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Immune profiling of SARS-CoV-2 infection during pregnancy reveals NK cell and γδ T cell perturbations - PubMed

  • ️Sun Jan 01 2023

. 2023 Apr 10;8(7):e167157.

doi: 10.1172/jci.insight.167157.

Brendon Y Chua  1   2 , Lukasz Kedzierski  1   3 , Kevin J Selva  1 , Timon Damelang  1 , Ebene R Haycroft  1 , Thi Ho Nguyen  1 , Hui-Fern Koay  1 , Suellen Nicholson  4 , Hayley A McQuilten  1 , Xiaoxiao Jia  1 , Lilith F Allen  1 , Luca Hensen  1 , Wuji Zhang  1 , Carolien E van de Sandt  1 , Jessica A Neil  1 , Katherine Pragastis  5 , Jillian Sy Lau  5   6 , Jaycee Jumarang  7 , E Kaitlynn Allen  8 , Fatima Amanant  9   10 , Florian Krammer  9 , Kathleen M Wragg  1 , Jennifer A Juno  1 , Adam K Wheatley  1   11 , Hyon-Xhi Tan  1 , Gabrielle Pell  12 , Susan Walker  12 , Jennifer Audsley  13 , Arnold Reynaldi  14 , Irani Thevarajan  13   15 , Justin T Denholm  13   15 , Kanta Subbarao  1   16 , Miles P Davenport  14 , P Mark Hogarth  17   18   19 , Dale I Godfrey  1 , Allen C Cheng  20   21 , Steven Yc Tong  15   22 , Katherine Bond  1   23 , Deborah A Williamson  1   23 , James H McMahon  5 , Paul G Thomas  8 , Pia S Pannaraj  7   24 , Fiona James  25 , Natasha E Holmes  25   26   27   28 , Olivia C Smibert  24   25   28   29   30 , Jason A Trubiano  28   29   30   31 , Claire L Gordon  1   25 , Amy W Chung  1 , Clare L Whitehead  32   33 , Stephen J Kent  1   11   34 , Martha Lappas  35 , Louise C Rowntree  1 , Katherine Kedzierska  1   2

Affiliations

Immune profiling of SARS-CoV-2 infection during pregnancy reveals NK cell and γδ T cell perturbations

Jennifer R Habel et al. JCI Insight. 2023.

Abstract

Pregnancy poses a greater risk for severe COVID-19; however, underlying immunological changes associated with SARS-CoV-2 during pregnancy are poorly understood. We defined immune responses to SARS-CoV-2 in unvaccinated pregnant and nonpregnant women with acute and convalescent COVID-19, quantifying 217 immunological parameters. Humoral responses to SARS-CoV-2 were similar in pregnant and nonpregnant women, although our systems serology approach revealed distinct antibody and FcγR profiles between pregnant and nonpregnant women. Cellular analyses demonstrated marked differences in NK cell and unconventional T cell activation dynamics in pregnant women. Healthy pregnant women displayed preactivated NK cells and γδ T cells when compared with healthy nonpregnant women, which remained unchanged during acute and convalescent COVID-19. Conversely, nonpregnant women had prototypical activation of NK and γδ T cells. Activation of CD4+ and CD8+ T cells and T follicular helper cells was similar in SARS-CoV-2-infected pregnant and nonpregnant women, while antibody-secreting B cells were increased in pregnant women during acute COVID-19. Elevated levels of IL-8, IL-10, and IL-18 were found in pregnant women in their healthy state, and these cytokine levels remained elevated during acute and convalescent COVID-19. Collectively, we demonstrate perturbations in NK cell and γδ T cell activation in unvaccinated pregnant women with COVID-19, which may impact disease progression and severity during pregnancy.

Keywords: Immunology; Infectious disease; Innate immunity; NK cells; T cells.

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Figures

Figure 1
Figure 1. COVID-19 pregnancy cohort and activation in antibody-secreting B cells and Tfh cells.

(A) Schematic depicting blood sample collection of pregnant and nonpregnant women with acute or convalescent COVID-19 or healthy individuals not exposed to SARS-CoV-2. (B) Proportions of pregnant (P) and nonpregnant (Non-P) women at different locations during acute COVID-19. (C and D) Median DPSO in (C) acute (P, n = 16; Non-P, n = 20) and (D) convalescent (P, n = 17; Non-P, n = 41) pregnant and nonpregnant donors. Donors with longitudinal sampling are represented for each time point collected. (E) Median age of pregnant and nonpregnant healthy (n = 21 and 42), acute (n = 17 and 20), or convalescent (n = 17 and 41) COVID-19 donors. Donors with longitudinal sampling are represented for each time point collected. (F) Antibody-secreting cells (ASCs) were defined as CD27+CD38+ from the CD19+CD3– B cell population. AF700, Alexa Fluor 700. (G) Frequencies of ASCs of B cells in healthy (P, n = 18; Non-P, n = 13), acute (P, n = 17; Non-P, n = 16), or convalescent (P, n = 17; Non-P, n = 18) pregnant or nonpregnant women. (H) Fold difference in the mean frequency of ASCs between healthy and acute COVID-19 for pregnant and nonpregnant donors. (I) LOESS regression kinetics of ASCs in pregnant and nonpregnant women with COVID-19. The 95% CI is shown in gray. (J) Tfh cells were defined as CXCR5+CD4+ T cells and activation determined by PD-1 and ICOS expression. (K–M) Frequencies of PD-1+ICOS+ of (K) total Tfh cells, (L) CXCR3+ Tfh1 cells, and (M) CXCR3– Tfh2/17 cells in healthy (P, n = 18; Non-P, n = 19), acute (P, n = 17; Non-P, n = 16), or convalescent (P, n = 17; Non-P, n = 19) pregnant or nonpregnant women. Median and range are shown in C–E. Means and SDs are shown in G and K–M. Significance determined by Mann-Whitney U test (C and D), Kruskal-Wallis test (E, G, and K–M), or Wald’s test (I). *P < 0.05; **P < 0.01.

Figure 2
Figure 2. Analysis of SARS-CoV-2–specific antibodies in pregnant and nonpregnant women.

(A) Log10-transformed RBD-specific or N-specific antibody titers in pregnant (P) and nonpregnant (Non-P) healthy (P, n = 10–16; Non-P, n = 21–31), acute COVID-19 (P, n = 13–15; Non-P, n = 19), and convalescent COVID-19 (P, n = 17; Non-P, n = 31–41) donors. Orange dashed lines indicate seroconversion cutoff calculated from the mean + 2 SD of the healthy pregnant and nonpregnant titers. (B) sVNT percentage inhibition in acute (P, n = 13; Non-P, n = 11) and convalescent (P, n = 15; Non-P, n = 28) pregnant or nonpregnant women. Seropositivity indicated by orange dashed line. (C) LOESS regression of RBD- and N-IgG kinetics for pregnant (red) and nonpregnant (blue) COVID-19 donors. The 95% CI is shown in gray in B and C. (D) Proportions of pregnant, nonpregnant, and cord blood donors who seroconverted with different combinations of RBD-specific or neutralizing antibodies. Seroconversion counted if a donor had a positive readout at any time point if longitudinal samples were collected. (E) Principal component plots showing pregnant (red, n = 13) and nonpregnant (blue, n = 11) donors with acute COVID-19 (left). Loading plot showing features separating pregnant and nonpregnant donors along the PC1 axis (right). (F) Principal component plots showing pregnant (red, n = 8) and nonpregnant (blue, n = 10) donors with convalescent COVID-19 (left). Loading plot showing features separating pregnant and nonpregnant donors along the PC1 axis (right). SARS2, SARS-CoV-2; SARS1, SARS-CoV-1; S, spike; S1, spike subunit 1 (head); S2, spike subunit 2 (stalk); N, nucleocapsid; RBD, receptor binding domain. Means and SDs are shown in A and B. Significance determined with a Kruskal-Wallis test (A and B [left]) or with Wald’s test (B [right] and C) *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.

Figure 3
Figure 3. Differential NK cell activation dynamics in pregnant women with COVID-19.

(A) CD3–CD56+ NK cell activation by HLA-DR expression. (B) HLA-DR+ NK cell frequencies in healthy (P, n = 18; Non-P, n = 13), acute (P, n = 17; Non-P, n = 17), and convalescent (P, n = 17; Non-P, n = 18) COVID-19 pregnant and nonpregnant women. (C) Fold difference in the mean frequency of HLA-DR+ NK cells between healthy and acute groups. (D) LOESS regression of HLA-DR+ NK cell frequencies and DPSO for pregnant and nonpregnant women with COVID-19. The 95% CI is shown in gray. (E) Proportions of CD56brightCD16–, CD56dimCD16+, and intermediate non–CD56bright/dim NK cells. (F) Frequencies of HLA-DR+ CD56brightCD16– (left) and CD56dimCD16+ (right) NK cells in healthy (P, n = 18; Non-P, n = 13), acute (P, n = 17; Non-P, n = 17), and convalescent (P, n = 17; Non-P, n = 18) pregnant and nonpregnant women. (G) Proportions of CD56brightCD16–, CD56dimCD16+, and intermediate non–CD56bright/dim in HLA-DR+ NK cells. (H and I) Proportions of granzyme and perforin expression in (H) CD56dimCD16+ or (I) CD56brightCD16– NK cells. Means and SDs are shown in B and E–G. Significance determined by Kruskal-Wallis test (B and E–G), Wald’s test (D), or permutations test (H and I). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.

Figure 4
Figure 4. Differential γδ T cell activation dynamics in pregnant women with COVID-19.

(A) CD3+γδTCR+ γδ T cell activation by HLA-DR and CD38 coexpression. (B) HLA-DR+CD38+ γδ T cell frequencies in healthy (P, n = 18; Non-P n = 13), acute (P, n = 17; Non-P, n = 16), and convalescent (P, n = 17; Non-P, n = 18) pregnant and nonpregnant women. (C) Fold difference in the mean frequency of HLA-DR+CD38+ γδ T cells between healthy and acute groups. (D) LOESS regression of HLA-DR+CD38+ γδ T cell frequencies and DPSO for pregnant and nonpregnant women with COVID-19. The 95% CI is shown in gray. (E) MAIT cells defined as MR1-5-OP-RU-tetramer+TCR-Vα7.2+. (F) Frequencies of MAIT cells in healthy (P, n = 11; Non-P, n = 11), acute (P, n = 8; Non-P, n = 13), and convalescent (P, n = 8; Non-P, n = 14) pregnant and nonpregnant women. (G) CD8+ T cell activation by HLA-DR and CD38 coexpression. (H) Frequencies of HLA-DR+CD38+ CD8+ T cells in healthy (P, n = 18; Non-P, n = 13), acute (P, n = 17; Non-P, n = 17), and convalescent (P, n = 17; Non-P, n = 18) pregnant and nonpregnant women. Means and SDs are shown in B, F, and H. Significance determined by Kruskal-Wallis test (B, F, and H) or Wald’s test (D). *P < 0.05; **P < 0.01.

Figure 5
Figure 5. Cytokine and chemokine concentrations and proportions within blood plasma.

(A) Concentrations of 13 cytokines/chemokines and IL-18/IL-12p70 ratio in pregnant and nonpregnant women who were healthy (P, n = 15; Non-P, n = 11) or had acute (P, n = 13; Non-P, n = 11) or convalescent (P, n = 14; Non-P, n = 26) COVID-19. Means and SDs are shown. Significance determined by Kruskal-Wallis test. (B) Heatmap depicting Spearman’s correlation coefficients for cytokine/chemokine concentrations against cellular immune parameters in acute COVID-19 pregnant (top) and nonpregnant (bottom) women. Significant correlations are depicted with an asterisk; P values are unadjusted. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.

Figure 6
Figure 6. Summary data of key differences in immune parameters between pregnant and nonpregnant women.

Heatmap depicting the mean of 36 selected immune parameters for healthy, acute, and convalescent pregnant and nonpregnant women. Z-score values are shown.

Figure 7
Figure 7. Factors driving differences between pregnant and nonpregnant women diminish during acute COVID-19.

(A–E) Volcano plots of 47 selected cellular and humoral immune parameters between (A) healthy or (B) acute or (C) convalescent pregnant and nonpregnant women, and between healthy and acute (D) pregnant or (E) nonpregnant women.

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