Are adenoviruses zoonotic? A systematic review of the evidence

Figures & data

Figure 1. Diagram of article screening process for a systematic review of evidence of adenovirus transmission between humans and other animals. The search captured 327 articles from 3 databases, 24 of which were included in the final review.

Table 1. Publications considered important in evaluating the zoonotic potential of adenoviruses

Evidence of Zoonoses
Publication		Country and Year	Main Summary	Type of Evidence
1.	Madisch et al. [25]	Global, 2005	Phylogenetic analysis of epitope ε and ץ encoding gene regions of the hexon and fibre genes, respectively, provided evidence of interspecies recombination in both the phylogeny of HAdV-E4 as well as SAdV-E25.	Phylogenetic evidence of zoonosis: ε determinant regions of hexon gene and ץ determinant regions of fibre gene.
2.	Purkayastha et al. [26]	USA, 2005	Genomic analysis of HAdV-4 reveals sequence similarity closer phylogenetic relationship to SAdVs than HAdVs, suggesting evolutionary origins of HAdV-4 as a product of zoonotic transmission; literature supports chimpanzee to human transmission. Recombination or lateral gene transfer of hexon from HAdV-4, presumably of chimpanzee origins, to HAdV-16.	Phylogenetic evidence of anthropozoonosis: complete and annotated genome sequence of HAdV-4.
3.	Phan et al. [27]	Japan, 2006	AdV type 1 with 100% identity and 97% identity to human AdV was detected in 1-year old female with acute gastroenteritis. The HAdV and feline AdV detected belong to the same AdV-1 cluster, prototype Adenoid 71.	Phylogenetic evidence of anthropozoonosis: 100% amino acid sequence homology in seven hypervariable regions of the hexon gene; 97% amino acid sequence homology in fibre genes (BLAST and Clustal X).
4.	Xiang et al. [28]	Cameroon, Côte D`Ivoire, Nigeria, Thailand, USA 2006	Humans in the U.S. had no neutralizing antibodies to chimpanzee AdVs, but human serum from Cameroon and Nigeria showed higher prevalence of antibodies to AdV-C6 and AdV-C1. Samples from Côte D`Ivoire high prevalence of antibodies to AdV-C68 and AdV-C6.	Serological evidence of anthropozoonosis: Sera from humans and chimpanzees were tested for neutralizing antibodies to chimpanzee-derived AdV- C68, -C6 and -C1.
5.	Roy et al. [29]	Global, 2009	Genomic sequencing of different primate species stool samples collected across Africa and the U.S. found a high prevalence of AdV which could be classified into species corresponding with HAdV B, C, and E groups	Phylogenetic evidence of zooanthroponosis: Samples first cultured and analyzed by PCR; 8 genes (hexon, penton base, protease, E1A, DBP, polymerase, pTP).
6.	Wevers et al. [30]	Global, 2011	HAdVs species A-G were detected in fecal, blood and tissue samples of wild or captive NHPs. The majority of human AdVs detected were in HAdV-E (46%), -B (35%), and –C (15%) clades.	Phylogenetic evidence of zooanthroponosis: Pan-primate AdV-specific PCR targeting highly conserved polymerase gene. Near complete sequencing of hexon gene.
7.	Chen et al. [31]	USA, 2011	Researcher at a primate research centre was in contact with monkey infected with TMAdV and developed acute respiratory illness. Two family members also developed ILI 1–2 weeks after researcher fell ill. Samples from the researcher and one ill family member were found positive for neutralizing Abs to TMAdV.	Serological evidence of anthropozoonosis: Four months after outbreak for researcher with direct contact and one year after outbreak for family members: Ab titre for researcher was 1:32 and for family member 1:8. Phylogenetic: Whole-genome sequencing found the TMAdV distinct from known HAdVs. Closest simian AdV relative is SAdV-3, -18 and -21.
8.	Roy et al. [32]	USA, 2012	Fecal sample from rhesus macaques from 5 primate facilities found 23 SAdV isolates. Sequencing revealed SAdV-18 related to HAdV F.	Phylogenetic evidence of zooanthroponosis: whole genome sequencing.
9.	Baker et al. [33]	Ghana, 2013	An Eidolon helvum (fruit bat) AdV-1 collected from urine yields a hexon protein sequence that clades near the HAdV clade, and shares 77% and 90% amino acid similarity across 58 and 63 amino acids, respectively, spanning the 900 amino acid hexon proteins.	Phylogenetic evidence of zooanthroponosis: Hexon sequence similarity across 58 and 63 amino acids, respectively, of the 900 amino acid protein.
10.	Chiu et al. [34]	USA, 2013	Following outbreak of four baboon AdVs at primate research facility, six facility personnel were found to have neutralizing Abs to BaADV-2 and -4 and five also had evidence of neutralizing Abs titres to BaAdV-1. Staff anecdotally reported ILI. None found to have neutralizing Abs to BaAdV-3. Five children under 5 years of age also tested as controls, all of whom were negative for neutralizing Abs to BaAdV -1, -2, -3, and -4.	Serological evidence of anthropozoonosis: Researcher with most contact with ill baboons had the highest neutralizing Ab response of 1:128.
11.	Dehghan el al. [35]	USA, 2013	From a comparative genomic analysis, SAdV type 35 (isolated by Roy et al. 2009) yielded similar identities with HAdV-B21 (89.7%); HAdV-B50 (89.2%) HAdV-B16 (87.8%); and HAdV-B7 (85.5%). A sequence recombination analysis also demonstrated an example of recombination between HAdVs and SAdVs.	Phylogenetic evidence of zoonosis: Whole genome and select gene sequences using BLAST, MAFFT and MEGA4 software; amino acid sequence analysis and nucleotide sequence analysis
12.	Dehghan el al. [20]	USA, 2013	Recombination or lateral DNA sequence transfer of ITR, and specifically the NF-1 viral replication protein binding site, from a HAdV-B species virus to HAdV-4, as host adaptation for optimal viral replication in human cells.	Phylogenetic evidence of anthropozoonosis: Whole genome sequencing; Sequence alignment and phylogenetics for the ITR and viral replication protein binding sequence.
13.	Hoppe et al. [36]	DRC, Rwanda, Uganda, 2015	Detected HAdV-B in seven wild gorilla samples; Sample from Eastern lowland gorilla in DRC found near complete genome sequence of HAdV-B. Evidence of intra-species recombination between HAdV-B obtained from wild gorillas and chimpanzees.	Phylogenetic evidence of zooanthroponosis: nearly full genome sequences, amplified widely overlapping PCR fragments with 19 sets of degenerate nested primers and long-distance PCR.
14.	Hoppe et al. [37]	Cameroon, CAR, Côte D`Ivoire, DRC, Gabon, Rwanda, Uganda 2015	HAdV-B -C -E and -F were detected by PCR in fecal samples from wild great apes (gorillas, bonobos and chimpanzees).	Phylogenetic evidence of zooanthroponosis: amplified block with V, pX, pVI and hexon genes, polymerase sequences, V gene using BLAST.
15.	Pauly et al. [38]	Côte D`Ivoire, 2015	A study of humans and domestic animals found no animal AdV in human feces but several HAdV types were detected in animal fecal samples and rectum swabs from pigs, dogs, goats and sheep.	Phylogenetic evidence of zooanthroponosis: PCR targeting hexon gene and phylogenetic analysis using BLAST.
16.	Sukmak et al. [39]	Thailand, 2017	Fecal samples of macaques found evidence of three AdVs, with two clustering in HAdV-G cluster, demonstrating close relationship to HAdV-52, supporting hypothesis HAdV-52 was originally a SAdV.	Phylogenetic evidence of zooanthroponosis: hexon and polymerase genes.
17.	*Dehghan et al. [40]	USA, 2019	From a comparative genomic analysis, HAdV-76 is nearly identical to SAdV type 35.1 and 35.2 (isolated by Roy et al. 2009), with whole genome sequence noted as 99.5% and 99.6% identical to genomes from SAdV-B35.1 and SAdV-B35.2, respectively. A sequence recombination analysis also demonstrated an example of recombination between HAdVs and SAdVs.	Phylogenetic evidence of zoonosis: whole genome sequencing; sequence alignment and phylogenetic analysis.
Lack of Evidence of Zoonoses
Publication		Country and Year	Main Summary	Type of Evidence
18.	Miller et al. [41]	USA, 1971	A serological study of a group of poultry-exposed persons and a control group of unexposed persons found no seropositivity in either group for avian AdV	Serological: neutralization in ovo (CELO virus), and neutralization by plaque reduction.
19.	Kayali et al. [42]	USA, 2009	The study found no serological evidence that exposed turkey workers were infected with hemorrhagic enteritis viruses (avian adenoviruses)	Serological: HEV antibody test kit used to test sera of exposed turkey workers and controls with no exposure; HAdV-2, -3, -41 also tested to control for cross-reactivity
20.	Li et al. [43]	USA, 2010	An analysis of bat guano for AdV among other viruses found “no close homologue of a known human viral pathogen” through phylogenetic evidence.	Phylogenetic: metagenomic analysis using second generation sequencing.
21.	Phan et al. [44]	USA, 2011	A characterization of fecal samples from rodents detected sequences of a novel AdV in a deer mouse, which clustered with murine AdV-2 but no genetic similarities with HAdVs.	Phylogenetic: two separate contigs encoding 10% of AdV Hexon protein
22.	Nkogue et al. [45]	Gabon, 2016	Surveillance of AdV infection in fecal samples from western lowland gorillas and humans residing in close proximity revealed a high prevalence of AdV in gorillas and humans. HAdV-B, -C, -and E were detected in gorillas. HAdV-C, and -D were detected in humans; however, the HAdV-C genes in humans and gorillas wer genetically distinct.	Phylogenetic: nested PCR targeting DPOL and hexon genes. Nucleotide sequences of amplicons confirmed using BLAST
23.	Zheng et al. [46]	China, 2016	Rectal swabs from bats and stool samples from outpatients with diarrhea were analyzed for bat and human AdVs. All bat and human AdVs detected were mastadenoviruses but only 57.1–69.3% aa similarity was detected between the two.	Phylogenetic: nested PCR targeting DPOL gene. Sequencing using BioEdit and comparison using BLAST
24.	Wang et al. [47]	USA, 2018	Nasal swabs from human subjects with influenza like illness who were living in close proximity to dense poultry and swine farming operations were examined for evidence of panspecies adenoviruses. No evidence of zoonotic adenoviruses was found.	Molecular: PCR targeting hexon gene
25.	Dadáková et al. [48]	Tanzania, 2018	Fecal samples from unhabituated eastern chimpanzees demonstrated HAdV-B, -C and -E strains; however, all were distinct from human, even gorilla and bonobo clusters, indicating strict host specificity of the viruses	Phylogenetic: PCR targeting DPOL gene partial DPOL and/or hexon sequencing; ClustalW amino acid alignment; BLAST analysis and hexon-based phylogenetic analysis

aa = amino acid; Abs = antibodies; AdV = adenovirus; AdV-2 = adenovirus serotype 2; AdV-C1 = adenovirus species C serotype 1; AdV-C6 = adenovirus species C serotype 6; AdV-C68 = adenovirus species C serotype 68; BaAdV = baboon adenovirus; BaAdV -1, -2, -3, and -4 = baboon adenoviruses serotypes 1, 2, 3 and 4; BLAST = Basic Local Alignment Search Tool; CAR = Central African Republic; CELO = chicken embryo lethal orphan; DBP = DNA-binding protein; DPOL = DNA polymerase gene; DRC = Democratic Republic of the Congo; HAdV = human adenovirus; HAdV-2 = human adenovirus serotype 2; HAdV-3 = human adenovirus serotype 3; HAdV-4 = human adenovirus serotype 4; HAdV-41 = human adenovirus serotype 41; HAdV-52 = human adenovirus serotype 52; HAdV-B = human adenovirus species B; HAdV-B7 = human adenovirus species B serotype 7; HAdV-B16 = human adenovirus species B serotype 16; HAdV-B21 = human adenovirus species B serotype 21; HAdV-B50 human adenovirus species B serotype 50; HAdV-C = human adenovirus species C; HAdV -E = human adenovirus species E; HAdV-E4 = human adenovirus species E serotype 4; HAdV-F = human adenovirus species F; HAdV-G = human adenovirus species G; ILI = influenza-like-illness; ITR = inverted terminal repeat; MAFFT = multiple alignment using fast Fourier transform; MEGA4 = Molecular Evolutionary Genetics Analysis version 4.0; PCR = polymerase chain reaction; pTP = terminal protein precursor; SAdV = simian adenovirus; SAdV-E25 = simian adenovirus species E serotype 25; TMAdV = titi monkey adenovirus.

*Note that Dehghan et al. [40] was published after the systematic review search, but has been included in this table due to relevance to the review.

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