John J. Mekalanos reviews the environmental signals that control the expression of virulence determinants in bacteria. He discusses how bacterial pathogens have evolved sophisticated signal transduction systems to coordinate the expression of virulence factors. These systems are crucial for the microbe's survival and multiplication within the host. Virulence factors include all factors contributing to infection and disease, excluding housekeeping functions. The regulation of virulence is often transcriptional and involves multiple DNA-binding regulatory proteins. Environmental cues such as low iron concentration and elevated temperature play significant roles in regulating virulence. Iron is a key regulator, as host tissues are rich in iron-binding proteins, and microbes must scavenge iron to survive. The regulation of iron-dependent virulence factors is often part of a global response to iron-limiting conditions. Temperature regulation is also important, with many pathogens adjusting their virulence gene expression in response to body temperature. Calcium levels also influence virulence gene expression in Yersinia species, with virulence genes being expressed in the absence of calcium. Osmolarity, anaerobiosis, and stress conditions such as starvation, acidic pH, and heat shock can also regulate virulence. Some regulatory systems do not have a clear environmental signal, yet they still control virulence gene expression. Mekalanos proposes five strategies for virulence gene regulation, including "no harm, no foul," "intentional foul," "transition game," "full-court press," and "four corners." These strategies highlight different ways microbes adapt to host environments to ensure survival and pathogenicity. Understanding these regulatory mechanisms is essential for identifying new virulence factors and developing effective vaccines and treatments.John J. Mekalanos reviews the environmental signals that control the expression of virulence determinants in bacteria. He discusses how bacterial pathogens have evolved sophisticated signal transduction systems to coordinate the expression of virulence factors. These systems are crucial for the microbe's survival and multiplication within the host. Virulence factors include all factors contributing to infection and disease, excluding housekeeping functions. The regulation of virulence is often transcriptional and involves multiple DNA-binding regulatory proteins. Environmental cues such as low iron concentration and elevated temperature play significant roles in regulating virulence. Iron is a key regulator, as host tissues are rich in iron-binding proteins, and microbes must scavenge iron to survive. The regulation of iron-dependent virulence factors is often part of a global response to iron-limiting conditions. Temperature regulation is also important, with many pathogens adjusting their virulence gene expression in response to body temperature. Calcium levels also influence virulence gene expression in Yersinia species, with virulence genes being expressed in the absence of calcium. Osmolarity, anaerobiosis, and stress conditions such as starvation, acidic pH, and heat shock can also regulate virulence. Some regulatory systems do not have a clear environmental signal, yet they still control virulence gene expression. Mekalanos proposes five strategies for virulence gene regulation, including "no harm, no foul," "intentional foul," "transition game," "full-court press," and "four corners." These strategies highlight different ways microbes adapt to host environments to ensure survival and pathogenicity. Understanding these regulatory mechanisms is essential for identifying new virulence factors and developing effective vaccines and treatments.