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Immune Repertoire Diversity Correlated with Mortality in Avian Influenza A (H7N9) Virus Infected Patients

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ABSTRACT

Specific changes in immune repertoires at genetic level responding to the lethal H7N9 virus are still poorly understood. We performed deep sequencing on the T and B cells from patients recently infected with H7N9 to explore the correlation between clinical outcomes and immune repertoire alterations. T and B cell repertoires display highly dynamic yet distinct clonotype alterations. During infection, T cell beta chain repertoire continues to contract while the diversity of immunoglobulin heavy chain repertoire recovers. Patient recovery is correlated to the diversity of T cell and B cell repertoires in different ways – higher B cell diversity and lower T cell diversity are found in survivors. The sequences clonally related to known antibodies with binding affinity to H7 hemagglutinin could be identified from survivors. These findings suggest that utilizing deep sequencing may improve prognostication during influenza infection and could help in development of antibody discovery methodologies for the treatment of virus infection.

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V and J gene usage in H7N9 infected patients by outcome.(a) shows frequency of IGHV gene usage in patients from non-survival group (red) and survival group (green). IGHV3-23 (9.73%), IGHV4-59 (8.76%) and IGHV3-30 (8.33%) were the three most frequent IGHV genes. (b) shows IGHJ gene usage frequency among patients. Expressing of IGHJ4 composed 44 ~ 64% of the repertoires. (c,d) show frequencies of TRBV and TRBJ genes usage. TRBV28 (14.28%), TRBV27 (12.69%) and TRBV20-1 (10.77%) accompanied by TRBJ1-1 (18.23%), TRBJ2-1 (16.31%) and TRBJ 2-3 (15.67%), were the three most frequent TRBV and TRBJ genes. Data are represented as mean ± SEM (See also Supplementary Figure S2).
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f4: V and J gene usage in H7N9 infected patients by outcome.(a) shows frequency of IGHV gene usage in patients from non-survival group (red) and survival group (green). IGHV3-23 (9.73%), IGHV4-59 (8.76%) and IGHV3-30 (8.33%) were the three most frequent IGHV genes. (b) shows IGHJ gene usage frequency among patients. Expressing of IGHJ4 composed 44 ~ 64% of the repertoires. (c,d) show frequencies of TRBV and TRBJ genes usage. TRBV28 (14.28%), TRBV27 (12.69%) and TRBV20-1 (10.77%) accompanied by TRBJ1-1 (18.23%), TRBJ2-1 (16.31%) and TRBJ 2-3 (15.67%), were the three most frequent TRBV and TRBJ genes. Data are represented as mean ± SEM (See also Supplementary Figure S2).

Mentions: To further investigate H7N9-specific alterations of immune repertoire during infection, we questioned if there was distinct V or J gene or V-J pairing bias in survivors. For IGH repertoires, most of the IGHV and IGHJ genes and pairs were comparable across different patients (Fig. 4a, Supplementary Figure S4a). There were some IGHV and IGHJ genes of low frequency identified more in non-survivors than in survivors (Fig. 4b). These signatures are similar with previously reported antibody repertoires after vaccination17. In IGH repertoires, the V and J gene usage distribution pattern was similar in each unique CDR3 and all CDR3 clones (r = 9.59, p < 0.001) (Supplementary Figure S4b). This suggests that the biased usage of V and J genes was not only a result of the high expression level of some clones but also the expansion of particular cell clones in IGH repertoire. Frequency of TRBV and TRBJ genes are also not significant between survivors and non-survivors (Fig. 4c,d), indicating that V-J gene usage is biased in patients but not related to their prognosis.


Immune Repertoire Diversity Correlated with Mortality in Avian Influenza A (H7N9) Virus Infected Patients
V and J gene usage in H7N9 infected patients by outcome.(a) shows frequency of IGHV gene usage in patients from non-survival group (red) and survival group (green). IGHV3-23 (9.73%), IGHV4-59 (8.76%) and IGHV3-30 (8.33%) were the three most frequent IGHV genes. (b) shows IGHJ gene usage frequency among patients. Expressing of IGHJ4 composed 44 ~ 64% of the repertoires. (c,d) show frequencies of TRBV and TRBJ genes usage. TRBV28 (14.28%), TRBV27 (12.69%) and TRBV20-1 (10.77%) accompanied by TRBJ1-1 (18.23%), TRBJ2-1 (16.31%) and TRBJ 2-3 (15.67%), were the three most frequent TRBV and TRBJ genes. Data are represented as mean ± SEM (See also Supplementary Figure S2).
© Copyright Policy - open-access
Related In: Results  -  Collection

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f4: V and J gene usage in H7N9 infected patients by outcome.(a) shows frequency of IGHV gene usage in patients from non-survival group (red) and survival group (green). IGHV3-23 (9.73%), IGHV4-59 (8.76%) and IGHV3-30 (8.33%) were the three most frequent IGHV genes. (b) shows IGHJ gene usage frequency among patients. Expressing of IGHJ4 composed 44 ~ 64% of the repertoires. (c,d) show frequencies of TRBV and TRBJ genes usage. TRBV28 (14.28%), TRBV27 (12.69%) and TRBV20-1 (10.77%) accompanied by TRBJ1-1 (18.23%), TRBJ2-1 (16.31%) and TRBJ 2-3 (15.67%), were the three most frequent TRBV and TRBJ genes. Data are represented as mean ± SEM (See also Supplementary Figure S2).
Mentions: To further investigate H7N9-specific alterations of immune repertoire during infection, we questioned if there was distinct V or J gene or V-J pairing bias in survivors. For IGH repertoires, most of the IGHV and IGHJ genes and pairs were comparable across different patients (Fig. 4a, Supplementary Figure S4a). There were some IGHV and IGHJ genes of low frequency identified more in non-survivors than in survivors (Fig. 4b). These signatures are similar with previously reported antibody repertoires after vaccination17. In IGH repertoires, the V and J gene usage distribution pattern was similar in each unique CDR3 and all CDR3 clones (r = 9.59, p < 0.001) (Supplementary Figure S4b). This suggests that the biased usage of V and J genes was not only a result of the high expression level of some clones but also the expansion of particular cell clones in IGH repertoire. Frequency of TRBV and TRBJ genes are also not significant between survivors and non-survivors (Fig. 4c,d), indicating that V-J gene usage is biased in patients but not related to their prognosis.

View Article: PubMed Central - PubMed

ABSTRACT

Specific changes in immune repertoires at genetic level responding to the lethal H7N9 virus are still poorly understood. We performed deep sequencing on the T and B cells from patients recently infected with H7N9 to explore the correlation between clinical outcomes and immune repertoire alterations. T and B cell repertoires display highly dynamic yet distinct clonotype alterations. During infection, T cell beta chain repertoire continues to contract while the diversity of immunoglobulin heavy chain repertoire recovers. Patient recovery is correlated to the diversity of T cell and B cell repertoires in different ways &ndash; higher B cell diversity and lower T cell diversity are found in survivors. The sequences clonally related to known antibodies with binding affinity to H7 hemagglutinin could be identified from survivors. These findings suggest that utilizing deep sequencing may improve prognostication during influenza infection and could help in development of antibody discovery methodologies for the treatment of virus infection.

No MeSH data available.


Related in: MedlinePlus