Why are some infections with certain flu virus strains fatal and others are not?


The answer may be found in human CD4+ T cells

Virus specific memory CD4+ T cells numbers predict the outcome of human influenza infections

Wilkinson et al. in 2012 showed that  CD4+ T cells that are activated by earlier influenza virus infections reduce the severity of the disease.

To gain insight into protective immunity against influenza virus infection mediated by neutralizing antibodies Wilkinson et al. in 2012 studied the role of T cells in humans that develop immunity against the influenza virus. The study enrolled 41 healthy human volunteers that had no detectable antibodies to the challenging viruses and challenged their immune system by inoculating them intranasally with serial dilutions of influenza A viruses H3N2 or H1N1. A large increase in influenza specific T cell responses could be observed by day 7. At this day the virus was completely cleared from the nasal samples and serum antibodies were still undetectable. Further, it was observed that preexisting CD4+ T cells responded to the influenza internal proteins, matrix and nucleoprotein. CD8+ T cells did not. The response of these CD+ T cells was associated with lower virus shedding and less severe illness. Furthermore, the CD4+ cells also responded to pandemic peptides from the H1N1 virus strain.

The researchers observed that immune responses from preexisting T cells against internal nucleoprotein and matrix protein as measured by IFN-γ responses were largely CD4+ T cell mediated in both H1N1 and H3N2 study groups. The following table contains a list of peptides that the research group identified at the single-peptide level.

M and NP Influenza A

M = matrix protein.   NP = nucleoprotein..

.

A list of peptides that showed responses of preexisting T cells in challenge study subjects is shown in the tables below.

Response to the challenge with H3N2

Protein Peptide ID Amino acid position Sequence CD4 of CD8 dependency
M MO1 1-15 MSLLTEVETYVLSIV 8
M MO2 6-22 EVETYVLSIVPSGPLKA 4
M MO7 40-57 EALMEWLKTRPILSPLTK 8
M MO8 48–64 TRPILSPLTKGILGFVF 8
M M09 55–72 LTKGILGFVFTLTVPSER 8
M M15 103–119 LKREITFHGAKEIALSY 4
M M23 159–175 HRSHRQMVATTNPLIKH 4
M M25 173–189 IKHENRMVLASTTAKAM 4
NP NP05 24–41 EIRASVGKMIDGIGRFYI 4
NP NP08 48–65 KLSDHEGRLIQNSLTIEK 4
NP NP14 95–111 PIYRRVDGKWMRELVLY 4
NP NP15 102–119 GKWMRELVLYDKEEIRRI 4
NP NP16 110–29 LYDKEEIRRIWRQANNGEDA 4
NP NP20 141–156 SNLNDATYQRTRALVR 8
NP NP21 147–163 TYQRTRALVRTGMDPRM 8
NP NP27 192–208 ELIRMVKRGINDRNFWR 4
NP NP31 221–238 RMCNILKGKFQTAAQRAM 4
NP NP32 229–246 KFQTAAQRAMVDQVRESR 8
NP NP57 404–420 GQTSVQPTFSVQRNLPF 4
NP NP58 411–428 TFSVQRNLPFEKSTIMAA 4

Response to the challenge with H1N1

Protein Peptide ID Amino acid position Sequence CD4 of CD8 dependency
M M8  57–74 KGILGFVFTLTVPSERGL 4
M M12  89–106 DPNNMDRAVKLYRKLKRE 4
M M13  97–114 VKLYRKLKREITFHGAKE 4
M M14 105–122 REITFHGAKEIALSYSAG 4
M M27 209–226 ARQMVQAMRAIGTHPSSS 4
NP NP09 65–82 RMVLSAFDERRNKYLEEH 4
NP NP14 105–122 VRELVLYDKEEIRRIWRQ 4
NP NP22 169–186 GSTLPRRSGAAGAAVKGV 8
NP NP27 209–226 GENGRKTRIAYERMCNIL 8
NP NP28 217–234 IAYERMCNILKGKFQTAA 8
NP NP52 409–426 QPTFSVQRNLPFDKTTIM 4

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Reference

Anne Kelso; CD4+ T cells limit the damage in influenza. Nature Medicine 18, 200–202 (2012). doi:10.1038/nm.2654.

Tom M Wilkinson, Chris K F Li, Cecilia S C Chui, Arthur K Y Huang, Molly Perkins, Julia C Liebner, Rob Lambkin-Williams, Anthony Gilbert, John Oxford, Ben Nicholas, Karl J Staples, Tao Dong, Daniel C Douek, Andrew J McMichael & Xiao-Ning Xu Preexisting influenza-specific CD4+ T cells correlate with disease protection against influenza challenge in humans. Nature Medicine 18, 274–280 (2012). doi:10.1038/nm.2612

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Categories: Antibodies, Antigens, Bioanalysis, Bioinformatics, CD4+ T Cells, Cell lines, Flu, H1N1, Matrix protein, Nucleoprotein, Peptide Synthesis, peptides, Protein, Protein Families, Protein Sequence, Protein Structure, Proteins, Sequence Annotation, Synthesis, T Cells, Vaccines, Virus

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1 reply

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