Mary Wilson
Well-known member
The American Journal of Pathology
Published: April 04, 2023
DOI: https://doi.org/10.1016/j.ajpath.2023.03.008
Yu Jin Lee [SUP]∗ [/SUP]Sang Hyeok Seok [SUP]∗ [/SUP]Na Yun Lee [SUP]∗ [/SUP]Ho Young Lee Jun Won Park [SUP]# [/SUP]Je Kyung Seong [SUP]#[/SUP]
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Abstract
The disease severity of COVID-19 varies considerably from asymptomatic to serious, with fatal complications associated with dysregulation of innate and adaptive immunity. Lymphoid depletion in lymphoid tissues and lymphocytopenia have both been associated with poor disease outcomes in COVID-19 patients, but the mechanisms involved remain elusive. In this study, hACE2 transgenic mouse models susceptible to SARS-CoV-2 infection were used to investigate the characteristics and determinants of lethality associated with the lymphoid depletion observed in SARS-CoV-2 infection. The lethality of Wuhan SARS-CoV-2 infection in K18-hACE2 mice was characterized by severe lymphoid depletion and apoptosis in lymphoid tissues related to fatal neuroinvasion. The lymphoid depletion was associated with a decreased number of antigen-presenting cells (APCs) and their suppressed functionality below basal levels. Lymphoid depletion with reduced APC function was a specific feature observed in SARS-CoV-2 infection but not in Influenza A infection and had the greatest prognostic value for disease severity in murine COVID-19. Comparison of transgenic mouse models resistant and susceptible to SARS-CoV-2 infection revealed that suppressed APC function could be determined by the hACE2expression pattern and interferon-related signaling. Thus, we demonstrated that lymphoid depletion associated with suppressed APC function characterizes the lethality of COVID-19 mouse models. Our data also suggest a potential therapeutic approach to prevent the severe progression of COVID-19 by enhancing APC functionality.
https://ajp.amjpathol.org/action/showPdf?pii=S0002-9440(23)00119-0
Published: April 04, 2023
DOI: https://doi.org/10.1016/j.ajpath.2023.03.008
Yu Jin Lee [SUP]∗ [/SUP]Sang Hyeok Seok [SUP]∗ [/SUP]Na Yun Lee [SUP]∗ [/SUP]Ho Young Lee Jun Won Park [SUP]# [/SUP]Je Kyung Seong [SUP]#[/SUP]
Show all authors
Abstract
The disease severity of COVID-19 varies considerably from asymptomatic to serious, with fatal complications associated with dysregulation of innate and adaptive immunity. Lymphoid depletion in lymphoid tissues and lymphocytopenia have both been associated with poor disease outcomes in COVID-19 patients, but the mechanisms involved remain elusive. In this study, hACE2 transgenic mouse models susceptible to SARS-CoV-2 infection were used to investigate the characteristics and determinants of lethality associated with the lymphoid depletion observed in SARS-CoV-2 infection. The lethality of Wuhan SARS-CoV-2 infection in K18-hACE2 mice was characterized by severe lymphoid depletion and apoptosis in lymphoid tissues related to fatal neuroinvasion. The lymphoid depletion was associated with a decreased number of antigen-presenting cells (APCs) and their suppressed functionality below basal levels. Lymphoid depletion with reduced APC function was a specific feature observed in SARS-CoV-2 infection but not in Influenza A infection and had the greatest prognostic value for disease severity in murine COVID-19. Comparison of transgenic mouse models resistant and susceptible to SARS-CoV-2 infection revealed that suppressed APC function could be determined by the hACE2expression pattern and interferon-related signaling. Thus, we demonstrated that lymphoid depletion associated with suppressed APC function characterizes the lethality of COVID-19 mouse models. Our data also suggest a potential therapeutic approach to prevent the severe progression of COVID-19 by enhancing APC functionality.
https://ajp.amjpathol.org/action/showPdf?pii=S0002-9440(23)00119-0