Dynamic single-cell RNA sequencing reveals BCG vaccination curtails SARS-CoV-2 induced disease severity and lung inflammation

Abstract

COVID-19 continues to exact a toll on human health despite the availability of several vaccines. Bacillus Calmette Guerin (BCG) has been shown to confer heterologous immune protection against viral infections including COVID-19 and has been proposed as vaccine against SARS-CoV-2 (SCV2). Here we tested intravenous BCG vaccination against COVID-19 using the golden Syrian hamster model together with immune profiling and single cell RNA sequencing (scRNAseq). We observed that BCG reduced both lung SCV2 viral load and bronchopneumonia. This was accompanied by an increase in lung alveolar macrophages, a reversal of SCV2-mediated T cell lymphopenia, and reduced lung granulocytes. Single cell transcriptome profiling showed that BCG uniquely recruits immunoglobulin-producing plasma cells to the lung suggesting accelerated antibody production. BCG vaccination also recruited elevated levels of Th1, Th17, Treg, CTLs, and Tmem cells, and differentially expressed gene (DEG) analysis showed a transcriptional shift away from exhaustion markers and towards antigen presentation and repair. Similarly, BCG enhanced lung recruitment of alveolar macrophages and reduced key interstitial macrophage subsets, with both cell-types also showing reduced IFN-associated gene expression. Our observations indicate that BCG vaccination protects against SCV2 immunopathology by promoting early lung immunoglobulin production and immunotolerizing transcriptional patterns among key myeloid and lymphoid populations.

Current Understanding of Bacillus Calmette-Guérin-Mediated Trained Immunity and Its Perspectives for Controlling Intracellular Infections

“…Single-cell transcriptome profiling demonstrated higher recruitment of plasma cells, Th1, Th17, regulatory T cells (Treg), cytotoxic T lymphocytes (CTLs), and memory T cells to the lungs of BCG-immunized mice. These findings were observed together with a transcriptional shift towards antigen presentation and tissue repair [56].…”

“…were as susceptible as the unvaccinated group to intranasal (i.n) or intratracheal (i.t) infection with SARS-CoV-2/SB2 (B.4 lineage) [29]. In turn, other studies demonstrated a different outcome [55,56]. Zhang et al, 2022, showed that i.v.…”

The nonspecific effects of COVID-19 vaccination upon non-COVID-19 all-cause mortality (NCACM) in the population of England: Effects of age, sex, COVID-19 variant, vaccination history, and time in a real-world study from Jan-21 to May-23

“…Given the implications of this study to the nonspecific effects of vaccines via ncRNAs and other heterologous mechanisms it is of interest to note the reported beneficial effects of prior BCG vaccination against COVID-19 infection [2,7,8,112,113]. Both influenzas, diphtheria, and tetanus vaccines have likewise been suggested to reduce serious COVID-19 outcomes [114].…”

Effect of Age, Sex, and COVID-19 Vaccination History on All-Cause Mortality: Unexpected Outcomes in a Complex Biological and Social System

“…Given the implications of this study to the non-specific effects of vaccines via ncRNAs and other heterologous mechanisms it is of interest to note the reported beneficial effects of prior BCG vaccination against COVID-19 infection [5,6,117,118]. Both influenzas, diptheria, and tetanus vaccines have likewise been suggested to reduce serious COVID-19 outcomes [119].…”