Analysis of Co-inhibitory Receptor Expression in COVID-19 Infection Compared to Acute Plasmodium falciparum Malaria: LAG-3 and TIM-3 Correlate With T Cell Activation and Course of Disease

TY - JOUR

T1 - Analysis of Co-inhibitory Receptor Expression in COVID-19 Infection Compared to Acute Plasmodium falciparum Malaria: LAG-3 and TIM-3 Correlate With T Cell Activation and Course of Disease

AU - Herrmann, Marissa

AU - Schulte, Sophia

AU - Wildner, Nils H.

AU - Wittner, Melanie

AU - Brehm, Thomas Theo

AU - Ramharter, Michael

AU - Woost, Robin

AU - Lohse, Ansgar W.

AU - Jacobs, Thomas

AU - Schulze zur Wiesch, Julian

N1 - Copyright © 2020 Herrmann, Schulte, Wildner, Wittner, Brehm, Ramharter, Woost, Lohse, Jacobs and Schulze zur Wiesch.

PY - 2020/8/26

Y1 - 2020/8/26

N2 - Coronavirus disease 2019 (COVID-19) which is caused by the novel SARS-CoV-2 virus is a severe flu-like illness which is associated with hyperinflammation and immune dysfunction. The virus induces a strong T and B cell response but little is known about the immune pathology of this viral infection. Acute Plasmodium falciparum malaria also causes acute clinical illness and is characterized by hyperinflammation due to the strong production of pro-inflammatory cytokines and a massive activation of T cells. In malaria, T cells express a variety of co-inhibitory receptors which might be a consequence of their activation but also might limit their overwhelming function. Thus, T cells are implicated in protection as well as in pathology. The outcome of malaria is thought to be a consequence of the balance between co-activation and co-inhibition of T cells. Following the hypothesis that T cells in COVID-19 might have a similar, dual function, we comprehensively characterized the differentiation (CCR7, CD45RO) and activation status (HLA-DR, CD38, CD69, CD226), the co-expression of co-inhibitory molecules (PD1, TIM-3, LAG-3, BTLA, TIGIT), as well as the expression pattern of the transcription factors T-bet and eomes of CD8+ and CD4+ T cells of PBMC of n = 20 SARS-CoV-2 patients compared to n = 10 P. falciparum infected patients and n = 13 healthy controls. Overall, acute COVID-19 and malaria infection resulted in a comparably elevated activation and altered differentiation status of the CD8+ and CD4+ T cell populations. T effector cells of COVID-19 and malaria patients showed higher frequencies of the inhibitory receptors T-cell immunoglobulin mucin-3 (TIM-3) and Lymphocyte-activation gene-3 (LAG-3) which was linked to increased activation levels and an upregulation of the transcription factors T-bet and eomes. COVID-19 patients with a more severe disease course showed higher levels of LAG-3 and TIM-3 than patients with a mild disease course. During recovery, a rapid normalization of these inhibitory receptors could be observed. In summary, comparing the expression of different co-inhibitory molecules in CD8+ and CD4+ T cells in COVID-19 vs. malaria, there is a transient increase of the expression of certain inhibitory receptors like LAG-3 and TIM-3 in COVID-19 in the overall context of acute immune activation.

AB - Coronavirus disease 2019 (COVID-19) which is caused by the novel SARS-CoV-2 virus is a severe flu-like illness which is associated with hyperinflammation and immune dysfunction. The virus induces a strong T and B cell response but little is known about the immune pathology of this viral infection. Acute Plasmodium falciparum malaria also causes acute clinical illness and is characterized by hyperinflammation due to the strong production of pro-inflammatory cytokines and a massive activation of T cells. In malaria, T cells express a variety of co-inhibitory receptors which might be a consequence of their activation but also might limit their overwhelming function. Thus, T cells are implicated in protection as well as in pathology. The outcome of malaria is thought to be a consequence of the balance between co-activation and co-inhibition of T cells. Following the hypothesis that T cells in COVID-19 might have a similar, dual function, we comprehensively characterized the differentiation (CCR7, CD45RO) and activation status (HLA-DR, CD38, CD69, CD226), the co-expression of co-inhibitory molecules (PD1, TIM-3, LAG-3, BTLA, TIGIT), as well as the expression pattern of the transcription factors T-bet and eomes of CD8+ and CD4+ T cells of PBMC of n = 20 SARS-CoV-2 patients compared to n = 10 P. falciparum infected patients and n = 13 healthy controls. Overall, acute COVID-19 and malaria infection resulted in a comparably elevated activation and altered differentiation status of the CD8+ and CD4+ T cell populations. T effector cells of COVID-19 and malaria patients showed higher frequencies of the inhibitory receptors T-cell immunoglobulin mucin-3 (TIM-3) and Lymphocyte-activation gene-3 (LAG-3) which was linked to increased activation levels and an upregulation of the transcription factors T-bet and eomes. COVID-19 patients with a more severe disease course showed higher levels of LAG-3 and TIM-3 than patients with a mild disease course. During recovery, a rapid normalization of these inhibitory receptors could be observed. In summary, comparing the expression of different co-inhibitory molecules in CD8+ and CD4+ T cells in COVID-19 vs. malaria, there is a transient increase of the expression of certain inhibitory receptors like LAG-3 and TIM-3 in COVID-19 in the overall context of acute immune activation.

KW - COVID-19

KW - LAG-3

KW - malaria

KW - PD-1

KW - Plasmodium falciparum

KW - SARS-CoV-2

KW - T cells

KW - TIM-3

KW - Betacoronavirus/genetics

KW - Pandemics

KW - Antigens, CD/metabolism

KW - Humans

KW - Middle Aged

KW - Male

KW - CD8-Positive T-Lymphocytes/immunology

KW - Pneumonia, Viral/immunology

KW - Adult

KW - Female

KW - Coronavirus Infections/immunology

KW - Severity of Illness Index

KW - Acute Disease

KW - Malaria, Falciparum/immunology

KW - Cells, Cultured

KW - CD4-Positive T-Lymphocytes/immunology

KW - Lymphocyte Activation/immunology

KW - Aged

KW - Plasmodium falciparum/isolation & purification

KW - Programmed Cell Death 1 Receptor/metabolism

KW - Hepatitis A Virus Cellular Receptor 2/metabolism

KW - Receptors, Antigen, T-Cell/metabolism

KW - Cohort Studies

UR - http://www.scopus.com/inward/record.url?scp=85090822475&partnerID=8YFLogxK

U2 - 10.3389/fimmu.2020.01870

DO - 10.3389/fimmu.2020.01870

M3 - SCORING: Journal article

C2 - 32983106

AN - SCOPUS:85090822475

VL - 11

SP - 1870

JO - FRONT IMMUNOL

JF - FRONT IMMUNOL

SN - 1664-3224

M1 - 1870

ER -