Post-acute COVID-19 associated with evidence of bystander T-cell activation and a recurring AMR bacterial pneumonia
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.
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Metagenomic analysis of respiratory samples from a COVID-19 ICU patientEuropean Nucleotide Archive, PRJEB40239.
Article and author information
Author details
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).
Reviewing Editor
- Anurag Agrawal, CSIR Institute of Genomics and Integrative Biology, India
Publication history
- Received: September 24, 2020
- Accepted: December 16, 2020
- Accepted Manuscript published: December 17, 2020 (version 1)
- Version of Record published: December 31, 2020 (version 2)
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.
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Further reading
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- Microbiology and Infectious Disease
The malaria parasite life cycle includes asexual replication in human blood, with a proportion of parasites differentiating to gametocytes required for transmission to mosquitoes. Commitment to differentiate into gametocytes, which is marked by activation of the parasite transcription factor ap2-g, is known to be influenced by host factors but a comprehensive model remains uncertain. Here, we analyze data from 828 children in Kilifi, Kenya with severe, uncomplicated, and asymptomatic malaria infection over 18 years of falling malaria transmission. We examine markers of host immunity and metabolism, and markers of parasite growth and transmission investment. We find that inflammatory responses associated with reduced plasma lysophosphatidylcholine levels are associated with markers of increased investment in parasite sexual reproduction (i.e. transmission investment) and reduced growth (i.e. asexual replication). This association becomes stronger with falling transmission and suggests that parasites can rapidly respond to the within-host environment, which in turn is subject to changing transmission.
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- Evolutionary Biology
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Many bacterial genomes carry prophages whose induction can eliminate competitors. In response, bacteria may become resistant by modifying surface receptors, by lysogenization, or by other poorly known processes. All these mechanisms affect bacterial fitness and population dynamics. To understand the evolution of phage resistance, we co-cultivated a phage-sensitive strain (BJ1) and a poly-lysogenic Klebsiella pneumoniae strain (ST14) under different phage pressures. The population yield remained stable after 30 days. Surprisingly, the initially sensitive strain remained in all populations and its frequency was highest when phage pressure was strongest. Resistance to phages in these populations emerged initially through mutations preventing capsule biosynthesis. Protection through lysogeny was rarely observed because the lysogens have increased death rates due to prophage induction. Unexpectedly, the adaptation process changed at longer time scales the frequency of capsulated cells in BJ1 populations increased again, because the production of capsule was fine-tuned, reducing the ability of phage to absorb. Contrary to the lysogens, these capsulated resistant clones are pan-resistant to a large panel of phages. Intriguingly, some clones exhibited transient non-genetic resistance to phages, suggesting an important role of phenotypic resistance in coevolving populations. Our results show that interactions between lysogens and sensitive strains are shaped by antagonistic co-evolution between phages and bacteria. These processes may involve key physiological traits, such as the capsule, and depend on the time frame of the evolutionary process. At short time scales, simple and costly inactivating mutations are adaptive, but in the long-term, changes drawing more favorable trade-offs between resistance to phages and cell fitness become prevalent.