Sex-Related Differences in Innate and Adaptive Immune Responses to SARS-CoV-2 - PubMed (original) (raw)
Sex-Related Differences in Innate and Adaptive Immune Responses to SARS-CoV-2
Sudhanshu Agrawal et al. Front Immunol. 2021.
Abstract
Coronavirus disease 2019 (COVID-19) exhibits a sex bias with males showing signs of more severe disease and hospitalizations compared with females. The mechanisms are not clear but differential immune responses, particularly the initial innate immune response, between sexes may be playing a role. The early innate immune responses to SARS-CoV-2 have not been studied because of the gap in timing between the patient becoming infected, showing symptoms, and getting the treatment. The primary objective of the present study was to compare the response of dendritic cells (DCs) and monocytes from males and females to SARS-CoV-2, 24 h after infection. To investigate this, peripheral blood mononuclear cells (PBMCs) from healthy young individuals were stimulated in vitro with the virus. Our results indicate that PBMCs from females upregulated the expression of HLA-DR and CD86 on pDCs and mDCs after stimulation with the virus, while the activation of these cells was not significant in males. Monocytes from females also displayed increased activation than males. In addition, females secreted significantly higher levels of IFN-α and IL-29 compared with males at 24 h. However, the situation was reversed at 1 week post stimulation and males displayed high levels of IFN-α production compared with females. Further investigations revealed that the secretion of CXCL-10, a chemokine associated with lung complications, was higher in males than females at 24 h. The PBMCs from females also displayed increased induction of CTLs. Altogether, our results suggest that decreased activation of pDCs, mDCs, and monocytes and the delayed and prolonged IFN-α secretion along with increased CXCL-10 secretion may be responsible for the increased morbidity and mortality of males to COVID-19.
Keywords: CXCL-10; SARS-CoV-2; dendritic cells; interferon-α; monocytes; sex differences.
Copyright © 2021 Agrawal, Salazar, Tran and Agrawal.
Conflict of interest statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Figures
Figure 1
Irradiated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a better activator of monocytes and DCs than heat inactivated SARS-CoV-2. PBMCs were stimulated o/n with irradiated (IRR) or heat-inactivated (HI) SARS-CoV-2 or Vero cell lysate (Vero). Flow cytometry was used to determine the upregulation of surface markers. Plasmacytoid dendritic cells (pDCs), myeloid dendritic cells (mDCs), and monocytes (mono control) are the unstimulated population gated on pDCs, mDCs, and monocytes. IRR, HI, and Vero are stimulated conditions from the same donors. (A) Gating strategy for pDCs, mDCs, and mono (monocytes); MFI of expression of activation markers HLA-DR and CD86 on (B) gated pDCs (lineage− HLADR+CD123+); (C) gated mDCs (lineage− HLADR+CD11c+); (D) gated CD14+ monocytes using flow cytometry. (E) Graphs depict the quantitation of cytokines/chemokines in the supernatant by multiplex. Mean ± SE. N = 12 subjects. _p_-value was calculated using one-way ANOVA followed by Tukey’s test.
Figure 2
Irradiated SARS-CoV-2 is a better inducer of cytotoxic T lymphocytes than heat-inactivated SARS-CoV-2. PBMCs stimulated with irradiated SARS-CoV-2 (IRR) or heat-inactivated (HI) or Vero cell lysate (Vero) were cultured for 7 days. Cells collected were stained for CD8, perforin, and granzyme B and acquired on a flow cytometer. (A) Gating strategy for the identification of these cells. (B) Dot plot depicts the % of cytotoxic CD8 T cells. (C) Quantitation of cytokines/chemokines in the supernatant by multiplex. Mean ± SE. N = 12 subjects. _p_-value was calculated using one-way ANOVA followed by Tukey’s test.
Figure 3
DCs and monocytes from females display enhanced activation in response to SARS-CoV-2 than males. PBMCs were stimulated o/n with irradiated SARS-CoV-2 virus for 24 h. The upregulation of HLA-DR and CD86 was determined using flow cytometry. Lines connect the unstimulated and stimulated conditions from the same subject. (A) Gated pDCs (lineage− HLADR+CD123+); (B) gated mDCs (lineage− HLADR+CD11c+); and (C) gated CD14+ monocytes. Mean ± SE. Females = 15; males = 15. _p_-value between the unstimulated control and SARS-CoV-2-stimulated condition in males and females was calculated using paired _t_-test (parametric).
Figure 4
Differential cytokine/chemokine secretion in males and females in response to SARS-CoV-2. PBMCs were stimulated o/n with irradiated SARS-CoV-2 virus for 24 h. Graphs depict the quantitation of cytokines/chemokines in the supernatant by multiplex. Lines connect the unstimulated and stimulated conditions from the same subject. Mean ± SE. Females = 15; males = 15. _p_-value between the control and SARS-CoV-2-stimulated condition in males and females was calculated using Wilcoxon matched pairs signed rank test. Significance between males and females was calculated using unpaired _t_-test (Mann–Whitney test).
Figure 5
Enhanced induction of cytotoxic CD8 T cells in females than males in response to SARS-CoV-2. PBMCs stimulated with irradiated SARS-CoV-2 were cultured for 7 days. Cells collected were stained for CD8, perforin, and granzyme B. (A) Dot plot depicts the % of these cells obtained using flow cytometry. (B) Quantitation of cytokines/chemokines in the supernatant by multiplex. Lines connect the unstimulated and stimulated condition from the same subject. Mean ± SE. Females = 15; males = 15. _p_-value between the control and SARS-CoV-2-stimulated condition in males and females was calculated using Wilcoxon matched pairs signed rank test. Significance between males and females was calculated using unpaired _t_-test.
References
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