Intrahost Monkeypox Virus Genome Variation in Patient with Early Infection, Finland, 2022

Vauhkonen, Hanna; Kallio‐Kokko, Hannimari; Hiltunen-Back, Eija; Lönnqvist, Lasse; Leppäaho-Lakka, Jaana; Mannonen, Laura; Kant, Ravi; Sironen, Tarja; Kurkela, Satu; Lappalainen, Maija; Zorec, Tomaž Mark; Zakotnik, Samo; Vlaj, Doroteja; Korva, Miša; Avšič–Županc, Tatjana; Poljak, Mario; Smura, Teemu; Vapalahti, Olli

doi:10.3201/eid2903.221388

Cited by 7 publications

(9 citation statements)

References 6 publications

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“…Some mutations are common to all samples and others are located in MPXV genomes infecting specific body tissues and/or dynamically evolving over time. Additionally, the existence of a mix of minority variants with mutations present at very low frequency was highlighted, thus suggesting that intra‐host evolution of MPXV can occur in the form of a quasi‐species, as already seen for other DNA viruses, 25,26 and also some evidence of intra‐host MPXV genome variations was observed 27 . Although the triggers inducing these mutations are still to be identified, our results illustrate MPXV adaptation to a continuously changing environment within the infected host and consequently demonstrate that tissue compartmentalization of MPXV can exist, mainly in patients with prolonged infections.…”

Section: Discussionmentioning

confidence: 56%

“…suggesting that intra-host evolution of MPXV can occur in the form of a quasi-species, as already seen for other DNA viruses, 25,26 and also some evidence of intra-host MPXV genome variations was observed. 27 Although the triggers inducing these mutations are still to be identified, our results illustrate MPXV adaptation to a continuously changing environment within the infected host and consequently demonstrate that tissue compartmentalization of MPXV can exist, mainly in patients with prolonged infections. It will be important to understand if this adaptation plays a significant role in forming a pool of genetic variability, thus contributing to viral persistence.…”

Section: Genetic Characterization and Hierarchical Clustering Analysismentioning

confidence: 64%

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Temporal intra‐host variability of mpox virus genomes in multiple body tissues

Rueca

Tucci

Mazzotta

et al. 2023

Journal of Medical Virology

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Whole‐genome sequencing (WGS) has been widely used for the genomic characterization and the phylogenesis of mpox virus (MPXV) 2022 multi‐country outbreak. To date, no evidence has been reported on intra‐host evolution within samples collected over time from a single patient with long‐term infection. Fifty‐one samples were collected from five patients at different time points post‐symptom onset. All samples were confirmed as MPXV DNA positive, amplified by a multiplexed PCR amplicon, and sequenced by WGS. Complete MPXV genomes were assembled by reference mapping and then aligned to perform phylogenetic and hierarchical clustering analysis. Large intra‐host variability was observed among the MPXV genomes sequenced from samples of two immunocompromised with advanced HIV‐1 infection patients with prolonged MPXV shedding. Overall, 20 nucleotide mutations were identified in the 32 genomes from HIV patients, differently distributed in samples collected from different tissues and at different time points. No sequence compartmentalization nor variation was observed in the three patients with rapid viral clearance. MPXV exhibits adaptation to changing environments within the infected host and consequently demonstrates tissue compartmentalization. Further studies are needed to elucidate the role of this adaptation in forming a pool of genetic variability and contributing to viral persistence and its clinical implications.

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Section: Discussionmentioning

confidence: 56%

Section: Genetic Characterization and Hierarchical Clustering Analysismentioning

confidence: 64%

Temporal intra‐host variability of mpox virus genomes in multiple body tissues

Rueca

Tucci

Mazzotta

et al. 2023

Journal of Medical Virology

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“…Poxviruses are large cytoplasmic DNA viruses, and as a family, can infect a wide variety of different animal species. The most notorious members of the poxvirus family include variola virus, the causative agent of smallpox, and monkeypox virus (MPXV), which is responsible for the recent global outbreaks of monkeypox infections since 2021 [9][10][11][12] . Vaccinia virus was used as the vaccine strain for the eradication of smallpox and is also the prototypic poxvirus that is best characterized 13,14 .…”

Section: Introductionmentioning

confidence: 99%

Human FAM111A inhibits vaccinia virus replication by degrading viral DNA-binding protein I3 and is antagonized by poxvirus host range factor SPI-1

Zhu

Gao

Zhang

et al. 2023

Preprint

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Poxviruses are large double-stranded DNA viruses that infect a wide range of animals including humans. Smallpox virus, the most notorious poxvirus, was eradicated globally in the 1970s. Since then, other members of the poxvirus family, such as monkeypox virus (MPXV) are still posing a great threat to public health. Vaccinia virus (VACV) is a prototypic poxvirus and was used as the vaccine strain for smallpox eradication. VACV encodes a serine protease inhibitor 1 (SPI-1) conserved in all orthopoxviruses, which has been recognized as a host range factor for modified vaccinia virus Ankara (MVA), an approved smallpox vaccine and a promising vaccine vector. FAM111A, a nuclear protein that regulates host DNA replication, was previously identified as a putative target of VACV-ΔSPI-1, which was unable to replicate in human cells unless FAM111A was repressed. Nevertheless, the detailed antiviral mechanisms of FAM111A were unresolved. Here, we show that FAM111A is a potent antiviral factor for VACV-ΔSPI-1 and MVA. Deletion of FAM111A was able to rescue the replication of MVA and VACV-ΔSPI-1. Overexpression of FAM111A significantly reduced viral DNA replication and virus titers but did not affect viral early gene expression. The antiviral effect of FAM111A required its functional serine protease domain and DNA binding domain but not the PCNA-interacting motif. We further discovered that FAM111A translocated into the cytoplasm upon VACV infection and this process was activated through the cGAS-STING signaling pathway. Infection-triggered FAM111A degraded the nuclear pore complex via its serine protease activity, translocated to the cytoplasm, and interacted with and promoted the degradation of virus uncoating factor I3 in a DNA-dependent manner. Interestingly, the serine protease activity of FAM111A was only needed for nuclear export but not I3 degradation. Further analysis suggested I3 was degraded through autophagy. Moreover, VACV SPI-1 was found primarily in the nucleus of infected cells and antagonized FAM111A by prohibiting its nuclear export. Mutations in the SPI-1 reactive-site loop (RSL) abolished its anti-FAM111A activity. SPI-1 from MPXV and lumpy skin disease virus could also inhibit human FAM111A. Our findings reveal the detailed mechanism by which FAM111A functions to restrict a cytoplasmic DNA virus and provide explanations for the immune evasive function of VACV SPI-1.

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“…Recent studies suggest a degree of intrapatient diversity of MPXV genomes, with apparent genomic variation both within and between anatomical sites of infection. 5,11,17 This potential intrapatient genomic diversity, coupled with the slow mutation rate of orthopoxviruses (estimated at 1-2 single-nucleotide polymorphisms [SNPs] per year), may make accurate inferences of interpatient transmission challenging, and requires rigorous validation of the variants observed in the current outbreak strains. 18 In Australia, mpox is a nationally notifiable disease, with 144 cases (confirmed and probable) diagnosed in Australia as of May 4, 2023.…”

Section: Introductionmentioning

confidence: 99%

“…To date, there are limited data on the utility of genomic data for assessing local transmission of mpox. Recent studies suggest a degree of intrapatient diversity of MPXV genomes, with apparent genomic variation both within and between anatomical sites of infection 5,11,17 . This potential intrapatient genomic diversity, coupled with the slow mutation rate of orthopoxviruses (estimated at 1–2 single‐nucleotide polymorphisms [SNPs] per year), may make accurate inferences of interpatient transmission challenging, and requires rigorous validation of the variants observed in the current outbreak strains 18 …”

Section: Introductionmentioning

confidence: 99%

Intra‐ and interhost genomic diversity of monkeypox virus

Taouk

Steinig

Taiaroa

et al. 2023

Journal of Medical Virology

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The impact and frequency of infectious disease outbreaks demonstrate the need for timely genomic surveillance to inform public health responses. In the largest known outbreak of mpox, genomic surveillance efforts have primarily focused on high‐incidence nations in Europe and the Americas, with a paucity of data from South‐East Asia and the Western Pacific. Here we analyzed 102 monkeypox virus (MPXV) genomes sampled from 56 individuals in Melbourne, Australia. All genomes fell within the 2022 MPXV outbreak lineage (B.1), with likely onward local transmission detected. We observed within‐host diversity and instances of co‐infection, and highlight further examples of structural variation and apolipoprotein B editing complex‐driven micro‐evolution in the current MPXV outbreak. Updating our understanding of MPXV emergence and diversification will inform public health measures and enable monitoring of the virus’ evolutionary trajectory throughout the mpox outbreak.

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Intrahost Monkeypox Virus Genome Variation in Patient with Early Infection, Finland, 2022

Cited by 7 publications

References 6 publications

Temporal intra‐host variability of mpox virus genomes in multiple body tissues

Temporal intra‐host variability of mpox virus genomes in multiple body tissues

Human FAM111A inhibits vaccinia virus replication by degrading viral DNA-binding protein I3 and is antagonized by poxvirus host range factor SPI-1

Intra‐ and interhost genomic diversity of monkeypox virus

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