrophages via the MAVS-IRF3-IFNAR signaling pathway. Application of exogenous SCFAs (acetate/propionate) reproduced the protective effect of Rg3 and Blautia spp. in Van-treated mice, enhancing intracellular Ca2+– and MAVS-dependent mtDNA release and activating the cGAS-STING-IFN-I axis by stimulating GPR43 signaling in macrophages. Our findings demonstrate that macrophage sensing of metabolites from specific commensal bacteria can prime the IFN-I signaling that is required for antiviral functions.
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