BCG immunization mitigates SARS-CoV-2 replication in macaques via monocyte efferocytosis and neutrophil recruitment in lungs
Mohammad Arif Rahman, Katherine C. Goldfarbmuren, Sarkis Sarkis, Massimiliano Bissa, Anna Gutowska, Luca Schifanella, Ramona Moles, Melvin N. Doster, Hanne Andersen, Yogita Jethmalani, Leonid Serebryannyy, Timothy Cardozo, Mark G. Lewis, Genoveffa Franchini
Mohammad Arif Rahman, Katherine C. Goldfarbmuren, Sarkis Sarkis, Massimiliano Bissa, Anna Gutowska, Luca Schifanella, Ramona Moles, Melvin N. Doster, Hanne Andersen, Yogita Jethmalani, Leonid Serebryannyy, Timothy Cardozo, Mark G. Lewis, Genoveffa Franchini
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Research Article Immunology Infectious disease

BCG immunization mitigates SARS-CoV-2 replication in macaques via monocyte efferocytosis and neutrophil recruitment in lungs

Abstract

Exposure to Bacillus Calmette-Guérin (BCG) or Canarypox ALVAC/Alum vaccine elicits pro- or antiinflammatory innate responses, respectively. We tested whether prior exposure of macaques to these immunogens protected against SARS-CoV-2 replication in lungs and found more efficient replication control after the pro-inflammatory immunity elicited by BCG. The decreased virus level in lungs was linked to early infiltrates of classical monocytes producing IL-8 with systemic neutrophils, Th2 cells, and Ki67+CD95+CD4+ T cells producing CCR7. At the time of SARS-CoV-2 exposure, BCG-treated animals had higher frequencies of lung infiltrating neutrophils and higher CD14+ cells expressing efferocytosis marker MERTK, responses correlating with decreased SARS-CoV-2 replication in lung. At the same time point, plasma IL-18, TNF-α, TNFSF-10, and VEGFA levels were also higher in the BCG group and correlated with decreased virus replication. Finally, after SARS-CoV-2 exposure, decreased virus replication correlated with neutrophils producing IL-10 and CCR7 preferentially recruited to the lungs of BCG-vaccinated animals. These data point to the importance of the spatiotemporal distribution of functional monocytes and neutrophils in controlling SARS-CoV-2 levels and suggest a central role of monocyte efferocytosis in curbing replication.

Authors

Mohammad Arif Rahman, Katherine C. Goldfarbmuren, Sarkis Sarkis, Massimiliano Bissa, Anna Gutowska, Luca Schifanella, Ramona Moles, Melvin N. Doster, Hanne Andersen, Yogita Jethmalani, Leonid Serebryannyy, Timothy Cardozo, Mark G. Lewis, Genoveffa Franchini

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Figure 5

Differences in T cell subsets between ALVAC/Alum and BCG following vaccination.

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Differences in T cell subsets between ALVAC/Alum and BCG following vacci...
(A) Heatmaps depict vaccine-induced changes in T cell populations in blood, sorted by change with time patterns at 1 week (left) or 3 weeks (right) relative to baseline for ALVAC/Alum and BCG groups separately (generalized estimating equations, P < 0.05). Alluvial flow connects each population across the time point intervals and is colored according to the pattern at 1 week after vaccination. Populations that had identical patterns in both ALVAC/Alum and BCG animals were omitted from the figure to highlight those populations that differed. Regs, CD4+ regulatory T cells; WPV, weeks postvaccination. (B–D) Correlation plots link vaccine-induced changes in cell frequencies in blood at (B) 1 week after vaccination or (C) 3 weeks postvaccination or (D) levels at 3 weeks postvaccination, with replicating VL in BAL at 7 days after SARS-CoV-2 infection, highlighting differences between ALVAC/Alum and BCG (Spearman’s P < 0.05). Cell populations that were not associated (Spearman’s P > 0.05) with replicating VL in BAL were omitted from the figure for clarity. Change with time, levels, and magnitude differences between groups are summarized from A on the right of each plot. Cell frequencies (“Level”) or magnitude of changes (“effect size”) that significantly differed between vaccine groups (2-tailed Mann-Whitney P < 0.05) are indicated by circles or stars, respectively. Open circles indicate differences between the groups at baseline. Eight rhesus macaques were analyzed in this figure: BCG vaccine (n = 4 for 1 week postvaccination, n = 3 for 3 weeks postvaccination), ALVAC/Alum vaccine (n = 4).