Regulation of host immune responses by modification of Salmonella virulence genes

Abstract

Modifying bacterial virulence genes to probe the nature of host immunity is mostly unexplored. Here we investigate whether host immune responses can be regulated by modification of bacterial virulence genes. In mice, attenuated Salmonella mutant strains with clinical relevance elicited differential host immune responses. Oral administration of a mutant strain with a PhoP-null phenotype promoted potent innate immune responses of macrophages that were sufficient for host defense. In contrast, administration of an Aro- mutant strain elicited stronger specific antibody and T-helper (Th)-cell responses, wherein Th1-type cells were required for clearance. Thus, genetic manipulation of bacteria may be used to broadly alter immune mechanisms that regulate attenuation within the host and to tailor host immunity to specific bacterial pathogens.

In vivo correction of genetic defects of monocyte/ macrophages using attenuated Salmonella as oral vectors for targeted gene delivery

“…In addition, different mutants have been identified, which are not harmful even for immunocompromised hosts. 26,27 Some safety considerations for the use of Gram-negative bacteria refer to the toxic effect of LPS. However, this concern has been ruled out by oral delivery and by the fact that Salmonella strains have been widely used as vaccines both in human and veterinary medicine.…”

Impaired Macrophage Function Underscores Susceptibility to Salmonella in Mice Lacking Irgm1 (LRG-47)

“…Two strains of S. typhimurium were used in these studies: a virulent strain SL1344 (30) and an aroA Ϫ strain SL7731 (31,32). The bacteria were cultured overnight in Luria-Bertani (LB) broth without shaking.…”

Recombinant live Salmonella spp. for human vaccination against heterologous pathogens

“…For example, in the mouse model, two S. typhimurium strains that carry identical attenuations but have been derived from di¡erent isolates elicit signi¢cantly di¡erent serum IgG and mucosal IgA antibody responses against a heterologous antigen [24]. In humans, identically constructed S. typhi aroC aroD deletion strains that have been derived from di¡erent isolates induce signi¢cantly di¡erent immune responses [16] which con¢rm and extend the mouse data.…”