PMID- 35051231
OWN - NLM
STAT- MEDLINE
DCOM- 20220218
LR  - 20220218
IS  - 1553-7374 (Electronic)
IS  - 1553-7366 (Print)
IS  - 1553-7366 (Linking)
VI  - 18
IP  - 1
DP  - 2022 Jan
TI  - Immunopeptidomic analysis of influenza A virus infected human tissues identifies 
      internal proteins as a rich source of HLA ligands.
PG  - e1009894
LID - 10.1371/journal.ppat.1009894 [doi]
LID - e1009894
AB  - CD8+ and CD4+ T cells provide cell-mediated cross-protection against multiple 
      influenza strains by recognising epitopes bound as peptides to human leukocyte 
      antigen (HLA) class I and -II molecules respectively. Two challenges in 
      identifying the immunodominant epitopes needed to generate a universal T cell 
      influenza vaccine are: A lack of cell models susceptible to influenza infection 
      which present population-prevalent HLA allotypes, and an absence of a reliable 
      in-vitro method of identifying class II HLA peptides. Here we present a mass 
      spectrometry-based proteomics strategy for identifying viral peptides derived 
      from the A/H3N2/X31 and A/H3N2/Wisconsin/67/2005 strains of influenza. We 
      compared the HLA-I and -II immunopeptidomes presented by ex-vivo influenza 
      challenged human lung tissues. We then compared these with directly infected 
      immortalised macrophage-like cell line (THP1) and primary dendritic cells fed 
      apoptotic influenza-infected respiratory epithelial cells. In each of the three 
      experimental conditions we identified novel influenza class I and II HLA peptides 
      with motifs specific for the host allotype. Ex-vivo infected lung tissues yielded 
      few class-II HLA peptides despite significant numbers of alveolar macrophages, 
      including directly infected ones, present within the tissues. THP1 cells 
      presented HLA-I viral peptides derived predominantly from internal proteins. 
      Primary dendritic cells presented predominantly viral envelope-derived HLA class 
      II peptides following phagocytosis of apoptotic infected cells. The most frequent 
      viral source protein for HLA-I and -II was matrix 1 protein (M1). This work 
      confirms that internal influenza proteins, particularly M1, are a rich source of 
      CD4+ and CD8+ T cell epitopes. Moreover, we demonstrate the utility of two 
      ex-vivo fully human infection models which enable direct HLA-I and -II 
      immunopeptide identification without significant viral tropism limitations. 
      Application of this epitope discovery strategy in a clinical setting will provide 
      more certainty in rational vaccine design against influenza and other emergent 
      viruses.
FAU - Nicholas, Ben
AU  - Nicholas B
AUID- ORCID: 0000-0003-1467-9643
AD  - Centre for Proteomic Research, Biological Sciences and Institute for Life 
      Sciences, University of Southampton, Southampton, United Kingdom.
AD  - Centre for Cancer Immunology and Institute for Life Sciences, Faculty of 
      Medicine, University of Southampton, Southampton, United Kingdom.
FAU - Bailey, Alistair
AU  - Bailey A
AUID- ORCID: 0000-0003-0023-8679
AD  - Centre for Proteomic Research, Biological Sciences and Institute for Life 
      Sciences, University of Southampton, Southampton, United Kingdom.
AD  - Centre for Cancer Immunology and Institute for Life Sciences, Faculty of 
      Medicine, University of Southampton, Southampton, United Kingdom.
FAU - Staples, Karl J
AU  - Staples KJ
AUID- ORCID: 0000-0003-3844-6457
AD  - Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, Faculty of 
      Medicine, University of Southampton, Southampton, United Kingdom.
FAU - Wilkinson, Tom
AU  - Wilkinson T
AD  - Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, Faculty of 
      Medicine, University of Southampton, Southampton, United Kingdom.
AD  - NIHR Southampton BRC, UHS NHS FT, Southampton, United Kingdom.
FAU - Elliott, Tim
AU  - Elliott T
AD  - Centre for Cancer Immunology and Institute for Life Sciences, Faculty of 
      Medicine, University of Southampton, Southampton, United Kingdom.
FAU - Skipp, Paul
AU  - Skipp P
AD  - Centre for Proteomic Research, Biological Sciences and Institute for Life 
      Sciences, University of Southampton, Southampton, United Kingdom.
LA  - eng
GR  - A21998/CRUK_/Cancer Research UK/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220120
PL  - United States
TA  - PLoS Pathog
JT  - PLoS pathogens
JID - 101238921
RN  - 0 (Antigens, Viral)
RN  - 0 (Epitopes, T-Lymphocyte)
RN  - 0 (Viral Proteins)
SB  - IM
MH  - Antigens, Viral/*immunology
MH  - CD4-Positive T-Lymphocytes/immunology
MH  - CD8-Positive T-Lymphocytes/immunology
MH  - Epitopes, T-Lymphocyte/*immunology
MH  - Humans
MH  - In Vitro Techniques
MH  - Influenza A Virus, H3N2 Subtype/*immunology
MH  - Influenza A virus/*immunology
MH  - Proteomics/methods
MH  - Viral Proteins/*immunology
PMC - PMC8806059
COIS- The authors have declared that no competing interests exist.
EDAT- 2022/01/21 06:00
MHDA- 2022/02/19 06:00
PMCR- 2022/01/20
CRDT- 2022/01/20 17:47
PHST- 2021/08/10 00:00 [received]
PHST- 2022/01/02 00:00 [accepted]
PHST- 2022/02/01 00:00 [revised]
PHST- 2022/01/21 06:00 [pubmed]
PHST- 2022/02/19 06:00 [medline]
PHST- 2022/01/20 17:47 [entrez]
PHST- 2022/01/20 00:00 [pmc-release]
AID - PPATHOGENS-D-21-01642 [pii]
AID - 10.1371/journal.ppat.1009894 [doi]
PST - epublish
SO  - PLoS Pathog. 2022 Jan 20;18(1):e1009894. doi: 10.1371/journal.ppat.1009894. 
      eCollection 2022 Jan.