Human adenoviruses: A suspect behind the outbreak of acute hepatitis in children amid the COVID-19 pandemic

Abstract

As of 10 May 2022, at least 450 cases of pediatric patients with acute hepatitis of unknown cause have been reported worldwide. Human adenoviruses (HAdVs) have been detected in at least 74 cases, including the F type HAdV41 in 18 cases, which indicates that adenoviruses may be associated with this mysterious childhood hepatitis, although other infectious agents or environmental factors cannot be excluded. In this review, we provide a brief introduction of the basic features of HAdVs and describe diseases caused by different HAdVs in humans, aiming to help understand the biology and potential risk of HAdVs and cope with the outbreak of acute child hepatitis.

Keywords: Acute hepatitis; HAdV41; Human adenoviruses; Pathogenesis.

Fig. 1

The genomic map and virion structure of human adenovirus. (a) Genomic map of adenovirus adapted from (Zhang and Huang, 2019; Kulanayake and Tikoo, 2021). Regions show the production of early genes (E1A, E1B, E2A, E2B, E3, and E4), major late transcripts including 52K, IIIA, Penton, VI, V, X, VI, Hexon, AVP (adenoviral protein), POL (DNA polymerase), ITR (viral inverted terminal repeats) and so on. (b) Virion structure of human adenovirus based on crystallography and cryo-electron microscopy. Fiber, Penton base and Hexon are capsid proteins. pIX, pIIIa, pVIII and pVI are minor proteins. Core proteins contains of pV, pVII, TP, Mu, pIVa2, AVP; TP (terminal protease). The lowercase “p” refers to protein. Based on (Russell, 2009; Kulanayake and Tikoo, 2021; Giberson et al., 2012).

Fig. 2

Phylogenomic analysis of fiber (a) and hexon (b) of 28 representative HAdVs. A bootstrapped maximum likelihood (ML) tree with 1000 repetitions is constructed using MEGAX software and generalized time-reversible (GTR) model. More than 50% bootstrap rate is displayed on branch nodes.

Fig. 3

The five major human adenovirus receptors and corresponding recognized HAdVs. Coxsackie and adenovirus receptor (CAR) comprises two immunoglobulin-like extracellular domains (D1-2); CD46 (human membrane cofactor protein), the extracellular part of which consists of four short consensus repeats (SCR, 1–4) and a serine, threonine and proline (STP)-rich region; Glycans: GD1a and Polysialic acid (polySia); Desmoglein-2(DSG-2) comprises five extracellular cadherin domains (EC1-5) in addition to a transmembrane segment and an intracellular domain. Based on (Stasiak and Stehle, 2020; Henaff et al., 2011; Arnberg, 2012; Persson et al., 2010; Harrison et al., 2016).

Fig. 4

The replicative cycle of human adenovirus (Dodge et al., 2021; Georgi and Greber, 2020; Charman et al., 2019). 1) HAdV virion bind to cognate receptors to mediate internalization into endosomes. 2) Virions escape from the endosome, dock on nuclear pore complex, and release genome into the nucleus. 3) Transcription of the early viral genes into mRNAs. The mRNAs are exported to the cytoplasm for translation of early viral proteins, which are imported into the nucleus. 4) Transcription of the late structural genes into mRNA from a common major late promoter (MLP). The mRNA are exported to the cytoplasm for translation of structural proteins, which are imported into the nucleus for assembly. 5) Virion assembly occurs in the nucleus. 6) Virion is released from the nucleus and then released from the cell by cytolysis.

Fig. 5

The mRNA and protein expression of CXADR (a), CD46 (b) and DSG2 (c) in human normal tissues in Human Protein Atlas (HPA) database (https://www.proteinatlas.org/). RNA expression (left) was plotted as nTPM (normalized protein-coding transcripts per million), corresponding to mean values of the different individual samples from each tissue. Protein expression data (right) is shown for the tissues. Color-coding is based on tissue groups, each consisting of tissues with functional features in common.