Alteration of macrophage immune phenotype in a murine sepsis model is associated with susceptibility to secondary fungal infection.

BACKGROUND: Secondary fungal infection is a major complication in patients with sepsis-associated immunosuppression. However, sepsis-induced immune alterations related to fungal susceptibility have not been well characterized. OBJECTIVES: To determine kinetic changes in the immune phenotype by determining the proportion of T cells, B cells and macrophages, and especially the expression of an immune exhaustion marker PD-1, in murine sepsis. In addition, sepsis -induced alterations of these immune cells were assessed in relation to susceptibility to secondary fungal infection. METHODS: Cecal ligation and puncture (CLP) was used as a mouse sepsis model, with Candida albicans as the secondary systemic fungal infection. Splenic T cells, B cells and macrophages were assessed by flow cytometry. RESULTS: Alterations in T cell and B cell numbers and the proportion of PD-1 expressing T cells and B cells in CLP mice were not clearly related to susceptibility to secondary Candida infection. By contrast, changes in levels of CD86+-activated macrophages, and the proportion of the PD-1+ population among the CD86+ macrophages in CLP mice were found to be related to secondary fungal infection susceptibility. CONCLUSIONS: Macrophage activation and exhaustion might be a significant determinant in susceptibility to fungal infection, and outcomes of infection. This study provided more comprehensive knowledge pertinent to patient evaluation and therapeutics design in restoring host defenses against secondary fungal infection in those with sepsis.

Blockade Of PD-1 Attenuated Postsepsis Aspergillosis Via The Activation of IFN-γ and The Dampening of IL-10.

BACKGROUND: Nosocomial aspergillosis in patients with sepsis has emerged in the past few years. Blockade of PD-1/PD-L pathway has tended to become a promising therapeutic strategy as it improved the outcome of bacterial sepsis and postsepsis secondary fungal infection. Recently, the controversial effects of PD-1 blockade on infectious diseases, including aspergillosis, have been demonstrated; therefore, the efficacy of anti-PD-1 drug still remains to be elucidated. METHODS: Cecal ligation and puncture (CLP) was conducted as a mouse sepsis model. Aspergillus fumigatus spores were intravenously inoculated on day 5 post-CLP, when the immune cells succumbed to exhaustion. Amphotericin B was medicated together with or without anti-PD-1 treatment after Aspergillus infection. RESULTS: Amphotericin B alone was not effective to treat the CLP-mice with secondary aspergillosis. In contrast, antifungal medication with the adjunctive anti-PD-1 treatment attenuated the fungal burdens in blood and internal organs, and improved the survival rate of the mice with secondary aspergillosis. These outcomes of PD-1 blockade were concurring with the enhanced CD86 expression on splenocytes, the augmented serum IFN-γ, and the dampened IL-10. Activated T cells from anti-PD-1-treated mice also highly increased IFN-γ and diminished IL-10 production. CONCLUSION: The blockade of PD-1 on postsepsis aspergillosis presumably reinvigorated exhausted antigen-presenting cells and T cells by upregulating CD86 expression and IFN-γ production, and dampened IL-10 production, which consequently leaded to the attenuation of secondary aspergillosis. The adjunctive anti-PD-1 therapy may become a promising strategy for the advanced immunotherapy against lethal fungal infection.

Gold nanoparticles attenuates bacterial sepsis in cecal ligation and puncture mouse model through the induction of M2 macrophage polarization.

BACKGROUND: Gold nanoparticles (AuNP) have several biochemical advantageous properties especially for a candidate of drug carrier. However, the non-conjugated AuNP has a higher rate of cellular uptake than the conjugated ones. Spherical AuNP in a proper size (20-30 nm) is non-toxic to mice and shows anti-inflammatory properties. We tested if the administration of AuNP, as an adjuvant to antibiotics, could attenuate bacterial sepsis in cecal ligation and puncture (CLP) mouse model with antibiotic (imipenem/cilastatin). RESULTS: Indeed, AuNP administration at the time of CLP improved the survival, blood bacterial burdens, kidney function, liver injury and inflammatory cytokines (TNF-α, IL-6, IL-1ß and IL-10). AuNP also decreased M1 macrophages (CD86 + ve in F4/80 + ve cells) and increased M2 macrophages (CD206 + ve in F4/80 + ve cells) in the spleens of sepsis mice. The weak antibiotic effect of AuNP was demonstrated as the reduction of E. coli colony after 4 h incubation. In addition, AuNP altered cytokine production of bone-marrow-derived macrophages including reduced TNF-α, IL-6 and IL-1ß but increased IL-10 at 6 and 24 h. Moreover, AuNP induced macrophage polarization toward anti-inflammatory responses (M2) as presented by increased Arg1 (Arginase 1) and PPARγ with decreased Nos2 (inducible nitric oxide synthase, iNos) and Nur77 at 3 h after incubation in vitro. CONCLUSIONS: The adjuvant therapy of AuNP, with a proper antibiotic, attenuated CLP-induced bacterial sepsis in mice, at least in part, through the antibiotic effect and the induction of macrophage function toward the anti-inflammatory responses.

Preparation of cross-linked magnetic chitosan particles from steel slag and shrimp shells for removal of heavy metals.

In this study, a new method for preparation of cross-linked magnetic chitosan particles (MCPs) from steel slag and shrimp shells using green tea extract as crosslinking reagent has been presented. The MCPs obtained were characterized by means of X-ray diffraction analysis, Fourier-transform infrared spectroscopy, scanning electron microscopy and magnetic properties, and then were used to investigate the adsorption properties of Cu(II) and Ni(II) ions in aqueous solutions. The influence of experimental conditions such as contact time, pH value, adsorbent dose and initial metal concentration, and the possibility of regeneration were studied systematically. The Cu(II) and Ni(II) adsorption isotherms, kinetics and thermodynamics have been measured and discussed. The results show that the synthesized MCPs have high adsorption capacity for both metal ions (126.58 mg/g for Cu(II) and 66.23 mg/g for Ni(II)), and have excellent regeneration stability with efficiency of greater than 83% after five cycles of the adsorption-regeneration process. The adsorption process of Ni(II) and Cu(II) on MCPs was feasible, spontaneous and exothermic, and better described by the Langmuir model and pseudo-second-order kinetic equation. The MCPs can be applied as a low cost and highly efficient adsorbent for removal of heavy metals from wastewater due to its high adsorption capacity, easy recovery and good reusability.