Using Whole Genome Sequences to Investigate Adenovirus Outbreaks in a Hematopoietic Stem Cell Transplant Unit

Myers, Chloe; Houldcroft, Charlotte J.; Roy, Sunando; Margetts, Ben; Best, Timothy; Venturini, Cristina; Guerra-Assunção, José Afonso; Williams, Charlotte A.; Williams, Rachel; Dunn, Helen; Hartley, John C.; Rao, Kanchan; Rolfe, Kathryn J.; Breuer, Judith

doi:10.3389/fmicb.2021.667790

Cited by 13 publications

(10 citation statements)

References 35 publications

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“…In a recent work on the healthcare-associated transmission of HAdV-A31, ≤3 SNPs were observed in epidemiologically linked monophyletic clusters and ≤2 SNPs within a single host, which is in accordance with our findings ( Myers et al. 2021 ).…”

Section: Discussionsupporting

confidence: 93%

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High genetic stability of co-circulating human adenovirus type 31 lineages over 59 years

et al. 2022

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Type 31 of human adenovirus species A (HAdV-A31) is a significant pathogen primarily associated with diarrhoea in children but also with life-threatening disseminated disease in allogeneic haematopoietic stem cell transplant (HSCT) recipients. Nosocomial outbreaks of HAdV-A31 have been frequently described. However, the evolution of HAdV-A31 has not been studied in detail. The evolution of other HAdV types is driven either by intertypic recombination, where different types exchange genome regions or immune escape selection of neutralisation determinants. Complete genomic HAdV-A31 sequences from 60 diagnostic specimens of the past 18 years (2003–2021) were generated, including 14 specimens of a presumed outbreak on two HSCT wards. Additionally, 23 complete genomes from GenBank were added to our phylogenetic analysis, as well as in silico generated and previously published restriction fragment polymorphism (RFLP) data. Phylogenetic analysis of 83 genomes indicated that HAdV-A31 evolved slowly with six lineages co-circulating. The two major lineages were lineage 1, which included the prototype from 1962 and nine recent isolates, and lineage 2, which split into four sublineages and included most isolates from 2003 to 2021. The average nucleotide identity within lineages was high (99.8 %) and identity between lineages was 98.7–99.2 %. RFLP data allowed the construction of a lower-resolution phylogeny with two additional putative lineages. Surprisingly, regions of higher diversity separating lineages were found in gene regions coding for non-structural and minor capsid proteins. Intertypic recombinations were not observed, but the phylogeny of lineage 3 was compatible with an interlineage recombination event in the fiber gene. Applying the phylogenetic analysis to the presumed nosocomial outbreak excluded two suspected transmission events and separated it into two different, simultaneous outbreaks caused by different sublineages of lineage 2. However, due to the high nucleotide identity within HAdV-A31 lineages, the proof of infection chains remains debatable. This in-depth study on the molecular phylogeny of HAdV-A31 highlights the high genetic stability of co-circulating HAdV-A31 lineages over almost six decades. It also supports the epidemiological hypothesis that HAdV-A31 circulates as an etiological agent of a childhood disease infecting immunologically naive patients without strong positive selection of immune escape variants and recombinants.

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Section: Discussionsupporting

confidence: 93%

“…However, results were not entirely proving transmission as the genetic diversity of the endemically circulating HAdV-A31 remained obscure ( Houldcroft et al. 2018 ; Myers et al. 2021 ).…”

Section: Introductionmentioning

confidence: 99%

High genetic stability of co-circulating human adenovirus type 31 lineages over 59 years

et al. 2022

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“…A total of 15 primer pairs were designed as part of the scheme. They were synthesised by Agilent Technologies, Santa Clara, California (Agilent Technologies, 2021) (available through Agilent's Community Designs programme: SSXT CD Pan Adenovirus and SSXT CD Pan HHV-6 and used previously 41,42 ).…”

Section: Bait Designmentioning

confidence: 99%

Genomic Investigations of Acute Hepatitis of Unknown Aetiology in Children

Morfopoulou

Buddle

Montaguth

et al. 2022

Preprint

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Since the first reports of hepatitis of unknown aetiology occurring in UK children, over 1000 cases have been reported worldwide, including 268 cases in the UK, with the majority younger than 6 years old. Using genomic, proteomic and immunohistochemical methods, we undertook extensive investigation of 28 cases and 136 control subjects. In five cases who underwent liver transplantation, we detected high levels of adeno-associated virus 2 (AAV2) in the explanted livers. AAV2 was also detected at high levels in blood from 10/11 non-transplanted cases. Low levels of Adenovirus (HAdV) and Human Herpesvirus 6B (HHV-6B), both of which enable AAV2 lytic replication, were also found in the five explanted livers and blood from 15/17 and 6/9 respectively, of the 23 non-transplant cases tested. In contrast, AAV2 was detected at low titre in 6/100 whole bloods from child controls from cohorts with presence or absence of hepatitis and/or adenovirus infection. Our data show an association of AAV2 at high titre in blood or liver tissue, with unexplained hepatitis in children infected in the recent HAdV-F41 outbreak. We were unable to find evidence by electron microscopy, immunohistochemistry or proteomics of HAdV or AAV2 viral particles or proteins in explanted livers, suggesting that hepatic pathology is not due to direct lytic infection by either virus. The potential that AAV2, although not previously associated with disease, may, together with HAdV-F41 and/or HHV-6, be causally implicated in the outbreak of unexplained hepatitis, requires further investigation.

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“…Relatively little is known about HAdV-F41 genomic diversity in adults or children from the UK. Some data is available from immune compromised and hospitalised children from before the COVID-19 pandemic [22,23], and pre-and post-2020-21 samples are available from Germany [24]. It is therefore important to have access to HAdV-F41 genomes associated with gastrointestinal disease from the UK from the period after 2020-21 COVID-19 restrictions.…”

Section: Introductionmentioning

confidence: 99%

Enteric adenovirus F41 genetic diversity comparable to pre-COVID-19 era: validation of a multiplex amplicon-MinION sequencing method

Maes¹,

Khokhar²,

Wilkinson³

et al. 2022

Preprint

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Human adenovirus F41 causes acute gastroenteritis in children, and has recently been associated with an apparent increase in paediatric hepatitis of unknown aetiology in the UK, with further cases reported in multiple countries. Relatively little is known about the genetic diversity of adenovirus F41 in otherwise-healthy individuals; and it is unclear what, if any, impact the COVID-19 pandemic has had on viral diversity in the UK. Methods that allow F41 to be sequenced from clinical samples without the need for viral culture are required to provide the genomic data to address these questions.We therefore evaluated an overlapping-amplicon method of sequencing adenovirus genomes from clinical samples using Oxford Nanopore technology. We applied this method to a small sample of adenovirus species F-positive extracts collected as part of standard care in the East of England region in January-May 2022. This method produced genomes with >75% coverage in 13/22 samples and >50% coverage in 19/22 samples.We identified two F41 lineages present in paediatric patients in East of England in 2022. Where F41 genomes from paediatric hepatitis cases were available (n=2), these genomes fell within the diversity of F41 from the UK and continental Europe sequenced before and after the 2020-21 phase of the COVID-19 pandemic.Our analyses suggest that overlapping amplicon sequencing is an appropriate method for generating F41 genomic data from high virus load clinical samples, and currently circulating F41 viral lineages were present in the UK and Europe before the COVID-19 pandemic.

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Using Whole Genome Sequences to Investigate Adenovirus Outbreaks in a Hematopoietic Stem Cell Transplant Unit

Cited by 13 publications

References 35 publications

High genetic stability of co-circulating human adenovirus type 31 lineages over 59 years

High genetic stability of co-circulating human adenovirus type 31 lineages over 59 years

Genomic Investigations of Acute Hepatitis of Unknown Aetiology in Children

Enteric adenovirus F41 genetic diversity comparable to pre-COVID-19 era: validation of a multiplex amplicon-MinION sequencing method

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