Abstract
The ppGpp molecule is part of a highly conserved regulatory system for mediating the growth response to various environmental conditions. This mechanism may represent a common strategy whereby pathogens such as Yersinia pestis, the causative agent of plague, regulate the virulence gene programs required for invasion, survival and persistence within host cells to match the capacity for growth. The products of the relA and spoT genes carry out ppGpp synthesis. To investigate the role of ppGpp on growth, protein synthesis, gene expression and virulence, we constructed a ΔrelA ΔspoT Y. pestis mutant. The mutant was no longer able to synthesize ppGpp in response to amino acid or carbon starvation, as expected. We also found that it exhibited several novel phenotypes, including a reduced growth rate and autoaggregation at 26°C. In addition, there was a reduction in the level of secretion of key virulence proteins and the mutant was>1,000-fold less virulent than its wild-type parent strain. Mice vaccinated subcutaneously (s.c.) with 2.5×104 CFU of the ΔrelA ΔspoT mutant developed high anti-Y. pestis serum IgG titers, were completely protected against s.c. challenge with 1.5×105 CFU of virulent Y. pestis and partially protected (60% survival) against pulmonary challenge with 2.0×104 CFU of virulent Y. pestis. Our results indicate that ppGpp represents an important virulence determinant in Y. pestis and the ΔrelA ΔspoT mutant strain is a promising vaccine candidate to provide protection against plague.
Highlights
Plague remains one of the most feared infectious diseases in humans
About 2000 cases of plague are reported to the World Health Organization each year [2]. Most of these cases are the bubonic form of the disease, usually a consequence of the transmission of bacteria to humans via bites from fleas that have previously fed on infected rodents contact with domestic cats that have been exposed to Y. pestis is another important transmission mode because of the higher than average incidence of pneumonic plague that occurs in these cases [1]
Typhimurium is effectively noninvasive for epithelial cells in vitro and is attenuated in BALB/c mice [18,19]. These genes were shown to play a crucial role in the regulation of genes in Salmonella pathogenicity islands 1 and 2 (SPI1, SPI2) and the spv virulence plasmid genes. These results suggest that ppGpp may play a universal role in bacterial virulence gene expression
Summary
The etiological agent of the disease, Yersinia pestis, is disseminated by fleas and infects both humans and rodents. About 2000 cases of plague are reported to the World Health Organization each year [2]. Most of these cases are the bubonic form of the disease, usually a consequence of the transmission of bacteria to humans via bites from fleas that have previously fed on infected rodents contact with domestic cats that have been exposed to Y. pestis is another important transmission mode because of the higher than average incidence of pneumonic plague that occurs in these cases [1]. Pneumonic plague is the most likely form to be encountered if Y. pestis is used as a biological weapon [3]
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