Parenteral BCG vaccine induces lung-resident memory macrophages and trained immunity via the gut–lung axis

TLDR

Evidence shows that mucosal‑resident innate immune memory can develop via a local inflammatory pathway following mucosal exposure, in addition to centrally induced trained immunity in bone marrow and blood by parenteral vaccination or infection. The study seeks to determine whether mucosal‑resident innate memory arises from distally generated immunological signals after parenteral vaccination or infection. Parenteral BCG vaccination disseminates mycobacteria, causing time‑dependent changes in the intestinal microbiome, barrier function, and microbial metabolites that alter circulating and lung metabolites, thereby inducing memory macrophages and trained immunity in the lung. Subcutaneous BCG vaccination induces memory alveolar macrophages and trained immunity in the lung, independently of circulating monocytes, through a gut–lung axis that alters the intestinal microbiome, barrier function, and metabolites, revealing a microbiota‑mediated pathway with implications for next‑generation respiratory vaccines.

Abstract

Aside from centrally induced trained immunity in the bone marrow (BM) and peripheral blood by parenteral vaccination or infection, evidence indicates that mucosal-resident innate immune memory can develop via a local inflammatory pathway following mucosal exposure. However, whether mucosal-resident innate memory results from integrating distally generated immunological signals following parenteral vaccination/infection is unclear. Here we show that subcutaneous Bacillus Calmette-Guérin (BCG) vaccination can induce memory alveolar macrophages (AMs) and trained immunity in the lung. Although parenteral BCG vaccination trains BM progenitors and circulating monocytes, induction of memory AMs is independent of circulating monocytes. Rather, parenteral BCG vaccination, via mycobacterial dissemination, causes a time-dependent alteration in the intestinal microbiome, barrier function and microbial metabolites, and subsequent changes in circulating and lung metabolites, leading to the induction of memory macrophages and trained immunity in the lung. These data identify an intestinal microbiota-mediated pathway for innate immune memory development at distal mucosal tissues and have implications for the development of next-generation vaccine strategies against respiratory pathogens.