Gene Expression Profiling of Bronchoalveolar Lavage Cells during Aspergillus Colonization of the Lung Allograft

Weigt, S. Samuel; Wang, X.; Palchevskiy, Vyacheslav; Patel, Neil; Derhovanessian, Ariss; Shino, Michael Y.; Sayah, David M.; Gregson, Aric L.; Lynch, John P.; Saggar, Rajan; Ross, David J.; Ardehali, A.; Elashoff, D.; Belperio, John A.

doi:10.1016/j.healun.2016.01.890

Cited by 5 publications

(6 citation statements)

References 23 publications

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“…For this purpose, a separate DEG run was employed for screening essential proteins as a potential druggable target. The screened pool was subjected to KEGG pathway analysis for shortlisting proteins involved in the metabolism (Weigt 2018 ). Enzymes were selected from the pool and were again subjected to host homology evaluation.…”

Section: Methodsmentioning

confidence: 99%

Quest for Novel Preventive and Therapeutic Options Against Multidrug-Resistant Pseudomonas aeruginosa

Irum

Andleeb

Ali

et al. 2021

Int J Pept Res Ther

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Pseudomonas aeruginosa ( P. aeruginosa ) is a critical healthcare challenge due to its ability to cause persistent infections and the acquisition of antibiotic resistance mechanisms. Lack of preventive vaccines and rampant drug resistance phenomenon has rendered patients vulnerable. As new antimicrobials are in the preclinical stages of development, mining for the unexploited drug targets is also crucial. In the present study, we designed a B- and T-cell multi-epitope vaccine against P. aeruginosa using a subtractive proteomics and immunoinformatics approach. A total of five proteins were shortlisted based on essentiality, extracellular localization, virulence, antigenicity, pathway association, hydrophilicity, and low molecular weight. These include two outer membrane porins; OprF (P13794) and OprD (P32722), a protein activator precursor pra (G3XDA9), a probable outer membrane protein precursor PA1288 (Q9I456), and a conserved hypothetical protein PA4874 (Q9HUT9). These shortlisted proteins were further analyzed to identify immunogenic and antigenic B- and T-cell epitopes. The best scoring epitopes were then further subjected to the construction of a polypeptide multi-epitope vaccine and joined with cholera toxin B subunit adjuvant. The final chimeric construct was docked with TLR4 and confirmed by normal mode simulation studies. The designed B- and T-cell multi-epitope vaccine candidate is predicted immunogenic in nature and has shown strong interactions with TLR-4. Immune simulation predicted high-level production of B- and T-cell population and maximal expression was ensured in E. coli strain K12. The identified drug targets qualifying the screening criteria were: UDP-2-acetamido-2-deoxy-d-glucuronic acid 3-dehydrogenase WbpB (G3XD23), aspartate semialdehyde dehydrogenase (Q51344), 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine pyrophosphokinase (Q9HV71), 3-deoxy-D-manno-octulosonic-acid transferase (Q9HUH7), glycyl-tRNA synthetase alpha chain (Q9I7B7), riboflavin kinase/FAD synthase (Q9HVM3), aconitate hydratase 2 (Q9I2V5), probable glycosyltransferase WbpH (G3XD85) and UDP-3-O-[3-hydroxylauroyl] glucosamine N-acyltransferase (Q9HXY6). For druggability and pocketome analysis crystal and homology structures of these proteins were retrieved and developed. A sequence-based search was performed in different databases (ChEMBL, Drug Bank, PubChem and Pseudomonas database) for the availability of reported ligands and tested drugs for the screened targets. These predicted targets may provide a basis for the development of reliable antibacterial preventive and therapeutic options against P. aeruginosa . Supplementary Information The online version contains supplementary material available at 10.1007/s10989-021-10255-3.

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Section: Methodsmentioning

confidence: 99%

Quest for Novel Preventive and Therapeutic Options Against Multidrug-Resistant Pseudomonas aeruginosa

Irum

Andleeb

Ali

et al. 2021

Int J Pept Res Ther

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“…BOS is a phenotype of chronic lung allograft dysfunction (CLAD) that manifests as progressive airflow obstruction. Aspergillus colonization, even in the absence of IFI, has also been linked to BOS and BOS-related mortality, independent of rejection (55,56). Colonization with small conidia (≤3.5 µm) of A. fumigatus, A. nidulans, A. terreus and A. flavipes, in particular, has been associated with BOS and death.…”

Section: Outcomes Of Ifismentioning

confidence: 99%

“…In one study, Aspergillus colonization preceded BOS by a median of 261 days. Transcriptional profiling of cell pellets from BAL fluid obtained from surveillance bronchoscopies of Aspergillus-colonized LTRs at 3 or 6-months post-transplant revealed enrichment of expression of genes involved in responses to host defense, inflammation and wounds compared with non-colonized LTR; moreover, expression of genes involved in these processes were significantly associated with progression to CLAD (56). These findings suggest that Aspergillus colonization might cause subclinical injury and subsequent repair that may ultimately lead to CLAD in some LTR.…”

Section: Outcomes Of Ifismentioning

confidence: 99%

Fungal infections in lung transplantation

Samanta¹,

Clancy²,

Nguyen³

2021

J Thorac Dis

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Lung transplant is a potential life-saving procedure for chronic lung diseases. Lung transplant recipients (LTRs) are at the greatest risk for invasive fungal infections (IFIs) among solid organ transplant (SOT) recipients because the allograft is directly exposed to fungi in the environment, airway and lung host defenses are impaired, and immunosuppressive regimens are particularly intense. IFIs occur within a year of transplant in 3-19% of LTRs, and they are associated with high mortality, prolonged hospital stays, and excess healthcare costs. The most common causes of post-LT IFIs are Aspergillus and Candida spp.; less common pathogens are Mucorales, other non-Aspergillus moulds, Cryptococcus neoformans, Pneumocystis jirovecii, and endemic mycoses. The majority of IFIs occur in the first year following transplant, although later onset is observed with prolonged antifungal prophylaxis. The most common manifestations of invasive mould infections (IMIs) include tracheobronchial (particularly at anastomotic sites), pulmonary and disseminated infections. The mortality rate of tracheobronchitis is typically low, but local complications such as bronchomalacia, stenosis and dehiscence may occur. Mortality rates associated with lung and disseminated infections can exceed 40% and 80%, respectively. IMI risk factors include mould colonization, single lung transplant and augmented immunosuppression. Candidiasis is less common than mould infections, and manifests as bloodstream or other non-pulmonary invasive candidiasis; tracheobronchial infections are encountered uncommonly. Risk factors for and outcomes of candidiasis are similar to those of non lung transplant recipients. There is evidence that IFIs and fungal colonization are risk factors for allograft failure due to chronic rejection. Mould-active azoles are frontline agents for treatment of IMIs, with local debridement as needed for tracheobronchial disease. Echinocandins and azoles are treatments for invasive candidiasis, in keeping with guidelines in other patient populations. Antifungal prophylaxis is commonly administered, but benefits and optimal regimens are not defined. Universal mould-active azole prophylaxis is used most often. Other approaches include targeted prophylaxis of high-risk LTRs or pre-emptive therapy based on culture or galactomannan (GM) (or other biomarker) results. Prophylaxis trials are needed, but difficult to perform due to heterogeneity in local epidemiology of IFIs and standard LT practices. The key to devising rational strategies for preventing IFIs is to understand local epidemiology in context of institutional clinical practices.

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“…241 Notably, Aspergillus colonization is associated with host gene expression involved in wound repair and with immune responses. 242 These pathways are also important in the pathogenesis of CLAD. It is not established whether prophylaxis to reduce Pseudomonas and Aspergillus colonization will affect CLAD risk, and further studies are warranted.…”

Section: Infectious Factorsmentioning

confidence: 99%

Chronic Lung Allograft Dysfunction: Evolving Concepts and Therapies

Amubieya

Ramsey

Derhovanessian

et al. 2021

Semin Respir Crit Care Med

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The primary factor that limits long-term survival after lung transplantation is chronic lung allograft dysfunction (CLAD). CLAD also impairs quality of life and increases the costs of medical care. Our understanding of CLAD continues to evolve. Consensus definitions of CLAD and the major CLAD phenotypes were recently updated and clarified, but it remains to be seen whether the current definitions will lead to advances in management or impact care. Understanding the potential differences in pathogenesis for each CLAD phenotype may lead to novel therapeutic strategies, including precision medicine. Recognition of CLAD risk factors may lead to earlier interventions to mitigate risk, or to avoid risk factors all together, to prevent the development of CLAD. Unfortunately, currently available therapies for CLAD are usually not effective. However, novel therapeutics aimed at both prevention and treatment are currently under investigation. We provide an overview of the updates to CLAD-related terminology, clinical phenotypes and their diagnosis, natural history, pathogenesis, and potential strategies to treat and prevent CLAD.

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Gene Expression Profiling of Bronchoalveolar Lavage Cells during Aspergillus Colonization of the Lung Allograft

Cited by 5 publications

References 23 publications

Quest for Novel Preventive and Therapeutic Options Against Multidrug-Resistant Pseudomonas aeruginosa

Quest for Novel Preventive and Therapeutic Options Against Multidrug-Resistant Pseudomonas aeruginosa

Fungal infections in lung transplantation

Chronic Lung Allograft Dysfunction: Evolving Concepts and Therapies

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