Local CCL18 and CCL21 expand lung fibrovascular niches and recruit lymphocytes, leading to tertiary lymphoid structure formation in prolonged COVID-19

Mothes, Ronja; Pascual-Reguant, Anna; Koehler, Ralf; Liebeskind, Juliane; Liebheit, Alina; Bauherr, Sandy; Dittmayer, Carsten; Laue, Michael; Manitius, Regina von; Elezkurtaj, Sefer; Heinrich, Frederik; Heinz, Gitta Anne; Guerra, Gabriela; Obermayer, Benedikt; Meinhardt, Jenny; Ihlow, Jana; Radke, Josefine; Heppner, Frank L.; Enghard, Philipp; Stockmann, Helena; Aschman, Tom; Schneider, Julia; Corman, Victor M.; Sander, Leif Erik; Mashreghi, Mir‐Farzin; Conrad, Thomas; Hocke, Andreas C.; Niesner, Raluca; Radbruch, Helena; Hauser, Anja E.

doi:10.1101/2022.03.24.22272768

Cited by 3 publications

(5 citation statements)

References 71 publications

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“…We divided the COVID-19 cohort into acute and late cases according to disease duration (14 days post infection as cut-off; Supplementary Table 1 ) due to marked differences in lung pathology seen in these patients 20 . Therefore, we first performed post hoc principal component analysis (PCA) of the differentially expressed proteins in the different comparisons (acute vs. control and late vs. control) of the brainstem.…”

Section: Resultsmentioning

confidence: 99%

“…We found CD4+ T cells but we also detected double positive (DP) CD4+ and CD8+ T cells in the perivascular space ( Figure 4 d ). DP T cells are a subpopulation known to accumulate in lung tissue of COVID-19 patients 20 and various other disorders 86 producing pro-inflammatory cytokines and displaying characteristics of memory CD8+ T lymphocytes 86 . Similar to blood derived T cells in severe COVID-19 85 , we identified T cells expressing granzyme B and PD-1, suggesting a still ongoing local (unconventional) activation within the perivascular space even in the late disease phase ( Figure 4 e ).…”

Section: Resultsmentioning

confidence: 99%

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The central nervous system’s proteogenomic and spatial imprint upon systemic viral infections with SARS-CoV-2

Radke

Meinhardt

Aschman

et al. 2023

Preprint

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In COVID-19 neurological alterations are noticed during the systemic viral infection. Various pathophysiological mechanisms on the central nervous system (CNS) have been suggested in the past two years, including the viral neurotropism hypothesis. Nevertheless, neurological complications can also occur independent of neurotropism and at different stages of the disease and may be persistent. Previous autopsy studies of the CNS from patients with severe COVID-19 show infiltration of macrophages and T lymphocytes, especially in the perivascular regions as well as pronounced microglial activation, but without signs of viral encephalitis. However, there is an ongoing debate about long-term changes and cytotoxic effects in the CNS due to the systemic inflammation. Here, we show the brain-specific host response during and after COVID-19. We profile single-nucleus transcriptomes and proteomes of brainstem tissue from deceased COVID-19 patients who underwent rapid autopsy. We detect a disease phase-dependent inflammatory type-I interferon response in acute COVID-19 cases. Integrating single-nucleus RNA sequencing and spatial transcriptomics, we could localize two patterns of reaction to severe systemic inflammation. One neuronal with direct focus on cranial nerve nuclei and one diffusely affecting the whole brainstem, the latter reflecting a bystander effect that spreads throughout the vascular unit and alters the transcriptional state of oligodendrocytes, microglia and astrocytes. Our results indicate that even without persistence of SARS-CoV-2 in the CNS, the tissue activates highly protective mechanisms, which also cause functional disturbances that may explain the neurological symptoms of COVID-19, triggered by strong systemic type-I IFN signatures in the periphery.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

The central nervous system’s proteogenomic and spatial imprint upon systemic viral infections with SARS-CoV-2

Radke

Meinhardt

Aschman

et al. 2023

Preprint

Self Cite

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“…The lack of expression of CCL19 and CCL21 in PBMCs points to affected organs or associated lymphoid tissue as likely sources of increased circulating levels in our COVID-19 cohorts. Supporting a link between pulmonary CCL21 production and impaired lung function, a recent preprint report demonstrated the formation of perivascular foci with strong expression of CCL21 in lung tissue from patients with severe COVID-19 [ 38 ]. These areas showed high expression of fibrosis-associated markers, and accumulation of immune cell aggregates with features consistent with tertiary lymphoid structures.…”

Section: Discussionmentioning

confidence: 99%

“…These areas showed high expression of fibrosis-associated markers, and accumulation of immune cell aggregates with features consistent with tertiary lymphoid structures. CCL19 expression was also elevated in these areas [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

High Circulating Levels of the Homeostatic Chemokines CCL19 and CCL21 Predict Mortality and Disease Severity in COVID-19

Tveita

Murphy

Holter

et al. 2022

The Journal of Infectious Diseases

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Background Immune dysregulation is a major factor in the development of severe Covid-19. The homeostatic chemokines CCL19 and CCL21 have been implicated as mediators of tissue inflammation, but data on their regulation in SARS-CoV-2 infection is limited. We thus investigated the levels of these chemokines in Covid-19 patients. Methods Serial blood samples were obtained from patients hospitalized with Covid-19 (n = 414). Circulating CCL19 and CCL21 levels during hospitalization and three-month follow-up were analyzed. In vitro assays and analysis of RNAseq data from public repositories were performed to further explore possible regulatory mechanisms. Results A consistent increase in circulating levels of CCL19 and CCL21 was observed, with high levels correlating with disease severity measures, including respiratory failure, need for intensive care, and 60-day all-cause mortality. High levels of CCL21 at admission were associated with persisting impairment of pulmonary function at the three-month follow-up. Conclusions Our findings highlight CCL19 and CCL21 as markers of immune dysregulation in Covid-19. This may reflect aberrant regulation triggered by tissue inflammation, as observed in other chronic inflammatory and autoimmune conditions. Determination of the source and regulation of these chemokines and their effects on lung tissue is warranted to further clarify their role in Covid-19.

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“…In addition, the serum levels of CCL21 were found to be high in patients with COVID-19 who did not survive 12 days after SARS-CoV-2 infection [ 76 ]. Furthermore, human lung tissue sections from samples of patients with acute COVID-19 showed that CCL21 expression was weakly detectable but was upregulated in later phases of the disease, and the local expression of CCL21 recruited CCR7 + T cells and T follicular helper-like cells and can contribute to the formation of tertiary lymphoid structures in the lungs [ 77 ]. The precise role of CCL21 in the activation and impairment of proper T cells during SARS-CoV-2 infection remains unclear; thus, a subsequent study may define the precise role of this chemokine post-SASR-CoV-2 infection.…”

Section: Role Of Pulmonary Homeostatic Chemokines Cxcl13 Ccl19 and Cc...mentioning

confidence: 99%

Considerations for Novel COVID-19 Mucosal Vaccine Development

Alturaiki

2022

Vaccines

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Mucosal surfaces are the first contact sites of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Most SARS-CoV-2 vaccines induce specific IgG responses but provide limited mucosal immunity. Cytokine B-cell activation factor (BAFF) and A proliferation-inducing ligand (APRIL) in the tumor necrosis factor (TNF) superfamily play key immunological functions during B cell development and antibody production. Furthermore, homeostatic chemokines, such as C-X-C motif chemokine ligand 13 (CXCL13), chemokine (C–C motif) ligand 19 (CCL19), and CCL21, can induce B- and T-cell responses to infection and promote the formation of inducible bronchus-associated lymphoid tissues (iBALT), where specific local immune responses and memory cells are generated. We reviewed the role of BAFF, APRIL, CXCL13, CCL19, and CCL21 in the activation of local B-cell responses and antibody production, and the formation of iBALT in the lung following viral respiratory infections. We speculate that mucosal vaccines may offer more efficient protection against SARS-CoV-2 infection than systematic vaccines and hypothesize that a novel SARS-CoV-2 mRNA mucosal vaccine using BAFF/APRIL or CXCL13 as immunostimulants combined with the spike protein-encoding mRNA may enhance the efficiency of the local immune response and prevent the early stages of SARS-CoV-2 replication and the rapid viral clearance from the airways.

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Local CCL18 and CCL21 expand lung fibrovascular niches and recruit lymphocytes, leading to tertiary lymphoid structure formation in prolonged COVID-19

Cited by 3 publications

References 71 publications

The central nervous system’s proteogenomic and spatial imprint upon systemic viral infections with SARS-CoV-2

The central nervous system’s proteogenomic and spatial imprint upon systemic viral infections with SARS-CoV-2

High Circulating Levels of the Homeostatic Chemokines CCL19 and CCL21 Predict Mortality and Disease Severity in COVID-19

Considerations for Novel COVID-19 Mucosal Vaccine Development

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