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

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 – 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

D50 values of IGH and TRB repertoires in H7N9 infected patients.(a) shows the logged relative ratios of IGH (green) and TRB (red) D50 values of samples collected from each patient. The D50 values >15 days were divided by D50 value <15 days and the logged result were drown as vertical axis values. Every pair of green and red bars represented an individual. (b) is the boxplot of the D50 value of IGH and TRB repertoires in 15–42 days after onset by group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5037391&req=5

f2: D50 values of IGH and TRB repertoires in H7N9 infected patients.(a) shows the logged relative ratios of IGH (green) and TRB (red) D50 values of samples collected from each patient. The D50 values >15 days were divided by D50 value <15 days and the logged result were drown as vertical axis values. Every pair of green and red bars represented an individual. (b) is the boxplot of the D50 value of IGH and TRB repertoires in 15–42 days after onset by group.

Mentions: Variation in immune response efficiency results in different infection severity and outcome. A proper diversity of the immune repertoire is crucial in order to mount an efficient adaptive immune response15. The overall D50 value of TRB and IGH in patients ranges from 0 ~ 5, indicating the repertoires are highly skewed (Fig. 2). For IGH repertoire, interestingly, the D50 values after 15 days were higher than the previous sample in all but one individual (Fig. 2a), suggesting an increasing tendency in IGH diversity. This is also the time point of neutralizing antibody (Nab) titers increasing in serologic measurements16 (Supplementary Figure S2). In contrast, the diversity of TRB repertoires did not increase over time. To simplify data analysis, we used the last sample of each patient, and the disease phase of these samples were comparable between groups (15–40 days in non-survival group and 15–46 days in survival group after onset). Importantly, D50 values of IGH repertoires were significantly lower in non-survivors than in survivors (P = 0.02, Student’s t test) (Fig. 2b), as were the Nab titers (Mann-Whitney U test, P = 0.04). On the contrary, survivors had lower D50 values of TRB repertoire than non-survivors (P = 0.02, Student’s t test) (Fig. 2b). As for IGL and IGK, the D50 values were comparable between the two groups (data not shown). For a more intuitive comparison of V-J rearrangement diversity of these repertoires, we performed 3D mapping of V-J pairing of two patients with different outcomes as examples (Fig. 3, Supplementary Figure S3). It is evident that the IGH repertoire of the non-survivor was significantly more convergent to several particular IGHV-IGHJ gene pairs than the survivor. On the contrary, the diversity of TRBV-TRBJ gene pairs in non-survivors was higher than that in the survivors. V-J pairs in IGK repertoire also skewed in the non-survivor (Supplementary Figure S3). These results, along with the finding that the IGH repertoire changed constantly over time in a single individual, indicate that as compared to other repertoires, the IGH repertoire diversity might be more associated with the patients’ recovery and the lower TCR diversity is related to the better outcome.


Immune Repertoire Diversity Correlated with Mortality in Avian Influenza A (H7N9) Virus Infected Patients
D50 values of IGH and TRB repertoires in H7N9 infected patients.(a) shows the logged relative ratios of IGH (green) and TRB (red) D50 values of samples collected from each patient. The D50 values >15 days were divided by D50 value <15 days and the logged result were drown as vertical axis values. Every pair of green and red bars represented an individual. (b) is the boxplot of the D50 value of IGH and TRB repertoires in 15–42 days after onset by group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5037391&req=5

f2: D50 values of IGH and TRB repertoires in H7N9 infected patients.(a) shows the logged relative ratios of IGH (green) and TRB (red) D50 values of samples collected from each patient. The D50 values >15 days were divided by D50 value <15 days and the logged result were drown as vertical axis values. Every pair of green and red bars represented an individual. (b) is the boxplot of the D50 value of IGH and TRB repertoires in 15–42 days after onset by group.
Mentions: Variation in immune response efficiency results in different infection severity and outcome. A proper diversity of the immune repertoire is crucial in order to mount an efficient adaptive immune response15. The overall D50 value of TRB and IGH in patients ranges from 0 ~ 5, indicating the repertoires are highly skewed (Fig. 2). For IGH repertoire, interestingly, the D50 values after 15 days were higher than the previous sample in all but one individual (Fig. 2a), suggesting an increasing tendency in IGH diversity. This is also the time point of neutralizing antibody (Nab) titers increasing in serologic measurements16 (Supplementary Figure S2). In contrast, the diversity of TRB repertoires did not increase over time. To simplify data analysis, we used the last sample of each patient, and the disease phase of these samples were comparable between groups (15–40 days in non-survival group and 15–46 days in survival group after onset). Importantly, D50 values of IGH repertoires were significantly lower in non-survivors than in survivors (P = 0.02, Student’s t test) (Fig. 2b), as were the Nab titers (Mann-Whitney U test, P = 0.04). On the contrary, survivors had lower D50 values of TRB repertoire than non-survivors (P = 0.02, Student’s t test) (Fig. 2b). As for IGL and IGK, the D50 values were comparable between the two groups (data not shown). For a more intuitive comparison of V-J rearrangement diversity of these repertoires, we performed 3D mapping of V-J pairing of two patients with different outcomes as examples (Fig. 3, Supplementary Figure S3). It is evident that the IGH repertoire of the non-survivor was significantly more convergent to several particular IGHV-IGHJ gene pairs than the survivor. On the contrary, the diversity of TRBV-TRBJ gene pairs in non-survivors was higher than that in the survivors. V-J pairs in IGK repertoire also skewed in the non-survivor (Supplementary Figure S3). These results, along with the finding that the IGH repertoire changed constantly over time in a single individual, indicate that as compared to other repertoires, the IGH repertoire diversity might be more associated with the patients’ recovery and the lower TCR diversity is related to the better outcome.

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