Host-Salmonella dynamics during the early phase of infection in the neonate host

• Applicant: Dr. Kaiyi Zhang
• Subject Area: Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 548604504

S. enterica sv. enterica subsp. Typhimurium (S. Tm.) is a significant cause of sepsis in human neonates in developing countries. An oral S. Tm. infection model was established in neonate mice, revealing notable differences from the well-established adult infection model and highlighting age-dependent variations in the host-microbial interaction. Strikingly, S. Tm. in the neonate host invades small intestinal epithelial cells and forms intraepithelial SCV-like microcolonies, a hallmark of Salmonella pathogenesis that can be readily visualized and characterized. This renders the neonatal model particularly suitable to study the early phase of the infection. Own studies have so far demonstrated the functional role of individual bacterial virulence factors in enterocyte invasion, intraepithelial proliferation, and apical-to-basolateral transmigration of the Salmonella-containing endosomal compartment. Additionally, a striking observation of enterocyte efferocytosis of S. Tm.-infected epithelial cells was reported. A second in vivo Dual RNA Seq approach has also been completed and is currently being analyzed. Taking advantage of the established neonatal infection model, my proposed research proposal in the first WP aims to extend the in-depth investigation of the early host-microbe interaction using global proteomics of isolated enterocytes, interactome of host molecules interacting with key bacterial effector molecules, and spatial transcriptomics. The second WP focuses on the features of Salmonella pathogenesis during early enterocyte translocation and the bacterial gene expression history during the early phase of infection using report system and Record-Seq. Finally, the third WP will address the functional importance of enterocyte efferocytosis employing FACS sorting, Daul RNA Seq, comparative analysis of efferosome- and SCV-containing enterocytes, and functional assays, intestinal epithelial stem cell organoids and genetically deficient animals. The evaluation will include the role of efferocytosis in immunomodulation, antimicrobial host defense, and metabolic homeostasis. The planned work builds on very significant preliminary data, my long-standing technical expertise with neonatal animals and protocols adapted in the last years. It includes several innovative and explorative methods and high-risk high-gain experiments but also offers alternative strategies. Individual approaches will be supported by collaborators with tools and technical expertise, and I will receive strong bioinformatic support. Together the proposed research project aims at a comprehensive understanding of the host-microbial interaction during the early phase of the infection and particularities of the antimicrobial host response in this vulnerable age-group. In addition, the proposal's results are expected to provide a strong foundation for future studies and advance my career as an independent researcher.

• DFG Programme: Research Grants