Zone-specific hepatocytes orchestrate the early onset of host immune defenses during Staphylococcus aureus...

Bloodstream infections (BSI) are life-threatening conditions initiated by pathogens entering the circulation, with Staphylococcus aureus among the most lethal causative agents. The liver is the primary site for the initial detection and clearance of blood-borne pathogens. Emerging evidence indicates that the hepatic immune response to pathological insults is influenced by liver zonation, exhibiting both spatial and cellular specialization. Because direct experimental evidence linking liver zonation to the immune response to BSI is currently lacking, this study aimed to characterize the compartmentalization of the early immune response in the liver to blood-borne S. aureus.

Using an intravenous infection model, we found that the liver captured ~90% of circulating S. aureus within 4 h and significantly reduced bacterial loads by 24 h, indicating rapid activation of intrahepatic immune defenses. Bulk RNA sequencing revealed strong induction of acute-phase and interferon-associated genes at 4h of infection, alongside elevated levels of IL-6, IL-1α/β, TNF-α, and IFN-γ. Single-cell transcriptomics identified hepatocytes as the principal responders, displaying pronounced zone-specific transcriptional programs along the porto-central axis. Periportal and midzonal hepatocytes showed the highest activation, whereas pericentral hepatocytes exhibited comparatively reduced transcriptional responses. Among the most highly upregulated genes was Bmper, encoding a regulator of bone morphogenetic proteins (BMPs) signaling that has not previously been linked to bacterial infections. Bmper induction was selective for periportal and midzonal hepatocytes. Chemokine production was likewise compartmentalized, with hepatocytes as the source of the neutrophil chemoattractant CXCL1, whereas Kupffer cells and liver sinusoidal endothelial cells expressed monocyte-attracting CCL chemokines. An expansion of Kupffer cells was also observed in infected livers, likely driven at least in part by the local proliferation of resident Kupffer cells.

This study demonstrates that the liver immune response to S. aureus BSI is highly compartmentalised, with hepatocytes acting as central orchestrators of the initial immune defence and exhibiting zone-specific transcriptional patterns. The strong, selective induction of Bmper suggests a previously unrecognized link between BMPs signaling and the acute-phase response to infection. Further investigation into the role of BMPER in the acute-phase response to BSI may reveal new strategies to enhance hepatic immunity or mitigate inflammation-induced liver injury.