Appendix G
Influenza A and SARS-CoV

INFLUENZA A

The influenza A virus proapoptotic PB1-F2 protein has been clearly implicated as a major virulence factor in some highly pathogenic influenza virus strains, but the H1N1 swine-origin influenza virus pandemic strain codes for a truncated PB1-F2 protein that terminates after 11 amino acids. It was predicted that the truncation would attenuate swine influenza pathogenesis, identifying a possible key mutation that could emerge to enhance H1N1 virulence and contribute to an expanding epidemic. However, disruption of PB1-F2 expression in several other influenza virus backgrounds or by intermixing functional PB1-F2 between strains had little effect on viral lung load in mice. The data suggests that the PB1-F2 virulence determinant may be context- or host-dependent, perhaps by enhancing virulence by other mechanisms that are independent of replication. The effects of restoring a full length functional PB1-F2 protein on 2009 swine H1N1 in vivo pathogenesis are difficult to predict because its virulence-enhancing activities may depend on co-evolutionary changes elsewhere in the genome. As a working model for predicting virulence from sequence information, the preponderance of influenza data suggest that restoration of a full length PB1-F2 protein will enhance the virulence of swine H1N1—a hypothesis that will probably be tested using reverse genetics in the near future (McAuley, Zhang et al.)

SARS-COV

It is also clear that distantly related viral proteins can interact with a conserved cellular protein target and thereby augment their pathogenic potential. Among coronaviruses as with many other viruses, receptor interactions are



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Appendix G Influenza A and SARS-CoV INFLUENZA A The influenza A virus proapoptotic PB1-F2 protein has been clearly im - plicated as a major virulence factor in some highly pathogenic influenza virus strains, but the H1N1 swine-origin influenza virus pandemic strain codes for a truncated PB1-F2 protein that terminates after 11 amino acids. It was predicted that the truncation would attenuate swine influenza pathogenesis, identify- ing a possible key mutation that could emerge to enhance H1N1 virulence and contribute to an expanding epidemic. However, disruption of PB1-F2 expression in several other influenza virus backgrounds or by intermixing functional PB1-F2 between strains had little effect on viral lung load in mice. The data suggests that the PB1-F2 virulence determinant may be context- or host-dependent, perhaps by enhancing virulence by other mechanisms that are independent of replication. The effects of restoring a full length functional PB1-F2 protein on 2009 swine H1N1 in vivo pathogenesis are difficult to pre- dict because its virulence-enhancing activities may depend on co-evolutionary changes elsewhere in the genome. As a working model for predicting virulence from sequence information, the preponderance of influenza data suggest that restoration of a full length PB1-F2 protein will enhance the virulence of swine H1N1—a hypothesis that will probably be tested using reverse genetics in the near future (McAuley, Zhang et al.) SARS-COV It is also clear that distantly related viral proteins can interact with a con - served cellular protein target and thereby augment their pathogenic potential. Among coronaviruses as with many other viruses, receptor interactions are 

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 APPENDIX G an important determinant of species specificity, tissue tropism, virulence, and pathogenesis. Pathogenesis depends upon the ability of a virus to dock and enter into a suitable human host cell. For example, the highly pathogenic emerging group 2 coronavirus that causes severe acute respiratory syndrome, coronavirus (SARS-CoV) and a distantly related less pathogenic group 1 human coronavirus, NL63-CoV, both encode a large 180/90kDa spike glycoprotein (S) that engages a host cellular receptor(s) to mediate docking and entry into cells. The SARS-CoV and NL63-CoV S glycoproteins are about 40 percent identical and encode novel, yet unrelated receptor binding domains (RBD) in S that engage the same cellular receptor, angiotensin-converting enzyme 2 (ACE2) to mediate virus docking and entry into cells. Despite the absence of structural homology in the RBD cores of NL63-CoV and SARS-CoV, the two viruses recognize common ACE2 regions by using novel protein-protein folds and interaction networks. On the basis of sequence, it was not possible to pre - dict that the two highly divergent coronavirus RBDs would engage a similar “hot spot” on the surface of the ACE2 receptor and thus mediate docking and entry into cells. Moreover, the pathogenic potential of the two human corona- viruses are distinct: SARS-CoV causes an atypical pneumonia that results in acute respiratory distress syndrome with mortality exceeding 50 percent in people over 60 years old, whereas NL63-CoV causes a self-limiting denuding bronchiolitis and croup, primarily in infants and children. Clearly, other factors besides virus-receptor interaction and entry are regulating severe acute end- stage lung-disease outcomes during SARS-CoV infection, and this complicates sequence-based predictions of virus-receptor interaction networks and viru - lence outcomes (Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):19970-19974. Epub 2009 Nov 9. Crystal structure of NL63 respiratory coronavirus receptor- binding domain complexed with its human receptor (Wu, Li et al. 2009).