Intracellular occupancy of the respiratory epithelium is a useful pathogenic strategy facilitating microbial replication and evasion of professional phagocytes or circulating antimicrobial drugs. A ...less appreciated but growing body of evidence indicates that the airway epithelium also plays a crucial role in host defence against inhaled pathogens, by promoting ingestion and quelling of microorganisms, processes that become subverted to favour pathogen activities and promote respiratory disease. To achieve a deeper understanding of beneficial and deleterious activities of respiratory epithelia during antimicrobial defence, we have comprehensively surveyed all current knowledge on airway epithelial uptake of bacterial and fungal pathogens. We find that microbial uptake by airway epithelial cells (AECs) is a common feature of respiratory host-microbe interactions whose stepwise execution, and impacts upon the host, vary by pathogen. Amidst the diversity of underlying mechanisms and disease outcomes, we identify four key infection scenarios and use best-characterised host-pathogen interactions as prototypical examples of each. The emergent view is one in which effi-ciency of AEC-mediated pathogen clearance correlates directly with severity of disease outcome, therefore highlighting an important unmet need to broaden our understanding of the antimicrobial properties of respiratory epithelia and associated drivers of pathogen entry and intracellular fate.
Chronic pulmonary aspergillosis (CPA) is estimated to affect 3 million people worldwide making it an under recognised, but significant health problem across the globe, conferring significant ...morbidity and mortality. With variable disease forms, high levels of associated respiratory co-morbidity, limited therapeutic options and prolonged treatment strategies, CPA is a challenging disease for both patients and healthcare professionals. CPA can mimic smear-negative tuberculosis (TB), pulmonary histoplasmosis or coccidioidomycosis. Cultures for
are usually negative, however, the detection of
IgG is a simple and sensitive test widely used in diagnosis. When a fungal ball/aspergilloma is visible radiologically, the diagnosis has been made late. Sometimes weight loss and fatigue are predominant symptoms; pyrexia is rare. Despite the efforts of the mycology community, and significant strides being taken in optimising the care of these patients, much remains to be learnt about this patient population, the disease itself and the best use of available therapies, with the development of new therapies being a key priority. Here, current knowledge and practices are reviewed, and areas of research priority highlighted.
Respiratory epithelia fulfil multiple roles beyond that of gaseous exchange, also acting as primary custodians of lung sterility and inflammatory homeostasis. Inhaled fungal spores pose a continual ...antigenic, and potentially pathogenic, challenge to lung integrity against which the human respiratory mucosa has developed various tolerance and defence strategies. However, respiratory disease and immune dysfunction frequently render the human lung susceptible to fungal diseases, the most common of which are the aspergilloses, a group of syndromes caused by inhaled spores of
. Inhaled
spores enter into a multiplicity of interactions with respiratory epithelia, the mechanistic bases of which are only just becoming recognized as important drivers of disease, as well as possible therapeutic targets. In this mini-review we examine current understanding of
-epithelial interactions and, based upon the very latest developments in the field, we explore two apparently opposing schools of thought which view epithelial uptake of
spores as either a curative or disease-exacerbating event.
To independently validate two biomarkers, a 44-gene DNA damage immune response (DDIR) signature and stromal tumor-infiltrating lymphocytes (sTILs), as prognostic markers in patients with ...triple-negative breast cancer (TNBC) treated with adjuvant doxorubicin (A) and cyclophosphamide (C) in SWOG 9313.
Four hundred twenty-five centrally determined patient cases with TNBC from S9313 were identified. DDIR signature was performed on RNA isolated from formalin-fixed paraffin-embedded tumor tissue, and samples were classified as DDIR negative or positive using predefined cutoffs. Evaluation of sTILs was performed as described previously. Markers were tested for prognostic value for disease-free survival (DFS) and overall survival (OS) using Cox regression models adjusted for treatment assignment, nodal status, and tumor size.
Among 425 patients with TNBC, 33% were node positive. DDIR was tested successfully in 90% of patients (381 of 425), 62% of which were DDIR signature positive. DDIR signature positivity was associated with improved DFS (hazard ratio HR, 0.67; 95% CI, 0.48 to 0.92;
= .015) and OS (HR, 0.61; 95% CI, 0.43 to 0.89;
= .010). sTILs density assessment was available in 99% of patients and was associated with improved DFS (HR, 0.70; 95% CI, 0.51 to 0.96;
= .026 for sTILs density ≥ 20%
< 20%) and OS (HR, 0.59; 95% CI, 0.41 to 0.85;
= .004 for sTILs density ≥ 20%
< 20%). DDIR signature score and sTILs density were moderately correlated (
= 0.60), which precluded statistical significance for DFS in a joint model. Three-year DFS and OS in a subgroup of patients with DDIR positivity and T1c/T2N0 disease were 88% and 94%, respectively.
The prognostic role of sTILs and DDIR in early-stage TNBC was confirmed. DDIR signature conferred improved prognosis in two thirds of patients with TNBC treated with adjuvant AC. DDIR signature has the potential to stratify outcome and to identify patients with less projected benefit after AC chemotherapy.
PURPOSE OF REVIEWThis review highlights key recent advances in fungal respiratory infections, encompassing developments in epidemiology, diagnostics and management, focussing on Aspergillus, ...Pneumocystis and Cryptococcus as key pathogens.
RECENT FINDINGSChronic pulmonary aspergillosis complicates existing lung diseases, particularly those associated with cavities or bullae, with a high global disease burden (prevalence estimate >1.1 million following tuberculosis) and significant under diagnosis (using Aspergillus IgG antibody). Several new treatment studies have been published (using caspofungin and voriconazole). Pneumocystis jirovecii demonstrates airborne transmission between infected and noninfected individuals necessitating isolation, and possibly identifying colonized patients. Early detection of serum cryptococcal antigenaemia in HIV may prevent development of meningitis, reducing morbidity and mortality, and routine testing of serum in community-acquired pneumonia cases in high endemicity areas may be helpful. Respiratory Aspergillus antigen and PCR testing is more sensitive than culture or serum testing. A new lateral flow antigen testing device may provide rapid bedside diagnosis of aspergillosis. Azole resistance to Aspergillus fumigatus is increasing across Europe.
SUMMARYThe field of fungal respiratory infection continues to evolve and develop, with many recent key advances. Patients, and possibly colonized patients, with Pneumocystis require isolation in hospitals and preferably segregation in outpatients. Challenges remain in almost all areas, with further work needed to identify the true burden of Aspergillus disease and address the increasing problem of azole resistance.
Blending with a hydrogen-bonding supramolecular polymer is shown to be a successful novel strategy to induce microphase-separation in the melt of a Pluronic polyether block copolymer. The ...supramolecular polymer is a polybutadiene derivative with urea-urethane end caps. Microphase separation is analysed using small-angle X-ray scattering and its influence on the macroscopic rheological properties is analysed. FTIR spectroscopy provides a detailed picture of the inter-molecular interactions between the polymer chains that induces conformational changes leading to microphase separation.
Triple-negative breast cancer (TNBC) is a heterogeneous disease. We previously showed that homologous recombination deficiency (HRD) and the DNA damage immune response (DDIR) signature are prognostic ...in TNBC. We hypothesized that these biomarkers reflect related but not completely interdependent biological processes, that their combined use would be prognostic, and that simultaneous assessment of the immunologic microenvironment and susceptibility to DNA damaging therapies might be able to identify subgroups with distinct therapeutic vulnerabilities.
We analyzed the dual DDIR/HRD classification in 341 patients with TNBC treated with adjuvant anthracycline-based chemotherapy on the SWOG S9313 trial and corroborated our findings in The Cancer Genome Atlas breast cancer data set.
DDIR/HRD classification is highly prognostic in TNBC and identifies biologically and immunologically distinct subgroups. Immune-enriched DDIR+/HRD+ TNBCs have the most favorable prognosis, and DDIR+/HRD- and DDIR-/HRD+ TNBCs have favorable intermediate prognosis, despite the latter being immune-depleted. DDIR-/HRD- TNBCs have the worst prognosis and represent an internally heterogeneous group of immune-depleted chemoresistant tumors.
Our findings propose DDIR/HRD classification as a potentially clinically relevant approach to categorize tumors on the basis of therapeutic vulnerabilities.
Blending with a hydrogen-bonding supramolecular polymer is shown to be a successful novel strategy to induce microphase-separation in the melt of a Pluronic polyether block copolymer. The ...supramolecular polymer is a polybutadiene derivative with urea-urethane end caps. Microphase separation is analysed using small-angle X-ray scattering and its influence on the macroscopic rheological properties is analysed. FTIR spectroscopy provides a detailed picture of the inter-molecular interactions between the polymer chains that induces conformational changes leading to microphase separation.
Melt blending of a supramolecular polymer with a pluronic block copolymer leads to microphase separation.
Background: A. fumigatus is an important human pathogen with disease manifestations being entirely dependent on the underlying state of the host immune system. Inhalation of A. fumigatus conidia ...forms the major route of infection and the bronchial epithelium forms the primary barrier to initial infection. However a paucity of data exists surrounding epithelial response in the presence of A. fumigatus, although recent evidence suggests it is more than a passive bystander. The contribution of genetic mutations and subtle immune deficiency to the pathogenesis of the most common forms of aspergillosis, severe asthma with fungal sensitisation (SAFS), allergic bronchopulmonary aspergillosis (ABPA) and chronic pulmonary aspergillosis (CPA) are also poorly defined.Aim: This thesis explores these areas using a variety of techniques to address three key hypotheses:1.The bronchial epithelium mounts an inflammatory response to the presence of inhaled conidia over the first 12 hours of infection.2.The tyrosine kinase Fer, mutated in some individuals with asthma, is involved in the response of the healthy bronchial epithelium to A. fumigatus3.Patients with CPA with deficiencies in the IL12-IFNγ axis display a specific disease phenotype and benefit from replacement IFNγResults: A combination of RNASeq analysis, computer modelling, flow cytometry and ELISA suggest that the bronchial epithelium mounts a permissive, perhaps phagocytic, transcriptional response; raising the possibility of the development of unchecked latent reservoirs of bronchial infection within the bronchial epithelium in early infection. There is no evidence of a transcriptional or secretory inflammatory epithelial response.Transcriptional and translational evaluation of Fer, using qRT-PCR and Western Blot, demonstrates the presence of Fer in multiple cell types, including bronchial and alveolar lung cell lines, and reduced expression in the presence of serum. No changes in the quantity or phosphorylation state of Fer were demonstrated over the first 12 hours of infection, or in the face of escalating conidial dose. Preliminary data also suggests that Fer may be secreted into the extracellular environment.Retrospective cohort analysis of 41 patients treated with IFNγ demonstrates that replacement therapy is tolerated and may be a useful adjunctive therapy in patients with deficiencies in the IL12-IFNγ axis. However no specific patient phenotype most associated with response could be identified, and multiple areas for future research were highlighted.Conclusion: This is the first description of the transcriptional response of the bronchial epithelium to A. fumigatus over 12 hours and the first significant exploration of Fer within the respiratory epithelium. In terms of therapy the demonstration of possible benefit from IFNγ therapy paves the way for further studies and highlights the need for greater research into assessment of the underlying disease phenotype in CPA. Overall important areas for further research have been highlighted and effective assays developed to facilitate this.
The ongoing coronavirus disease 2019 (COVID-19) pandemic poses a severe threat to public health worldwide. We combine data on demography, contact patterns, disease severity, and health care capacity ...and quality to understand its impact and inform strategies for its control. Younger populations in lower-income countries may reduce overall risk, but limited health system capacity coupled with closer intergenerational contact largely negates this benefit. Mitigation strategies that slow but do not interrupt transmission will still lead to COVID-19 epidemics rapidly overwhelming health systems, with substantial excess deaths in lower-income countries resulting from the poorer health care available. Of countries that have undertaken suppression to date, lower-income countries have acted earlier. However, this will need to be maintained or triggered more frequently in these settings to keep below available health capacity, with associated detrimental consequences for the wider health, well-being, and economies of these countries.
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