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. 2010 Jan;71(1):14-22.
doi: 10.1016/j.humimm.2009.08.012.

HLA class I molecules reflect an altered host proteome after influenza virus infection

Angela Wahl  1 , Fredda Schafer, Wilfried Bardet, William H Hildebrand
Affiliations

HLA class I molecules reflect an altered host proteome after influenza virus infection

Angela Wahl et al. Hum Immunol. 2010 Jan.

Abstract

Class I HLA sample and display peptides from thousands of endogenous proteins at the cell surface. During infection, the influenza virus modifies the host cell proteome by triggering host antiviral responses, hijacking host processes, and inhibiting host mRNA processing. In turn, the catalog of HLA class I peptides that decorate the surface of an infected cell is positioned to reflect an altered host cell proteome. To understand the host-encoded peptides presented by class I molecules after influenza infection, we compared by mass spectrometry (MS) the peptides eluted from the HLA of naive and infected cells. We identified 20 peptide ligands unique to infected cells and 347 peptides with increased presentation after infection. Infection with different influenza strains demonstrated that proteome changes are predominantly strain-specific, with few individual cellular interactions observed for multiple viral strains. Modeling by pathway analysis, however, revealed that strain specific host peptide changes represent different routes to the same destination; host changes mediated by influenza are found predominantly clustered around HLA-B, ACTB, HSP90AB1, CDK2, and ANXA2. The class I HLA proteome scanning of influenza-infected cells therefore indicates how divergent strains of influenza pursue alternate routes to access the same host cell processes.

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Figures

Fig. 1
Fig. 1
Identification of unique and increased peptides by mass spectrometry following influenza A virus infection. The annexin A2202–213 (SVIDYELIDQDA) ligand was unique to influenza 309 infected cells. An ion with the mass of 690.87 atomic mass units (amu) was identified as unique to infected cells by aligning the MS spectra of corresponding infected (A) and naïve (B) RP-HPLC fractions at 20 amu increments. Amino acid sequencing of the unique ion by MS/MS fragmentation identified a peptide derived from annexin A2 (SVIDYELIDQDA) (C). TLYEHNNEL, a nine amino acid peptide derived from the AAAS protein, was increased following infection with all three influenza A virus strains (fold increase: PR8-2.49, 7485-2.84, and 309-2.2). The amino acid sequence was determined by MS/MS fragmentation (D).
Fig. 2
Fig. 2
Host encoded HLA-A*0201 peptides that are unique or increased following influenza A virus infection. Comparative mass spectrometric analysis of class I HLA-A*0201 peptides purified from naïve and influenza infected HeLa cells identified host-encoded peptides with unique or increased presentation following influenza infection. A Venn diagram reveals overlap in the presentation of unique and increased peptides observed between the PR8 (blue), 7485 (red), and 309 (green) influenza strains. The twenty host peptides unique to influenza infection were presented on a strain-by strain basis (PR8-5, 7485-14, and 309-1). While the majority of peptides with upregulated presentation following influenza infection were limited to the infecting strain, 39 host encoded HLA-A*0201 peptides had increased presentation during infection with both H1N1 strains (PR8 and 7485), 6 peptides were upregulated following 7485 and 309 infection, and 5 peptides exhibited increased presentation during infection with all influenza A virus three strains.
Fig. 3
Fig. 3
Source proteins encoding HLA-A*0201 peptides with unique or increased presentation following influenza A virus infection. HLA-A*0201 self peptides with unique or increased presentation following influenza A virus infection were encoded by 297 different proteins. A Venn diagram illustrates the overlap between PR8 (blue), 7485 (red), and 309 (green) influenza strains in regard to the source proteins encoding unique and increased peptides identified during influenza infection. Minimal overlap was observed in the host proteins sampled by class I HLA among the three influenza A virus strains. The most extensive overlap was displayed by the two H1N1 influenza virus strains (44/297). Both PR8 and 7485 H1N1 strains exhibited slight overlap with the recent H3N2 isolated 309. Only 9 host proteins were shared by the three influenza strains.
Fig. 4
Fig. 4
Direct interactions of proteins encoding unique/increased HLA-A*0201 following PR8, 7485, and 309 influenza infection. Direct interactions between the source proteins of all unique and increased HLA-A*0201 peptides following PR8, 7485, and 309 infection were mapped by Ingenuity Pathway Analysis. Proteins encoding unique and/or increased peptides that were sampled by HLA-A*0201 during infection with all three influenza strains are shown in red. Host proteins shared by H1N1 influenza A virus strains PR8 and 7485 are illustrated in blue and proteins common to the recent H1N1 and H3N2 isolates 7485 and 309 are colored yellow. The remaining source proteins were unique to either PR8 (light blue), 7485 (pink), or 309 (green) influenza strains. The five most prominent hubs of protein interaction were centered around the HLA-B, ACTB, HSP90AB1, CDK2, and ANXA2 molecules which are circled and labeled in accordance to their dominance in the protein network.
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