Role of pulmonary microorganisms in the development of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a chronic obstructive respiratory disease characterized by irreversible airway limitation and persistent respiratory symptoms. The main clinical symptoms of COPD are dyspnoea, chronic cough, and sputum. COPD is often accompanied by other respiratory diseases, which can cause worsening of the disease. COPD patients with dyspnoea and aggravation of cough and sputum symptoms represent acute exacerbations of COPD (AECOPD). There is mounting evidence suggesting that dysbiosis of pulmonary microbiota participates in the disease. However, investigations of dysbiosis of pulmonary microbiota and the disease are still in initial phases. To screen, diagnose, and treat this respiratory disease, integrating data from different studies can improve our understanding of the occurrence and development of COPD and AECOPD. In this review, COPD epidemiology and the primary triggering mechanism are explored. Emerging knowledge regarding the association of inflammation, caused by pulmonary microbiome imbalance, and changes in lung microbiome flora species involved in the development of the disease are also highlighted. These data will further our understanding of the pathogenesis of COPD and AECOPD and may yield novel strategies for the use of pulmonary microbiota as a potential therapeutic intervention.

MrMid2, encoding a cell wall stress sensor protein, is required for conidium production, stress tolerance, microsclerotium formation and virulence in the entomopathogenic fungus Metarhizium rileyi.

Transmembrane proteins as sensors encoded by fungal genes activate specific intracellular signal pathways in response to stress cues to help the fungus survive in a changing environment. To better understand the role of the cell wall integrity (CWI) pathway in the entomopathogenic fungus Metarhizium rileyi, an ortholog encoding the transmembrane protein Mid2, MrMid2, was identified and characterized functionally. Transcriptional analysis indicated that MrMid2 was involved in dimorphic transition, conidiation, and microsclerotium formation. After a targeted deletion of MrMid2, all three traits were impaired. Compared with the wild-type strain, the △MrMid2 mutants were hypersensitive to thermal stress, and cell wall and oxidative stress. Insect bioassays revealed that △MrMid2 mutants had decreased virulence levels following topical (22.5%) and injection bioassays (38.7%). Furthermore, transcription analysis showed that other genes of the CWI pathway, with the exception of another major sensor protein encoding gene, MrWsc1, were down-regulated in △MrMid2 mutants. These results suggest that MrMid2 plays important roles in dimorphic transition, conidiation, the stress response, virulence, and microsclerotium development in M. rileyi.

Interactions between invasive fungi and symbiotic bacteria.

Infection rates and mortality associated with the invasive fungi Candida, Aspergillus, and Cryptococcus are increasing rapidly in prevalence. Meanwhile, screening pressure brought about by traditional antifungal drugs has induced an increase in drug resistance of invasive fungi, which creates a great challenge for the preservation of physical health. Development of new drugs and novel strategies are therefore important to meet these growing challenges. Recent studies have confirmed that the dynamic balance of microorganisms in the body is correlated with the occurrence of infectious diseases. This discovery of interactions between bacteria and fungi provides innovative insight for the treatment of invasive fungal infections. However, different invasive fungi and symbiotic bacteria interact with each other through various ways and targets, leading to different effects on their growth, morphology, and virulence. And the mechanism and implication of these interactions remains largely unknown. The present review aims to summarize the research progress into the interaction between invasive fungi and symbiotic bacteria with a focus on the anti-fungal mechanisms of symbiotic bacteria, providing a new strategy against drug-resistant fungal infections.

Efficacy and safety of PD-1/PD-L1 plus CTLA-4 antibodies ± other therapies in lung cancer: a systematic review and meta-analysis.

PURPOSE: To investigate the efficacy and safety of programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) plus cytotoxic T lymphocyte antigen-4 (CTLA-4) antibodies ± other therapies in patients with advanced lung cancer. METHODS: In accordance with the retrieval strategy, we searched electronic databases for randomised controlled trials testing PD-1/PD-L1 plus CTLA-4 antibodies in patients with lung cancer; RR (for objective response rate (ORR), overall survival (OS), progression-free survival (PFS), and immune-related adverse events (irAEs)) from individual studies were calculated and pooled by using random-effects models or fixed-effects models; heterogeneity and publication bias analyses were also performed, using Review Manager 5.3 and Stata 15.1 for statistical analysis. RESULTS: We included six studies. Four different immune checkpoint inhibitors (nivolumab, pembrolizumab, durvalumab, tremelimumab) were used. Dual checkpoint inhibitors ± other therapies for advanced lung cancer showed significant improvements in ORR (RR 1.49, 95% CI 1.11 to 1.98; p=0.007), OS (HR 0.72, 95% CI 0.63 to 0.83; p<0.00001), and PFS (HR 0.72, 95% CI 0.63 to 0.82; p<0.00001). The subgroup analyses were consistent with the pooled results. The PD-L1 ≥1% (HR 0.67, 95% CI 0.54 to 0.82; p<0.0001) subgroup differences indicated a statistically significant subgroup effect, but the PD-L1 <1% subgroup (HR 0.88, 95% CI 0.75 to 1.05; p=0.15) was not statistically significant. The incidence of adverse events (grade ≥3) was lower than that of the control group (RR 0.90, 95% CI 0.80 to 1.02; p=0.09), but was not significant. CONCLUSIONS: PD-1/PD-L1 inhibitors combined with CTLA-4 inhibitors ± other therapies can improve the ORR, OS and PFS of patients with advanced or metastatic lung cancer, but the incidence of adverse reactions is high although generally tolerable. PROSPERO REGISTRATION: CRD42020149216.

Pulmonary Micro-Ecological Changes and Potential Microbial Markers in Lung Cancer Patients.

The relationship between the microbiome and disease has been investigated for many years. As a highly malignant tumor, biomarkers for lung cancer are diverse. However, precision of these biomarkers has not yet been achieved. It has been confirmed that lung microecology changes in lung cancer patients compared with healthy individuals. Furthermore, the abundance of some bacterial species shows obvious changes, suggesting their potential use as a microbial marker for the detection of lung cancer. In addition, recent studies have confirmed that inflammation, immune response, virulence factors, and metabolism may be potential mechanisms linking the microbiome with carcinogenesis. In this review, microbiome studies of lung cancer, potential mechanisms, potential microbial markers, and the influence of the microbiome on the diagnosis and treatment of lung cancer are summarized, providing theoretical strategies for the diagnosis and treatment of lung cancer.

[Analysis of Pulmonary Microbial Diversity in Patients with Advanced Lung Cancer Based on High-throughput Sequencing Technology].

BACKGROUND: The pulmonary microbiome is closely related to the occurrence of pulmonary diseases. The morbidity and mortality of lung cancer are relatively high in the world. It has been confirmed that lung microecology changes in lung cancer patients compared with healthy individuals. Furthermore, the abundance of some bacterial species shows obvious changes, suggesting their potential use as a microbial marker for the detection of lung cancer. The composition of the pulmonary microbiome in patients with different histological types of lung cancer has not been determined. We aim to study the correlation and difference of microbiome between different histological types of lung cancer. METHODS: Illumina HiSeq high-throughput sequencing technology was used to sequenced the 16S rDNA V3-V4 region of bacterial in sputum samples of patients with advanced lung cancer. RESULTS: It was found that Streptococcus, Neisseria and Prevotella were the main bacteria of lung cancer patients. Advantage bacterium group differ between different histological types of lung cancer. Adenocarcinoma (AD) group was dominated by Streptococcus and Neisseria, followed by Veillonella. Small cell lung cancer (SCLC) group was dominated by Neisseria, followed by Streptococcus. Squamous carcinoma (SCC) group was dominated by Streptococcus, followed by Veillonella. Combined small cell lung cancer (C-SCLC) group was dominated by Streptococcus, followed by Prevotella. CONCLUSIONS: The pulmonary bacterial microbiome of lung cancer of different histological types is different. This experiment enrichs the pulmonary bacterial microbiome data of lung cancer and fills the gap of pulmonary microbiome of small cell lung cancer.