Biology subjects

Surewaard, B. G. J.

Publications and source records attributed to Surewaard, B. G. J..

3 recordsLinked to original sources

bioRxiv2026

A niche-specific role for ArlRS enables Staphylococcus aureus growth within Kupffer cells

Staphylococcus aureus bloodstream infections cause severe morbidity and mortality despite antibiotic therapy. We previously identified Kupffer cells (KCs) as the primary hepatic macrophages that rapidly clear circulating S. aureus, yet a subset of bacteria survives intracellularly and seeds systemic infection. Here, using spinning-disk intravital and super-resolution microscopy, we show that bacterial two-component system (TCS) signaling is required for intracellular replication within KCs in vivo. A global mutant lacking all non-essential TCSs failed to form intracellular microcolonies, and targeted analysis identified the ArlRS system as specifically required for KC replication. {Delta}arlRS bacteria remained as single non-replicating organisms within KCs, exhibited reduced dissemination and kidney abscess formation, and showed attenuated virulence with improved host survival. Complementation with arlRS restored the wildtype phenotype. Notably, the intracellular replication defect was not observed in primary or cultured macrophages, indicating that ArlRS-dependent replication is highly niche-specific and not reproduced by conventional in vitro models. Furthermore, restricting the KC reservoir with vancomycin treatment after infection further reduced renal infection by {Delta}arlRS bacteria. These findings identify ArlRS as a critical regulator of intracellular replication within KCs and establish the KC intracellular reservoir as a key driver of S. aureus pathogenesis and a potential therapeutic target during bloodstream infection.

microbiology↗

bioRxiv2021

Human macrophage polarization determines bacterial persistence of Staphylococcus aureus in a liver-on-chip-based infection model

Infections with Staphylococcus aureus (S. aureus) have been reported from various organs ranging from asymptomatic colonization to severe infections and sepsis associated with multiple organ dysfunction. Although considered an extracellular pathogen, S. aureus can invade and persist in professional phagocytes such as monocytes and macrophages. Its capability to persist and manipulate phagocytes is considered a critical step to evade host antimicrobial reactions. For the first time we leveraged a human liver-on-chip model and tailored image analysis algorithms to demonstrate that S. aureus (USA300) specifically targets macrophages in the liver models as essential niche facilitating bacterial persistence and phenotype switching to small colony variants (SCVs). In vitro M2 polarization was found to favor SCV-formation and was associated with increased intracellular bacterial loads in macrophages, increased cell death, and impaired recruitment of circulating monocytes to sites of infection. These findings expand the knowledge about the role of liver macrophages in the course of systemic infection. Further, the results might be relevant for understanding infection mechanisms in patients with chronic liver disease such as fibrosis that display increased frequencies of M2 polarized liver macrophages and have a higher risk for developing chronic infections and relapsing bacteremia.

microbiology↗

bioRxiv2021

Single cell chronoatlas of regenerating mouse livers reveals early Kupffer cell proliferation

The liver is exemplar to study tissue regeneration due to its inherent ability of repair and regrowth. It replaces its lost or injured tissue by the proliferation, interaction and temporal coordination of multiple residential cell types. Until now we lacked a detailed description of the specific contributions of each cell type to the regenerative process, and therefore analyzed mouse livers 0, 3, 6, and 24 hours following two-thirds partial hepatectomy (PHx) by single cell RNA-sequencing (scRNA-seq) and mass cytometry. Our resulting genome wide temporal atlas contains the time dependent transcriptional changes in hepatocytes, endothelial cells, bone marrow-derived macrophages (BMDM) and Kupffer cells. In addition, it describes the cell specific contribution of mitogenic growth factors from biliary epithelial, endothelial and stellate cells as well as chemokines and cytokines from BMDM and granulocytes. And interestingly, Kupffer cells as opposed to hepatocytes emerged as the first cell to proliferate presenting a new dynamic in the liver following PHx. Here, we provide a robust data set at cellular resolution to uncover new elements and revisit current dogmas on the mechanisms underlying liver regeneration. To facilitate access to the data, we have launched the portal www.phxatlas.ch in which the scRNA-seq data can be visualized.

developmental biology↗