Abstract There is an urgent need to develop phage therapies for multidrug-resistant bacterial infections. However, although bacteria have been shown to be susceptible to phage therapy, phage therapy is not sufficient in some cases. PhiMR003 is a methicillin-resistant Staphylococcus aureus phage previously isolated from sewage influent, and it has demonstrated high lytic activity and a broad host range to MRSA clinical isolates in vitro. To investigate the potential of phiMR003 for the treatment of MRSA infection, the effects of phiMR003 on immune responses in vivo were analysed using phiMR003-susceptible MRSA strains in a mouse wound infection model. Additionally, we assessed whether phiMR003 could affect the immune response to infection with a nonsusceptible MRSA strain. Interestingly, wounds infected with both susceptible and nonsusceptible MRSA strains treated with phiMR003 demonstrated decreased bacterial load, reduced inflammation and accelerated wound closure. Moreover, the infiltration of inflammatory cells in infected tissue was altered by phiMR003. While the effects of phiMR003 on inflammation and bacterial load disappeared with heat inactivation of phiMR003. Transcripts of proinflammatory cytokines induced by lipopolysaccharide were reduced in mouse peritoneal macrophages. These results show that the immune modulation occurring as a response to the phage itself improves the clinical outcomes of phage therapy. 

/pdf/modification-of-the-immune-response-by-bacteriophages-alters-10rxirob.pdf

Modification of the immune response by bacteriophages alters methicillin-resistant Staphylococcus aureus infection

Myricetin exerts anti-biofilm activity and attenuates osteomyelitis by inhibiting the TLR2/MAPK pathway in experimental mice.

We aimed to study the effects of methyltransferase 3 (METTL3) inhibitor on osteomyelitis in this study. Bone marrow cells (BMs) and peripheral blood mononuclear cells (PBMCs) were isolated. Primary BMs-derived macrophages (BMDMs) were incubated with lipopolysaccharide (LPS), poly (I: C), or PAM3CSK4 after pretreatment with STM2457. S.aureus was injected into the intramedullary canal to construct an osteomyelitis C57BL/6 mice model, which was further treated with STM2457. The body weight, μCT three-dimensional analysis, and bacterial burdens were obtained. Up-regulated METTL3 expression was found in both BMs and PBMCs of osteomyelitis patients. LPS and PAM3CSK4-induced IL-6 and TNF-α secretion in BMDMs could be inhibited by STM2457 pretreatment, while STM2457 pretreatment did not affect the relative expression of NOS2, IL-6, and TNF-α after incubation with poly (I: C). STM2457 alleviated the symptom of osteomyelitis mice with increased body weight, diminished reactive bone formation and cortical bone loss, increased bacterial burdens, and decreased IL-6 and TNF-α secretion. STM2457 pretreatment down-regulated the relative expression of MyD88, p-TAK, and p-IKKα/β in LPS-stimulated BMDMs, while it did not show any effect on poly (I:C)-stimulated BMDMs. STM2457 alleviates the onset of osteomyelitis in mice by down-regulating the relative expression of MyD88 and NF-κB relevant inflammation molecules in macrophages.

/pdf/mettl3-inhibitor-alleviates-the-onset-of-osteomyelitis-in-3q2qkxpu.pdf

METTL3 inhibitor alleviates the onset of osteomyelitis in mice model by targeting MyD88.

Abstract Persistent biofilm infections pose a critical health threat with their relentless presence and amplified antibiotic resistance. Traditional antibacterial photodynamic therapy can inhibit bacteria extracellularly but struggles to control biofilm formation and virulence. Thus, there is an urgent need to develop photosensitizers, such as ultra‐small gold nanoclusters (AuNCs), that can penetrate biofilms and internalize into bacteria. However, AuNCs still face the challenge of insufficient reactive oxygen species (ROS) production and limited near‐infrared light absorption. This study develops a model of indocyanine green (ICG)‐sensitized AuNCs with atomic‐precision size effect. This approach achieved near‐infrared light absorption while inhibiting radiation transitions, thereby regulating the generation of ROS. Notably, different‐sized AuNCs (Au 10 NCs, Au 15 NCs, Au 25 NCs) yielded varied ROS types, resulting from different energy level distributions and electron transfer rates. ICG‐Au 15 NCs achieved a treatment efficacy of 99.94% against Staphylococcus aureus infections in vitro and significantly accelerated wound healing in vivo. Moreover, this study highlights the unique role of ICG‐AuNCs in suppressing quorum sensing, virulence, and ABC transporters compared to their larger counterparts. This strategy demonstrates that atomic‐precision size effect of AuNCs paves the way for innovative approaches in antibacterial photodynamic therapy for infection control. 

Enhancing antibacterial photodynamic therapy with NIR‐activated gold nanoclusters: Atomic‐precision size effect on reducing bacterial biofilm formation and virulence

In the immune system, the detection of pathogens through various mechanisms triggers immune responses. Several types of specific programmed cell deaths play a role in the inflammatory reaction. This study emphasizes the inflammatory response induced by Actinomycetes. Actinomyces spp. are resident bacteria in human oral plaque and often serve as a bridge for pathogenic bacteria, which lack affinity to the tooth surface, aiding their colonization of the plaque. We aim to investigate the potential role of Actinomyces oris in the early stages of oral diseases from a new perspective. Actinomyces oris MG-1 (A. oris) was chosen for this research. Differentiated THP-1 (dTHP-1) cells were transiently treated with A. oris to model the inflammatory reaction. Cell viability, as well as relative gene and protein expression levels of dTHP-1 cells, were assessed using CCK-8, quantitative real-time polymerase chain reaction (RT-qPCR), enzyme-linked immunosorbent assay (ELISA), and Western blot assay. The treatment decreased cell viability and increased the expression of inflammatory genes such as IL-1R1 and NLRP3. It was also observed to significantly enhance the release of IL-1β/IL-18 into the supernatant. Immunoblot analysis revealed a notable increase in the expression of N-gasdermin D persisting up to 24 h. Conversely, in models pre-treated with TLR2 inhibitors, N-gasdermin D was detectable only 12 h post-treatment and absent at 24 h. These results suggest that Actinomyces oris MG-1 induces pyroptosis in dTHP-1 cells via TLR2, but the process is not solely dependent on TLR2. 

TLR2-dependent and independent pyroptosis in dTHP-1 cells induced by Actinomyces oris MG-1

TLR2, TLR4, and NLRP3 mediated the balance between host immune-driven resistance and tolerance in Staphylococcus aureus-infected mice.

Prostaglandin D2 (PGD2) synthesis is closely associated with the innate immune response mediated by pattern recognition receptors (PPRs). We determined PGD2 synthesis whether mediated by Toll-like receptor 2 (TLR2), TLR4 and Nod-like receptor pyrin domain-containing protein 3 (NLRP3) in Escherichia coli (E. coli)-, lipopolysaccharide (LPS)- and Braun lipoprotein (BLP)-stimulated macrophages. Our data demonstrate that TLR2, TLR4, and NLRP3 could regulate the synthesis of PGD2 through cyclo-oxygenase-2 (COX-2) and hematopoietic PGD synthase (H-PGDS) in E. coli-, LPS- or BLP-stimulated macrophages, suggesting that TLR2, TLR4, and NLRP3 are critical in regulating PGD2 secretion by controlling PGD2 synthetase expression in E. coli-, LPS- or BLP-stimulated macrophages. The H-PGDS (a PGD2 specific synthase) inhibitor pre-treatment could down-regulate the secretion of TNF-α, RANTES and IL-10 in LPS- and E. coli-stimulated macrophage. Meanwhile, H-PGDS inhibitor could down-regulate the secretion of TNF-α, while up-regulated RANTES and IL-10 secretion in BLP-stimulated macrophages, suggesting that PGD2 could regulate the secretion of cytokines and chemokines in E. coli-, LPS- or BLP-stimulated macrophages. Furthermore, exogenous PGD2 regulates the secretion of cytokines and chemokines through activation of MAPK and NF-κB signaling pathways after E. coli-, LPS- or BLP stimulation in macrophages. Taken together, PGD2 is found able to regulate E. coli-induced inflammatory responses through TLR2, TLR4, and NLRP3 in macrophages. 

Prostaglandin D2 regulates Escherichia coli-induced inflammatory responses through TLR2, TLR4, and NLRP3 in macrophages.

Staphylococcus aureus (S. aureus) is one of the most infamous and widespread bacterial pathogens, causing a hard-to-estimate number of uncomplicated skin infections and probably hundreds of thousands to millions of more severe, invasive infections globally per year. S. aureus may also be acquired from animals, especially in the livestock industry. The interaction mechanism of host and S. aureus has significance for finding ways to against S. aureus infection and control inflammatory response of host, while the molecular biological activities after S. aureus infection, particular in inflammatory and immune cells are not fully clear. The present study aimed to explore whether pattern recognition receptors (PRRs) mediate prostaglandin D2 (PGD2) synthesis and PGD2 participates in the regulation of inflammatory response in macrophages during S. aureus infection or synthetic bacterial lipopeptide (Pam2CSK4) stimulation. PGD2 secretion level was enhanced by mice peritoneal macrophages infected with the S. aureus. The results indicated that PGD2 secretion was impaired in S. aureus infected-macrophages from toll-like receptors 2 (TLR2)-deficient and NLR pyrin domain-containing 3 (NLRP3)-deficient mice. PGD2 synthetase (hematopoietic PGD synthase, HPGDS) inhibitors could reduce the activation of macrophage mitogen-activated protein kinase (MAPK)/nuclear factor-κ-gene binding (NF-κB) signaling pathways. HPGDS inhibition impaired cytokines (TNF-α, IL-1β, IL-10 and RANTES) secretion and macrophage phagocytosis during S. aureus infection. In addition, inhibition of endogenous PGD2 synthesis was unable to affect the TLR2 and NLRP3 expression in S. aureus-infected macrophages. Taken together, macrophage PGD2 secretion after S. aureus infection depended on receptors TLR2 and NLRP3, and the induced PGD2 participated in the regulation of inflammatory response in S. aureus-infected macrophages. Interestingly, it was found that exogenous PGD2 down-regulated the cytokines secretion and had no effect on phagocytosis in the S. aureus-infected macrophages. 

Prostaglandin D2 is involved in the regulation of inflammatory response in Staphylococcus aureus-infected mice macrophages.

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TLR2, TLR4, and NLRP3 mediated the balance between host immune-driven resistance and tolerance in Staphylococcus aureus-infected mice.

Prostaglandin D2 regulates Escherichia coli-induced inflammatory responses through TLR2, TLR4, and NLRP3 in macrophages.

Prostaglandin D2 is involved in the regulation of inflammatory response in Staphylococcus aureus-infected mice macrophages.