Attenuated Molecular Response to SARS-CoV-2 in MDMs Isolated from Immunosuppressed Transplanted Patients

TL;DR

This study shows that immunosuppressed kidney transplant patients have a weaker immune response in macrophages when exposed to SARS-CoV-2 variants compared to healthy individuals.

Contribution

The study reveals altered macrophage responses to SARS-CoV-2 variants in immunosuppressed patients through transcriptomic analysis.

Findings

SARS-CoV-2 variants were transcriptionally active but caused minimal transcriptomic changes in immunosuppressed macrophages.

Key innate immunity genes were down-regulated in immunosuppressed macrophages compared to healthy controls.

The study highlights the impact of immunosuppressive therapies on the immune response to SARS-CoV-2.

Abstract

Immunosuppressive therapies used in clinics to reduce the risk of rejection in transplanted patients unfortunately also decrease the response of the immune system to the pathogens. Previous data has shown that the most diffuse SARS-CoV-2 variants of concern between 2020 and 2021 showed a different modulation of the host immune response in healthy subjects, with the Delta B.1.617.2 variant leading to a failure in the activation of the adaptive immune response. In this study, the transcriptomic profiles of monocyte-derived macrophages (MDM), isolated from four immunosuppressed kidney transplant patients and exposed to SARS-CoV-2 VOCs, were analyzed and compared with previously published data gathered from immune-competent subjects. Human monocytes were isolated from peripheral blood mononuclear cells (PBMCs) of four kidney transplant patients admitted to the IRCCS Policlinico San Matteo of Pavia (Italy), differentiated into macrophages, and exposed to the active and the UV-inactivated particles of the different SARS-CoV-2 VOCs (D614G, Alpha B.1.1.7, Gamma P.1, Delta B.1.617.2 and Omicron BA.1). Bulk RNA-Seq was performed and significant transcripts were assessed based on Student’s t-test (p-value < 0.05) and Fold change > 2. RNA-Seq data analyses of immunosuppressed MDMs showed that SARS-CoV-2 VOCs, although transcriptionally active, did not induce strong alterations in the transcriptomic profiles of these cells, while a strong down-regulation of key genes involved in the innate immunity pathways was observed when comparing these data to the ones obtained from immunocompetent participants. Overall, this study suggests that patients under immunosuppressive therapies do have an altered macrophage response to SARS-CoV-2 viral infection.

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