From past to present: the crosstalk between type VI secretion system of Salmonella and host.

Salmonella encounters dual selective pressures during infection - from the host immune system and competing gut microbiota. The Type VI secretion system (T6SS) is a versatile transmembrane nanomachine that delivers effector proteins into target cells or the extracellular environment, enabling diverse functions including bacterial competition, virulence, and niche adaptation. Emerging evidence demonstrates that some T6SS effectors exhibit dual targeting capability, affecting both eukaryotic and prokaryotic cells. This dual-targeting strategy confers competitive advantages by simultaneously eliminating bacterial rivals through contact-dependent killing and subverting host defenses via apoptosis induction, facilitating niche domination. Although T6SS-mediated interbacterial competition is well characterized, the mechanisms by which Salmonella coordinately utilizes T6SS to circumvent host defenses and outcompete gut microbiota require elucidation. Here we synthesize recent advances supporting the T6SS effector dual-targeting hypothesis and propose an integrated niche adaptation model. We aim to provide a systematic review of the crosstalk between the T6SS of Salmonella and its host, spanning from past discoveries to current understanding and future perspectives. Our analysis provides a conceptual framework for understanding pathogenesis in Salmonella and related Gram-negative enteric pathogens, with implications for developing targeted intervention strategies.