Post-acute COVID-19 associated with evidence of bystander T-cell activation and a recurring AMR bacterial pneumonia
- University of Bristol, United Kingdom
- North Bristol NHS Trust, United Kingdom
- Bristol Veterinary School in the Faculty of Health Sciences, United Kingdom
- Imperial College London, United Kingdom
- University of Birmingham, United Kingdom
Abstract
Here we describe the case of a COVID-19 patient who developed recurring ventilator-associated pneumonia caused by Pseudomonas aeruginosa that acquired increasing levels of antimicrobial resistance (AMR) in response to treatment. Metagenomic analysis revealed the AMR genotype, while immunological analysis revealed massive and escalating levels of T-cell activation. These were both SARS-CoV-2 and P. aeruginosa specific, and bystander activated, which may have contributed to this patient's persistent symptoms and radiological changes.
Data availability
Human-filtered sequencing data for this study have been deposited in the European Nucleotide Archive (ENA) at EMBL-EBI under accession PRJEB40239.
-
Metagenomic analysis of respiratory samples from a COVID-19 ICU patientEuropean Nucleotide Archive, PRJEB40239.
Article and author information
Author details
Michaela Gregorova
Mahableshwar Albur
Funding
Southmead Hospital Charity
- Fergus Hamilton
Wellcome Trust (212258/Z/18/Z)
- Ruth C Massey
Elizabeth Blackwell Institute
- Laura Rivino
UKRI (MR/S019553/1)
- Rosemary J Boyton
UKRI (MR/R02622X/1)
- Daniel M Altmann
Cystic Fibrosis Trust (CF Trust SRC 015)
- David K Butler
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: The patient was enrolled onto the DISCOVER study (Diagnostic and Severity markers of COVID-19 to Enable Rapid triage study), a single centre prospective study recruiting consecutive patients admitted with COVID-19, from 30.03.2020 until present (Ethics approval via South Yorkshire REC: 20/YH/0121, CRN approval no: 45469). Blood/serum samples from pre-pandemic healthy controls and asymptomatic healthy controls were obtained under the Bristol Biobank (NHS Research Ethics Committee approval ref 14/WA/1253).
Copyright
© 2020, Gregorova et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 3,094
- views
-
- 348
- downloads
-
- 25
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Post-acute COVID-19 associated with evidence of bystander T-cell activation and a recurring AMR bacterial pneumonia
eLife 9:e63430.
https://doi.org/10.7554/eLife.63430
Further reading
-
- Microbiology and Infectious Disease
Non-inheritable antibiotic or phenotypic resistance ensures bacterial survival during antibiotic treatment. However, exogenous factors promoting phenotypic resistance are poorly defined. Here, we demonstrate that Vibrio alginolyticus are recalcitrant to killing by a broad spectrum of antibiotics under high magnesium. Functional metabolomics demonstrated that magnesium modulates fatty acid biosynthesis by increasing saturated fatty acid biosynthesis while decreasing unsaturated fatty acid production. Exogenous supplementation of unsaturated and saturated fatty acids increased and decreased bacterial susceptibility to antibiotics, respectively, confirming the role of fatty acids in antibiotic resistance. Functional lipidomics revealed that glycerophospholipid metabolism is the major metabolic pathway remodeled by magnesium, where phosphatidylethanolamine biosynthesis is reduced and phosphatidylglycerol production is increased. This process alters membrane composition, increasing membrane polarization, and decreasing permeability and fluidity, thereby reducing antibiotic uptake by V. alginolyticus. These findings suggest the presence of a previously unrecognized metabolic mechanism by which bacteria escape antibiotic killing through the use of an environmental factor.
-
- Biochemistry and Chemical Biology
- Microbiology and Infectious Disease
Paramyxovirus membrane fusion requires an attachment protein for receptor binding and a fusion protein for membrane fusion triggering. Nipah virus (NiV) attachment protein (G) binds to ephrinB2 or -B3 receptors, and fusion protein (F) mediates membrane fusion. NiV-F is a class I fusion protein and is activated by endosomal cleavage. The crystal structure of a soluble GCN4-decorated NiV-F shows a hexamer-of-trimer assembly. Here, we used single-molecule localization microscopy to quantify the NiV-F distribution and organization on cell and virus-like particle membranes at a nanometer precision. We found that NiV-F on biological membranes forms distinctive clusters that are independent of endosomal cleavage or expression levels. The sequestration of NiV-F into dense clusters favors membrane fusion triggering. The nano-distribution and organization of NiV-F are susceptible to mutations at the hexamer-of-trimer interface, and the putative oligomerization motif on the transmembrane domain. We also show that NiV-F nanoclusters are maintained by NiV-F–AP-2 interactions and the clathrin coat assembly. We propose that the organization of NiV-F into nanoclusters facilitates membrane fusion triggering by a mixed population of NiV-F molecules with varied degrees of cleavage and opportunities for interacting with the NiV-G/receptor complex. These observations provide insights into the in situ organization and activation mechanisms of the NiV fusion machinery.
