Microbes and Infection最新文献

TLR2 is a key component of the innate immune system, responsible for recognizing Gram-positive bacterial components and initiating inflammatory signaling cascades that activate defense responses. However, little is known about the regulatory effects of Pseudomonas aeruginosa (P. aeruginosa) on TLR2 expression. In this study, we investigated the potential link between P. aeruginosa-derived DnaJ and TLR2 expression in macrophages, as well as the activation of downstream signaling pathways. Our findings revealed that DnaJ significantly induced TLR2 expression in a dose- and time-dependent manner, predominantly affecting TLR2 with minimal impact on other TLRs, such as TLR4 and TLR5, which detect bacterial PAMPs. The DnaJ-mediated TLR2 induction was driven by activation of the PI3K-SGK1 signaling pathway, with TLR10 playing a crucial role in facilitating these effects. This increase in TLR2 expression led to enhanced production of inflammatory cytokines in response to secondary Staphylococcus aureus infections, indicating a role in boosting host defense mechanisms. In conclusion, these findings suggest that P. aeruginosa-derived DnaJ promotes TLR2 expression via TLR10-mediated activation of the PI3K-SGK1 pathway, thereby enhancing host immune responses against Gram-positive bacterial infections.

Background: Dendritic cells (DCs) loaded with HIV-1 antigens have been explored as a promising therapeutic approach to overcome HIV-1 infection. Heat shock proteins (Hsps) can improve cross-presentation of linked antigens by DCs. Our aim was a comprehensive in silico, in vitro, and in vivo evaluation of fusion proteins comprising the N- and C-terminal regions of Hsp70 (i.e., NT-Hsp70 and CT-Hsp70) as an adjuvant linked to HIV-1 Nef antigen in development of DCs-based vaccine candidates.

Methods: Computational analyses of the NT-Hsp70-Nef and CT-Hsp70-Nef fusion constructs were performed, and their structural features and docking ability with toll-like or endocytic receptors were evaluated. The effectiveness of DCs loaded with the fusion proteins in eliciting immunity was assessed in mice. Cytokine secretion levels from splenocytes exposed to single-cycle replicable (SCR) HIV-1 were also measured in vitro.

Results: The DCs pulsed with the fusion constructs induced robust cellular and humoral immune responses in mice and infected splenocytes. The CT-Hsp70 region showed better docking scores with immune receptors and superior adjuvanticity for inducing Nef-specific immune responses (Th1 and CTL activity) compared to the NT-Hsp70 region in DC-based immunization.

Conclusions: The CT-Hsp70-Nef protein demonstrated promising results in both computational and experimental analyses compared to the NT-Hsp70-Nef protein.

Endogenous retroviruses (ERVs) are inherited retroviral genomic elements that integrated into the mammalian genome through germline infections and insertions during evolution. Human ERVs (HERVs) comprise approximately 8 % of the human genome and are increasingly recognized to be involved in the etiology and pathophysiology of numerous brain disorders. In this narrative review, we summarize the existing evidence linking abnormal HERV expression to neurodevelopmental and psychosis-related disorders and discuss how these retroviral elements may contribute to the heterogeneity in clinical outcomes. We also review the findings suggesting that aberrant HERV expression contribute to late-onset cognitive disorders with neurodegenerative components, such as Alzheimer's disease (AD) and other forms of dementia. The evidence implicating abnormal HERV expression in neurodevelopmental, psychotic, and cognitive disorders is manifold and stems from diverse research fields, including human post-mortem brain studies, serological investigations, gene expression analyses, and clinical trials with HERV-specific pharmacological compounds. The recent establishment and use of animal models offer a complementary experimental platform that will help establish causal relationships and identify specific disease pathways affected by abnormal HERV expression. Yet, significant gaps persist in understanding the role of HERVs in neurodevelopmental, psychotic, and cognitive disorders, particularly concerning the specificity and stability of abnormal HERV expression in these conditions. Addressing these questions appears crucial for optimizing the potential benefits of therapeutic interventions aimed at targeting abnormal HERV expression across the broad spectrum of HERV-associated disorders of the central nervous system.

In the context of long-term therapy in virologically suppressed people living with HIV-1 (PLWH), the identification of new biomarkers associated with immuno-virological discordance, and the risk of disease progression is needed. Herein we investigated HERVs expression in association with immuno-virological discordance parameters for the identification of novel markers for the clinical monitoring of virologically suppressed PLWH. It is known the human endogenous retroviruses (HERVs), relics of ancestral exogenous retroviral infections comprising 8 % of human genome, could be reactivated by exogenous viruses including HIV-1. The study included 31 virologically suppressed PLWH and 10 healthy donors; blood HIV-DNA levels and residual plasma viremia were quantified by droplet digital-PCR, the expression of HERVs by RT-Real time PCR, and immunophenotyping by flow cytometry. The results revealed a dynamic association of HERVs with several virological and immunological parameters such as the HIV-1 reservoir, CD4 cell count, CD4 nadir and with CD8 and CD19 lymphocyte activation. In an era of searching innovative biomarkers for people living with HIV-1, the interconnection of HERVs with the HIV-1 reservoir and lymphocyte activation opens to further investigation on HERVs role in persistent immune activation in virologically suppressed PLWH, proposing them as potential new markers for clinical monitoring.

Purpose: To demonstrate the efficacy of the bacteriocinogenic Enterococcus faecalis 14 (E. faecalis 14) in the control of induced necrotic enteritis (NE) in broilers.

Methods: Six groups of 504 broilers consisting of an infected untreated control (IUC) group, an infected and amoxicillin treated control (ITC) group, and groups receiving prophylactically (2 groups) or therapeutically (2 groups) E. faecalis 14 or its Δbac mutant were used. All groups were challenged with Clostridium perfringens 56 to induce NE. To predispose the boilers to develop subclinical NE, a high protein grower diet containing 15% fishmeal and a coccidial inoculum were administered.

Results: NE lesions were observed on D26 in all groups except ITC and those receiving prophylactically and therapeutically E. faecalis 14. On D27, only ITC and the group prophylactically treated with E. faecalis 14 (T03 T03) were without lesions. Average body weight and daily weight gain remained lower in the treated groups compared to the ITC group, but there was a clear improvement in the period between D21 to D27, especially in the group prophylactically treated with E. faecalis 14. Specifically, the daily weight gain (DWG) in this period for group T03, was second highest after the group ITC. Metataxonomic analyses showed a positive effect of E. faecalis 14 in maintaining the diversity and richness of the intestinal microbiota, in contrast to ITC group and other conditions.

Conclusions: The results of this in vivo study demonstrated the efficacy of the prophylactic administration of the bacteriocinogenic E. faecalis 14 in preventing of the NE lesions caused by C. perfringens.

Leptospirosis is a zoonosis caused by spirochete Leptospira. Pathogenic leptospires evade the Complement System, enabling their survival upon contact with normal human serum in vitro. In a previous study, we demonstrated that proteases secreted by pathogenic leptospires cleave several Complement proteins, including C3 and the opsonins C3b and iC3b. We hypothesize that these Leptospira proteases, such as thermolysin and leptolysin, may decrease the phagocytic activity of murine peritoneal macrophages. We observed decreased amounts of CR3 and CR4 using flow cytometry when these cells were treated with supernatant from the culture of pathogenic leptospires (SPL) for 24 h. Through confocal microscopy, we observed a reduction in TLR2, CD11b, and CD206 (mannose receptor) levels when these cells were treated with SPL or recombinant thermolysin for 24 h. Furthermore, opsonins such as C3b/iC3b deposited on the surface of pathogenic leptospires were clearly degraded in the presence of recombinant thermolysin or recombinant leptolysin. Consequently, when opsonized bacteria and macrophages were previously incubated with these proteases, phagocytic activity was diminished. These observations lead us to suggest that proteases secreted by pathogenic leptospires could degrade opsonins present in normal serum or deposited on the bacterial membrane, as well as cleave or inhibit macrophage surface molecules. Therefore, these proteases could interfere with the recognition and internalization by murine macrophages, favoring the spread of leptospires in the host.