Deciphering the Salmonella T6SS toolkit: two decades of research decoding a versatile bacterial weapon

The Type VI Secretion System (T6SS) is a critical fitness and virulence factor of many Gram-negative bacteria. Five T6SS gene clusters have been described in Salmonella, each one encoded within different pathogenicity islands (i.e., SPI-6, SPI-19, SPI-20, SPI-21, and SPI-22). The events of gain and loss of these T6SS gene clusters have contributed to shape the genome evolution of different Salmonella serotypes. In addition, the differential distribution of T6SS and the ever-increasing repertoire of predicted effector proteins is likely to play an important role in the environmental fitness and pathogenic potential of different Salmonella serotypes. This review summarizes the current knowledge on the role played by T6SS in Salmonella biology, highlighting the major milestones in the field over the past two decades. We discuss the expanding repertoire of T6SS effector proteins identified to date and examine the current understanding of mechanisms controlling T6SS expression in Salmonella, focusing on host-derived cues and regulators involved. Finally, we provide a critical analysis of conflicting reports and suggest future directions for the research in the field. A better understanding of these processes could expand our knowledge of Salmonella biology, and the mechanisms behind how this versatile secretion system enables Salmonella to thrive in competitive microbial environments and contribute to host colonization.