Identification of Rare PB2-D701N Mutation from a Patient with Severe Influenza: Contribution of the PB2-D701N Mutation to the Pathogenicity of Human Influenza

Abstract

Several amino acid changes have been previously implicated in adaptation of avian influenza viruses to human hosts, among them the D701N change in the PB2 polymerase subunit that also is the main determinant of avian virus pathogenesis in animal models. However, previous studies using recombinant viruses did not provide conclusive information of the contribution of this PB2 residue to pathogenicity in human influenza virus strains. We identified this mutation in an A(H1N1)pdm09-like human influenza virus isolated from an infected patient with pneumonia and acute respiratory failure, admitted to the intensive care unit. An exhaustive search has revealed PB2-D701 as a highly conserved position in all available H1N1 human virus sequences in NCBI database, showing a very low prevalence of PB2-D701N change. Presence of PB2-701N amino acid correlates with severe or fatal outcome in those scarce cases with known disease outcome of the infection. In these patients, the residue PB2-701N may contribute to pathogenicity as it was previously reported in humans infected with avian viruses. This study helps to clarify a debate that has arisen regarding the role of PB2-D701N in human influenza virus pathogenicity.

Pathway mapping of leukocyte transcriptome in influenza patients reveals distinct pathogenic mechanisms associated with progression to severe infection

“…Influenza can cause a mild respiratory illness but can also lead to respiratory failure and death [2,3]. Virulence factors (of different virus strains) contribute significantly to this variability in infection severity [4,5]. However, it is increasingly being recognized that host factors also play an important role in contributing to infection severity [6][7][8][9][10].…”

Detection of respiratory viruses directly from clinical samples using next‐generation sequencing: A literature review of recent advances and potential for routine clinical use

“…The rapid diffusion of NGS into clinical laboratories for detecting respiratory viruses will be based on whether the challenges relating to NGS can be addressed. 39,42,46,48,49,78 Notably, the cost of NGS has been reduced over time, which will attract more laboratories to bring this technique into their research and make efforts in optimising NGS protocols.…”

“…14 Nieto et al observed the D701N mutation of polymerase basic protein 2 (PB2) segment of the H1N1pdm09 virus in one patient with severe influenza. 46 The study provided evidence on the association between the PB2-D701N mutation and viral pathogenicity in humans and suggested that this mutation may result in more severe clinical outcomes of human infections.…”

“…Five out of 18 studies (27.8%) reported the successful detection of mutations in influenza viruses through the WGS using the NGS technique. 14,38,[44][45][46] For example, Piralla et replicate more effectively in the lower respiratory tract and be more likely to increase the severity of the disease. 14 Nieto et al observed the D701N mutation of polymerase basic protein 2 (PB2) segment of the H1N1pdm09 virus in one patient with severe influenza.…”

“…considering implementing NGS in routine diagnosis: (i) the cost of conducting NGS work is still relatively high compared to currently available standard diagnostic tools, 39,40,48,49,78 (ii) the whole process of NGS work requires lengthy turnaround times and skilled laboratory staff, especially the library preparation step. Existing diagnostic tests, such as RT-PCR or rapid antigen tests, have shorter turnaround times in providing the results and simple processing requirements, 39,49,78 (iii) the high volume and complexity of sequence data require sophisticated downstream bioinformatic analyses conducted by skilled laboratory staff, 46,48,49,78 (iv) contamination from the host or microbiota cells may result in low viral genetic material, especially when nasal specimens were used for metagenomic sequencing, 42,46,55 S2). 2G platforms from Illumina were the most selected instrument in previous studies (40/52, 76.9%), primarily because of its higher accuracy (about 99%) of sequence data with a lower error rate compared to other NGS platforms.…”