Salmonella is a Gram-negative [Gram(−)] bacteria, distributed widely in such natural environments as soil, dust, or river water, causing food poisoning as well as oral infections such as Typhi or Paratyphi. Salmonella is highly tissue invasive, easily spreading throughout the whole body after initial growth in the phagocytic vesicles of macrophages as an intra-cellular parasite. Because there remain many unknown elements in the Salmonella-macrophage interaction, I started my study by focusing on the molecules and mechanisms underlying the interaction; for example, how Salmonella escapes natural biodefense systems armed by macrophages, and how macrophages surround and inactivate Salmonella. In addition, I developed insight into Salmonella survival in the face of both environmental stresses and immunological stresses, including attacks from macrophages, based on the idea that “pathogenicity” is not limited simply to an attack, but to both the attack and defense against hazards. In this study, I found a novel pathogenicity-related protein of Salmonella, SEp22, an iron-chelating protein of MW 18.7 kDa, to cope with reactive-oxygen intermediates (ROIs) generated by activated macrophages pre-treated with lipopolysaccharides (LPS), one of the major components of Salmonella outer membrane. We also showed that Salmonella attacks macrophages by a novel mechanism through the induction of apoptosis with large amounts of LPS and protein synthesis inhibition, in addition to the well-known mechanisms of type-three secretion system (TTSS)-induced cell damage, including InvA, an attacking, virulent factor of Salmonella. We showed that macrophages could escape from this type of cell death by LPS-induced macrophage activation and LPS-tolerance.