Heterogeneity in Kupffer cell-mediated killing of <em>Staphylococcus aureus</em>

Abstract

<em>Staphylococcus aureus</em>, an opportunistic pathogen, exhibits remarkable adeptness in evading the host's innate immune defenses to establish infections. In this context, Kupffer cells, specialized resident macrophages in the liver, serve as the initial line of defense against <em>S. aureus</em>. However, some of these cells fall short in effectively containing the infection, thereby enabling the escape and widespread dissemination of <em>S. aureus</em> through various evasion tactics. Through in vivo experimentation, we observed that a strategically organized distribution of Kupffer cells, rather than a uniform arrangement along sinusoidal zones, significantly enhances immune response efficacy against systemic bacterial dissemination. Intriguingly, despite the predominant presence of Kupffer cells in periportal regions—aimed at shielding the central vein from pathogenic intrusion—these cells exhibit impaired capability in eradicating <em>S. aureus</em>. Conversely, Kupffer cells positioned in proximity to the central vein and its sinusoids demonstrate heightened proficiency in combatting the pathogen. In-depth analysis through dual-RNAseq of host-pathogen interactions during <em>S. aureus</em> infection unveils a distinctive interplay with the adaptive immune system. Moreover, the central vein microenvironment orchestrates anti-apoptotic pathways, facilitating resilience and cell survival against <em>S. aureus</em> infection and AIM expression and secretion is dependent on the presence of NKT type II. In summary, our findings underscore the pivotal role of spatial zonation in the context of <em>S. aureus</em> infection. Specifically, we highlight the enhanced capabilities of central vein-residing Kupffer cells in managing bacterial escape, potentially attributed to their interaction with type II NKT cells. This interaction, in turn, fosters elevated survival rates and augments the arsenal of antibacterial defense mechanisms.