Unique Immunological Profile In Patients With COVID-19

Varchetta, Stefania; Mele, Dalila; Oliviero, Barbara; Mantovani, Stefania; Ludovisi, Serena; Cerino, Antonella; Vecchia, Marco; Roda, Silvia; Sachs, Michele; Bruno, Raffaele; Mondelli, Mario U.

doi:10.21203/rs.3.rs-23953/v1

Cited by 43 publications

(68 citation statements)

References 11 publications

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“…Studies from other coronaviruses suggest that type 1 immunity is the primary mechanism controlling the infection (Janice Oh et al, 2012;Shin et al, 2019). In severe COVID-19, blood CD4 + T, CD8 + T and NK cells expressed markers of exhaustion (Varchetta et al, 2020), a finding not mirrored in moderately sick Syrian hamsters. In contrast, T and NK responses were effective and self-resolving.…”

Section: Discussionmentioning

confidence: 99%

Longitudinal omics in Syrian hamsters integrated with human data unravel complexity of moderate immune responses to SARS-CoV-2

Nouailles

Wyler

Pennitz

et al. 2020

Preprint

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In COVID-19, the immune response largely determines disease severity and is key to therapeutic strategies. Cellular mechanisms contributing to inflammatory lung injury and tissue repair in SARS-CoV-2 infection, particularly endothelial cell involvement, remain ill-defined. We performed detailed spatiotemporal analyses of cellular and molecular processes in SARS-CoV-2 infected Syrian hamsters. Comparison of hamster single-cell sequencing and proteomics with data sets from COVID-19 patients demonstrated inter-species concordance of cellular and molecular host-pathogen interactions. In depth vascular and pulmonary compartment analyses (i) supported the hypothesis that monocyte-derived macrophages dominate inflammation, (ii) revealed endothelial inflammation status and T-cell attraction, and (iii) showed that CD4+ and CD8+ cytotoxic T-cell responses precede viral elimination. Using the Syrian hamster model of self-limited moderate COVID-19, we defined the specific roles of endothelial and epithelial cells, among other myeloid and non-myeloid lung cell subtypes, for determining the disease course.

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Section: Discussionmentioning

confidence: 99%

Longitudinal omics in Syrian hamsters integrated with human data unravel complexity of moderate immune responses to SARS-CoV-2

Nouailles

Wyler

Pennitz

et al. 2020

Preprint

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“…They still, however, claim their findings suggest that T-cell activation and exhaustion play a role in Covid-19 and posit T-cell targeted treatment options may be of interest ( 16 ). Varchetta et al report an increase in TIM-3 and CD69 expression in CD8+ T cells and note the extent of CD8+ T cell lymphopenia was significantly greater in patients that succumbed to Covid-19 ( 17 ). They describe this as a hyperactivated/exhausted state and observed that during recovery TIM-3 and CD69 expression on T cells fell and CD8+ lymphocyte count rose.…”

Section: Discussionmentioning

confidence: 99%

Akt-Fas to Quell Aberrant T Cell Differentiation and Apoptosis in Covid-19

Leonardi

Proenca

2020

Front. Immunol.

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Aberrant T cell differentiation and lymphopenia are hallmarks of severe COVID-19 disease. Since T cells must race to cull infected cells, they are quick to differentiate and achieve cytotoxic function. With this responsiveness, comes hastened apoptosis, due to a coupled mechanism of death and differentiation in both CD4+ and CD8+ lymphocytes via CD95 (Fas) and serine-threonine kinase (Akt). T cell lymphopenia in severe cases may represent cell death or peripheral migration. These facets depict SARS-Cov-2 as a lympho-manipulative pathogen; it distorts T cell function, numbers, and death, and creates a dysfunctional immune response. Whether preservation of T cells, prevention of their aberrant differentiation, and expansion of their population may alter disease course is unknown. Its investigation requires experimental interrogation of the linked differentiation and death pathway by agents known to uncouple T cell proliferation and differentiation in both CD4+ and CD8+ T cells.

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“…54 A recent study also pointed out that NK cells from patients with coronavirus disease 2019 (COVID-19) downregulate NKG2D; although this study did not investigate MICA/B shedding, soluble MICA/B proteins are frequently linked to NKG2D downregulation, and thereby, COVID-19 patients may have higher levels of soluble MICA/B shed in their blood circulations. 55 Taken together, MICA/B shedding is a conserved mechanism of immune escape that is also relevant to viral infections, and thus, the inhibition of MICA/B shedding may confer a significant benefit for patients infected with viruses such as HIV, HBV, HCMV and coronavirus.…”

Section: Virally Infected Cells Express and Shed Mica/bmentioning

confidence: 99%

NKG2D and MICA/B shedding: a ‘tag game’ between NK cells and malignant cells

Xing

Andrade

2020

Clin & Trans Imm

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Natural killer (NK) cells are innate lymphocytes with cytotoxic functions and recognise target cells with the NK group 2D (NKG2D) receptor. Tumor cells are marked for NK‐cell‐mediated destruction upon expression of MICA and MICB (MICA/B), which are NKG2D ligands upregulated by many human cancers in response to cellular stress pathways associated with malignant transformation such as DNA damage and accumulation of misfolded proteins. However, MICA/B proteins are downregulated by tumor cells via intriguing molecular mechanisms, such as post‐translational modifications in which the external domains of MICA/B are proteolytically cleaved by surface proteases and shed into the extracellular space. MICA/B shedding by cancer cells causes effective escape from NKG2D recognition and allows the development of cancers. Patients frequently have increased concentrations of soluble MICA/B molecules shed in the blood plasmas and sera, thus indicating that MICA/B shedding is a therapeutic target in immune‐oncology. Here, we review the clinical significance of MICA/B shedding in cancer as well as novel immunotherapeutic approaches that aim to restore NKG2D‐mediated surveillance. We also briefly discuss potential roles of MICA/B shedding beyond oncology, such as in viral infections and immune tolerance. This review will help to inform the future developments of NKG2D‐based immunotherapies.

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Unique Immunological Profile In Patients With COVID-19

Cited by 43 publications

References 11 publications

Longitudinal omics in Syrian hamsters integrated with human data unravel complexity of moderate immune responses to SARS-CoV-2

Longitudinal omics in Syrian hamsters integrated with human data unravel complexity of moderate immune responses to SARS-CoV-2

Akt-Fas to Quell Aberrant T Cell Differentiation and Apoptosis in Covid-19

NKG2D and MICA/B shedding: a ‘tag game’ between NK cells and malignant cells

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