Bacterial type IV secretion system induces specific and nonspecific protective immunity

ABSTRACT Pathogenic microbes trigger rapid and robust innate immune responses that effectively restrict pathogen replication and promote long-lasting adaptive immunity. The differential recognition of pathogenic versus non-pathogenic microbes occurs through the detection of host cell damage or pathogen molecules secreted via virulence factors, such as specialized bacterial secretion systems. Despite the well-established role of bacterial secretion systems in pathogenesis and subversion of host cell responses, their impact on immune activation remains largely unexplored. Here, we used Legionella pneumophila, an intracellular bacterial pathogen that expresses the Dot/Icm type IV secretion system (T4SS), to assess the importance of T4SS in inducing specific and nonspecific long-lasting immunity. Using thymidine auxotrophic L. pneumophila strains that are competent for T4SS expression but unable to multiply in mouse tissues, we found that infection with T4SS-sufficient bacteria, but not T4SS-deficient bacteria, induces protective immunity. Mechanistically, this process requires MyD88 signaling but not individual TLRs, Trif, TNF-α, IFN-γ, IL-12, IL-17, IL-23, or inflammasomes. CCR2+ monocytes and CD4+ T cells were partially involved in T4SS-induced responses that conferred protection against secondary infections with L. pneumophila, Legionella longbeachae, and the pathogenic fungus Cryptococcus neoformans. Our findings contribute to the identification of pathogen determinants that induce specific and nonspecific immunity, a process central to understanding host-pathogen interactions and with potential implications for vaccine development.IMPORTANCEUnderstanding how bacteria interact with the immune system is crucial for developing better treatments and vaccines. This study reveals that a bacterial secretion system, the type IV secretion system (T4SS) of Legionella pneumophila, triggers a targeted immune response but also enhances broader, nonspecific immunity. Using advanced infection models, the research shows that T4SS-driven immunity protects against multiple pathogens, including bacteria and fungi, even in the absence of traditional immune signaling pathways. These findings suggest that bacterial secretion systems can serve as novel tools for training the immune system, with potential applications in vaccine development and immunotherapy. By uncovering new ways bacteria influence immune memory, this work advances our understanding of host defense mechanisms and opens new avenues for designing strategies to enhance protection against infectious diseases.