SPACIOUS PHAGOSOME FORMATION WITHIN MOUSE MACROPHAGES CORRELATES WITHSALMONELLA SEROTYPE PATHOGENICITY AND HOST SUSCEPTIBILITY

Light microscopic studies indicated a correlation between the virulenc e for mice of different Salmonella serotypes and the ability to form o r maintain spacious phagosomes (SP) within mouse macrophages. Although Salmonella typhimurium induced membrane ruffling, macropinocytosis, a nd SP formation in macrophages from BALB/c mice, serotypes which are n onpathogenic for mice produced markedly fewer SP. SP formation correla ted with both serotype survival within mouse macrophages and reported lethality for mice. Time-lapse video microscopy demonstrated that the human pathogen S. typhi induced generalized macropinocytosis and SP fo rmation in human monocyte-derived macrophages, indicating a similar mo rphology for the initial phases of this host-pathogen interaction. In contrast to bone marrow-derived macrophages from BALB/c mice, macropha ges from S. typhimurium-resistant outbred (CD-1) and inbred (CBA/HN) m ice did not initiate generalized macropinocytosis after bacterial infe ction and formed markedly fewer SP. These deficiencies were not due to the Ity resistance genotype of these mice, as macrophages from mice t hat were congenic except for the Ity locus demonstrated equal SP forma tion in response to S. typhimurium. The observation that S. typhimuriu m-resistant CD-1 and CBA/HN mice are deficient in the ability to form and/or maintain SP indicates that a variable host component is importa nt for SP formation and suggests that the ability to induce or form SP affects susceptibility to S. typhimurium. When serotypes nonpathogeni c for mice were used to infect BALB/c macrophages, or when CD-1 or CBA /HN mouse macrophages were infected by S. typhimurium, some of the SP that formed shrank within seconds. This rapid shrinkage suggests that SP maintenance is also important for S. typhimurium survival within ma crophages. These studies indicate that both host and bacterial factors contribute to SP formation and maintenance, which correlate with Salm onella intracellular survival and the ability to cause lethal enteric (typhoid) fever.