Spacious phagosome formation within mouse macrophages correlates with Salmonella serotype pathogenicity and host susceptibility

Abstract

Light microscopic studies indicated a correlation between the virulence for mice of different Salmonella serotypes and the ability to form or maintain spacious phagosomes (SP) within mouse macrophages. Although Salmonella typhimurium induced membrane ruffling, macropinocytosis, and SP formation in macrophages from BALB/c mice, serotypes which are nonpathogenic for mice produced markedly fewer SP. SP formation correlated 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 formation in human monocyte-derived macrophages, indicating a similar morphology for the initial phases of this host-pathogen interaction. In contrast to bone marrow-derived macrophages from BALB/c mice, macrophages from S. typhimurium-resistant outbred (CD-1) and inbred (CBA/HN) mice did not initiate generalized macropinocytosis after bacterial infection and formed markedly fewer SP. These deficiencies were not due to the Ity resistance genotype of these mice, as macrophages from mice that were congenic except for the Ity locus demonstrated equal SP formation in response to S. typhimurium. The observation that S. typhimurium-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 important for SP formation and suggests that the ability to induce or form SP affects susceptibility to S. typhimurium. When serotypes nonpathogenic 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 macrophages. These studies indicate that both host and bacterial factors contribute to SP formation and maintenance, which correlate with Salmonella intracellular survival and the ability to cause lethal enteric (typhoid) fever.

Intracellular phenotype of Mycobacterium avium enters macrophages primarily by a macropinocytosis‐like mechanism and survives in a compartment that differs from that with extracellular phenotype

“…An important question relates to why the IG phenotype of M. avium induces the macropinosome-like structure upon entry into macrophages. One possible explanation is that it establishes an optimal microenvironment for survival, as has been postulated for Salmonella (Alpuche-Aranda et al, 1995). This hypothesis is strengthened by previous observations that, while TNF-a stimulation of EG-infected macrophages results in inhibition of the bacterial growth within the cell, it has no effect on the outcome of IG infection of macrophages (Bermudez et al, 1997).…”

“…A number of other bacteria have been shown to use macropinocytosis as a mechanism for entering host cells. S. typhimurium, for instance, invades both macrophages and epithelial cells by this mechanism (Alpuche- Aranda et al, 1995;Garcia-del Portillo and Finlay, 1994). Like the Salmonella macropinosome, the M. avium macropinosomelike structure does not decrease in size over the time in our assays.…”

Drinking a lot is good for dendritic cells

“…As outlined above, Salmonella typhimurium can induce ruffling and phagocytosis in epithelial cells 6 or macrophages. 4,5 This process is advantageous for the bacterium, as ablation of the gene responsible for the induction of spacious phagocytosis significantly reduces virulence. A number of other intracellular bacteria, including Mycobacterium tuberculosis, 63 are also known to exploit this pathway during entry into cells.…”

The cellular microbiology of Salmonellae interactions with macrophages

“…It also led to the definition that S. Typhimurium can enter macrophages by macropinocytosis and the formation of a spacious phagosome independent of the Salmonella pathogenicity island (SPI1) type III secretion system that uses effector proteins to rearrange the actin cytoskeleton and enter non-phagocytic cells through macropinocytosis and actin-based ruffling (Alpuche-Aranda, Racoosin, Swanson, & Miller, 1994). Spacious phagosome formation correlates with pathogenicity of Salmonella serotypes for their hosts and inbred mouse susceptibility to S. Typhimurium (Alpuche- Aranda, Berthiaume, Mock, Swanson, & Miller, 1995). Though…”