The emergence of multidrug- and extensively drug-resistant Acinetobacter baumannii has made it difficult to treat and control infections caused by this bacterium. Thus, alternatives to conventional antibiotics for management of severe A. baumannii infections is urgently needed. In our previous study, we found that a capsule depolymerase Dpo48 could strip bacterial capsules, and the non-capsuled A. baumannii were significantly decreased in the presence of serum complement in vitro. Here, we further explored its potential as a therapeutic agent for controlling systemic infections caused by extensively drug-resistant A. baumannii. Prior to mammalian studies, the anti-virulence efficacy of Dpo48 was first tested in a Galleria mellonella infection model. Survival rate of Dpo48-pretreated bacteria or Dpo48 treatment group was significantly increased compared to the infective G. mellonella without treatment. Furthermore, the safety and therapeutic efficacy of Dpo48 to mice were evaluated. The mice treated with Dpo48 displayed normal serum levels of TBIL, AST, ALT, ALP, Cr, BUN and LDH, while no significant histopathology changes were observed in tissues of liver, spleen, lung, and kidney. Treatment with Dpo48 could rescue normal and immunocompromised mice from lethal peritoneal sepsis, with the bacterial counts in blood, liver, spleen, lung, and kidney significantly reduced by 1.4–3.3 log colony-forming units at 4 h posttreatment. Besides, the hemolysis and cytotoxicity assays showed that Dpo48 was non-homolytic to human red blood cells and non-toxic to human lung, liver and kidney cell lines. Overall, the present study demonstrated the promising potential of capsule depolymerases as therapeutic agents to prevent antibiotic-resistant A. baumannii infections.

Circular RNAs (circRNAs) have been reported as effective diagnostic and therapeutic biomarkers in many diseases, but the potential of using this easy‐to‐monitor and highly stable materials for diagnosing Community‐acquired pneumonia (CAP) remains unexplored. Here, aiming to identify potential CAP‐related circRNAs in peripheral blood and seeking to deepen the understanding of how circRNA‐miRNA‐mRNA regulatory networks may contribute to CAP, we applied microarrays profiling analysis and identified 8296 differentially expressed (DE) circRNAs between patients with CAP (n = 6) and healthy controls (n = 6). Subsequently, we validated the accumulation trends for the top 100 DE circRNAs based on qPCR in an independent validation cohort (30 patients vs 30 controls), and ultimately identified a panel of four circRNAs that perform extremely well as sensitive and specific biomarkers for diagnosing CAP: hsa_circ_0018429 (area under the curve [AUC] = 0.8216), hsa_circ_0026579 (AUC = 0.7733), hsa_circ_0125357 (AUC = 0.7730), and hsa_circ_0099188 (AUC = 0.6978); combined as a panel (AUC = 0.8776). In addition, hsa_circ_0026579 exhibited good performance in differentiating viral from bacterial or mixed infection, with an AUC of 0.863. We also identified 10 miRNAs that most likely to interact with these four circRNAs, and then predicted 205 mRNA target genes. The KEGG pathway enrichment analysis suggested highly plausible functional implications related to inflammation and to virus‐infection‐related signaling pathways (such as HTLV‐1 infection and hepatitis B infection). Thus, we generated a genetic network of potential CAP‐related regulatory interactions that should inform future hypothesis‐driven research into the causes and potential treatment of this widespread and frequently fatal disease.

Carbapenem-resistant Klebsiella pneumoniae (CRKP) pose a significant threat to global public health. In present research, a total of 80 CRKP strains belonging to ST11 were collected with 70% (56 of 80 isolates) expressing a K47 capsular type. Thus, it is significant to prevent and control infections caused by these bacteria. Capsule depolymerases could degrade bacterial surface polysaccharides to reduce their virulence and expose bacteria to host immune attack. Previous studies have demonstrated the potential of phage-encoded depolymerases as antivirulent agents in treating CRKP infections in vitro and in vivo. Here, two capsule depolymerases (Dpo42 and Dpo43) derived from phage IME205 were expressed and characterized. Although both depolymerases act on strains with a capsular serotype K47, they are active against different subsets of strains, indicating subtle differences in capsule composition that exist within this serotype. The host range of phage IME205 matched to the sum of specificity range of Dpo42 and Dpo43. These two enzymes maintained stable activity in a relatively broad range of pH levels (pH 5.0-8.0 for Dpo42 and pH 4.0-8.0 for Dpo43) and temperatures (20-70 • C). Besides, both Dpo42 and Dpo43 could make host bacteria fully susceptible to the killing effect of serum complement and display no hemolytic activity to erythrocytes. In summary, capsule depolymerases are promising antivirulent agents to combat CRKP infections.

No abstract

Bacterial isolate X39 was isolated from a community-acquired pneumonia patient in Beijing, China. A phylogenetic tree based on rpoB genes and average nucleotide identity data confirmed that isolate X39 belonged to Klebsiella variicola. The genome of K. variicola X39 contained one circular chromosome and nine plasmids. Comparative genomic analyses with other K. variicola isolates revealed that K. variicola X39 contained the most unique genes. Of these unique genes, many were prophages and transposases. Many virulence factors were shared between K. variicola X39 and Klebsiella pneumoniae F1. The pathogenicity of K. variicola X39 was compared with that of K. pneumoniae F1 in an abdominal infection model. The results indicated that K. variicola X39 was less virulent than typical clinical K. pneumoniae F1. The genome of K. variicola X39 also contained some genes involved in plant colonization, nitrogen fixation, and defense against oxidative stress. GFP-labeled K. variicola X39 could colonize maize as an endophytic bacterium. We concluded that K. variicola X39 was a kingdom-crossing strain.

Female sex workers (FSWs) play an important role in the heterosexual transmission of HIV and sexually transmitted infections (STIs) in China. We conducted a cross-sectional study of 609 FSWs from various venues in Changzhou to investigate risk behaviours and prevalences of HIV and STIs among FSW subgroups. Structured questionnaires were used in face-to-face interviews to collect information. Blood and cervical specimens were collected to test for HIV, syphilis, Neisseria gonorrhoeae (NG) and Chlamydia trachomatis (CT) infections. The overall prevalences of syphilis, NG and CT were 5.6, 2.3 and 17.0%, respectively. The highest prevalence of syphilis (13.8%, P < 0.001) was observed among FSWs in low-class (LC) venues. No case of HIV infection was found. Less than half of all FSWs (40.7%) reported consistent condom use with clients during the last month. A multivariate analysis revealed a 13-fold increased risk for FSWs with NG infection to be infected with syphilis and a four-fold increased risk for FSWs aged 30-39 years to have a CT infection relative to FSWs aged 15-20 years. The prevalences of STIs were high, and risky sexual behaviours were common, especially among FSWs in LC venues. More tailored and comprehensive prevention programmes should be developed for specific FSW subgroups.

Pro-tumoral and immunosuppressive M2-like tumor-associated macrophages (TAMs) contribute to tumor progression, recurrence and distal metastasis. However, current TAMs-modulating therapeutic strategies often encounter challenges including insufficient immune activation, weak antigen presentation ability and unsatisfactory antitumor immune performance. Herein, cyclic RGD peptide functionalized and manganese doped eumelanin-like nanocomposites (RMnMels) are reported for combined hyperthermia-immunotherapy against PC3 prostate cancer. The RMnMels could promote M2-to-M1 macrophage repolarization via scavenging multiple reactive oxygen species and remodeling the immunosuppressive tumor microenvironment. Following near-infrared light irradiation, RMnMels-mediated thermal ablation not only could destroy tumor cells directly, but also elicit the release of damage associated molecular patterns and tumor-associated antigens, provoking robust tumor immunogenicity and strong antitumor immune responses. The results showed that RMnMels could effectively scavenge reactive oxygen species and promote M2-to-M1 macrophage repolarization both in vitro and in vivo. Synergistically enhanced anti-tumor therapeutic efficacy was achieved following single administration of RMnMels plus single round of laser irradiation, evidenced by decreased primary tumor sizes and decreased number of distant liver metastatic nodules. The as-developed RMnMels may represent a simple and high-performance therapeutic nanoplatform for immunomodulation and enhanced antitumor immune responses. Graphical Abstract

Resveratrol shows promizing anti-inflammatory effects in recent clinical trials, however its function in cardiovascular patients remains conflicting, suggesting there may be new mechanisms underlying its cardioprotective activity. Acute sympathetic stress induces early activation of the NLR family, pyrin domain containing 3 (NLRP3) inflammasome in cardiomyocytes as a critical step for triggering cardiac inflammation. Thus, this study explored targets of resveratrol activity involved in the inhibition of early inflammasome activation in cardiomyocytes following acute sympathetic stress. Network pharmacology was used to analyze common candidate targets in the sympathetic stress pathway, resveratrol activity, and myocardial inflammation and showed the Phosphoinositol 3—kinase (PI3K)/serine threonine protein kinase (Akt) signaling pathway and the target AKT1 may play a critical role. Molecular docking provided support for potential binding of resveratrol on AKT1. Furthermore, the effect of resveratrol on AKT1 activation was determined in cardiomyocytes. resveratrol dose-dependently inhibited AKT1 activation after activation of β-adrenoceptor. The AKT1 inhibitor A-674563 suppressed the activation of the NLRP3 inflammasome in cardiomyocytes following β-adrenoceptor activation, suggesting that AKT1 is a critical regulator molecule upstream of the NLRP3 inflammasome. Consistently, treatment with resveratrol suppressed β-adrenoceptor-mediated NLRP3 inflammasome activation in both cardiomyocytes and mouse hearts, as well as the resultant cardiac inflammation. In conclusion, resveratrol targets AKT1 to inhibit NLRP3 inflammasome activation in cardiomyocytes and cardiac inflammation following acute sympathetic stress. AKT1 is an important target of resveratrol, which should be considered as a treatment option for cardiovascular patients, especially those at risk of acute sympathetic stress.