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Zoonotic origin, molecular evolution and adaptation of human respiratory pathogen revealed through genomics and bioinformatics

Computational analysis of four human adenovirus type 4 genomes reveals molecular evolution through two interspecies recombination events

Read the full article on ScienceDirect.

How do viruses arise? Specifically, how do pathogens *POP* into the population and become persistent and ubiquitous? Adenoviruses are double-stranded DNA viruses that have intersected with humans both as pathogens affecting many diverse tissues and as invaluable research and clinical tools since 1953. As one of the original respiratory viral pathogens studied, it was an important model organism, providing insights into molecular biology (e.g., mRNA splicing), cell biology (e.g., first cell-free eukaryotic DNA replication system) and immunology (e.g., T-cells/antigen presentation). It’s still an important model organism, with high-resolution genome data enabling a paradigm shift for adenovirus typing and taxonomy and a glimpse into the origins, molecular evolution and adaptation of viral pathogens.

HAdV-E4 was isolated from and limited to military personnel for approximately three decades, necessitating two separate multi-million dollar vaccine development efforts. As of the last formal report, this strain constituted over 99.8% of the adenovirus respiratory pathogens isolated from sick military trainees in the mid-2000s. Currently controlled in the U.S. military by an exclusive vaccine, HAdV-E4 remains a highly contagious, respiratory pathogen associated with significant morbidity and mortality in civilian populations world-wide. HAdV-E4 is shown to have chimpanzee origins, with adenoviral interspecies recombination of a gene sequence encoding the major human virus shell protein as a step in zoonosis. A subsequent recombination, substituting a human transcription factor binding site, expedited adaptation to human hosts. As HAdVs and simian AdVs are candidate vectors for human gene delivery technology, understanding relationships between these viruses is critical to minimize unintended side-effects.

Genomic analysis of human adenovirus type 4 (HAdV-E4FS1). A) The genome sequence of HAdV-E4FS1 contains a recombination event revealed with the Bootscan option of Simplot. SAdV-E26 is a simian (chimpanzee) adenovirus (SAdV) and HAdV-B16 is a human adenovirus. For reference, three viral shell protein coding regions are noted along the top, with the percent identity of the sequences along the y-axis and the genome nucleotide positions along the x-axis. The recombinant hexon, comprising a majority of the shell, is found in four HAdV-E4 genomes sequenced. These four viruses were isolated from patients with acute respiratory disease, spanning fifty-two years, i.e., 1952 (‘p’ for prototype), 1962 (‘vac’ for vaccine strain), 2003 (‘FS1’ for field strain 1) and 2004 (‘FS2’). This interspecies recombination, reported here for the first time, between two HAdV species (B and E) may have enabled a successful zoonosis. B) The 5’-end ‘Inverted Terminal Repeat’ contains conserved DNA replication motifs (core, NF-I and NF-III), as shown for six SAdVs, five HAdV-E4s and three HAdV-Bs; the latter eight cause acute respiratory disease in humans. The ‘B’ and ‘E’ notations denote the species group of HAdV. Host-supplied human transcription factor NF-I is required for optimal adenoviral replication, and is recombined into recent HAdV-E4 genomes. ‘Jax’ is a HAdV-E4 strain isolated in 1978 (partially sequenced). It is thought the mid-1970s represents a transition point, with this second recombination event expediting the molecular adaptation of a former chimpanzee virus to a human host, with HAdV-E4 now causing epidemics in both military and civilian populations world-wide.
Genomic analysis of human adenovirus type 4 (HAdV-E4FS1). A) The genome sequence of HAdV-E4FS1 contains a recombination event revealed with the Bootscan option of Simplot. SAdV-E26 is a simian (chimpanzee) adenovirus (SAdV) and HAdV-B16 is a human adenovirus. For reference, three viral shell protein coding regions are noted along the top, with the percent identity of the sequences along the y-axis and the genome nucleotide positions along the x-axis. The recombinant hexon, comprising a majority of the shell, is found in four HAdV-E4 genomes sequenced. These four viruses were isolated from patients with acute respiratory disease, spanning fifty-two years, i.e., 1952 (‘p’ for prototype), 1962 (‘vac’ for vaccine strain), 2003 (‘FS1’ for field strain 1) and 2004 (‘FS2’). This interspecies recombination, reported here for the first time, between two HAdV species (B and E) may have enabled a successful zoonosis. B) The 5’-end ‘Inverted Terminal Repeat’ contains conserved DNA replication motifs (core, NF-I and NF-III), as shown for six SAdVs, five HAdV-E4s and three HAdV-Bs; the latter eight cause acute respiratory disease in humans. The ‘B’ and ‘E’ notations denote the species group of HAdV. Host-supplied human transcription factor NF-I is required for optimal adenoviral replication, and is recombined into recent HAdV-E4 genomes. ‘Jax’ is a HAdV-E4 strain isolated in 1978 (partially sequenced). It is thought the mid-1970s represents a transition point, with this second recombination event expediting the molecular adaptation of a former chimpanzee virus to a human host, with HAdV-E4 now causing epidemics in both military and civilian populations world-wide.

Introducing the authors

Professor Donald Seto discusses data with graduate student Amirhossein Shamsaddini (left) and research scientist Shoaleh Dehghan (right). Photo by George Mason University, Creative Services.
Professor Donald Seto discusses data with graduate student Amirhossein Shamsaddini (left) and research scientist Shoaleh Dehghan (right). Photo by George Mason University, Creative Services.

About the research

Computational analysis of four human adenovirus type 4 genomes reveals molecular evolution through two interspecies recombination events

Virology, Volume 443, Issue 2, 1 September 2013, Pages 197-207
Shoaleh Dehghan, Jason Seto, Elizabeth B. Liu, Michael P. Walsh, David W. Dyer, James Chodosh, Donald Seto

Read the full article on ScienceDirect.