Antivirulence genes: insights into pathogen evolution through gene loss - PubMed (original) (raw)

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Antivirulence genes: insights into pathogen evolution through gene loss

Kimberly A Bliven et al. Infect Immun. 2012 Dec.

Abstract

The emergence of new pathogens and the exploitation of novel pathogenic niches by bacteria typically require the horizontal transfer of virulence factors and subsequent adaptation--a "fine-tuning" process--for the successful incorporation of these factors into the microbe's genome. The function of newly acquired virulence factors may be hindered by the expression of genes already present in the bacterium. Occasionally, certain genes must be inactivated or deleted for full expression of the pathogen phenotype to occur. These genes are known as antivirulence genes (AVGs). Originally identified in Shigella, AVGs have improved our understanding of pathogen evolution and provided a novel approach to drug and vaccine development. In this review, we revisit the AVG definition and update the list of known AVGs, which now includes genes from pathogens such as Salmonella, Yersinia pestis, and the virulent Francisella tularensis subspecies. AVGs encompass a wide variety of different roles within the microbe, including genes involved in metabolism, biofilm synthesis, lipopolysaccharide modification, and host vasoconstriction. More recently, the use of one of these AVGs (lpxL) as a potential vaccine candidate highlights the practical application of studying AVG inactivation in microbial pathogens.

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Figures

Fig 1

Fig 1

Inhibition of pathogenesis in Shigella. Pathogenesis phenotypes interrupted by Shigella AVGs. The product of the lysine decarboxylase reaction, cadaverine, inhibits ShET1/ShET2 enterotoxin activity (part 1), phagosome escape (part 4), and PMN transepithelial migration (part 6). Another small molecule, quinolinic acid, is the product of the nadA/nadB enzymatic reactions and inhibits both Shigella invasion (part 3) and intracellular spread (part 5). Inactivation of speG, which encodes the spermidine acetyltransferase, allows spermidine to accumulate within the phagosome and ultimately promotes bacterial survival in the macrophage (part 2). OmpT, an outer membrane protease, cleaves IcsA from the bacterial surface, preventing actin tail polymerization and inhibiting cell-to-cell spread (part 5).

Fig 2

Fig 2

Metabolic pathways lost in Shigella. Compounds or enzymes still present in Shigella are marked in black; those that have been lost are marked in red. (A) Lysine decarboxylation. (B) Biosynthetic and salvage NAD pathways. (C) Spermidine metabolism.

Fig 3

Fig 3

Inhibition of pathogenesis in Yersinia. nghA and rcsA encode proteins that inhibit biofilm formation in Yersinia: NghA directly degrades formed biofilm, and RcsA increases the repression ability of RcsB, an inhibitor of biofilm formation. Inactivation of these genes allows Yersinia to form a biofilm on the proventriculus of the flea, enabling bacterial transmission. LpxL mediates hexa-acetylation of lipid A on bacterial LPS, thus activating TLR4 and stimulating the host immune response to this pathogen. Loss of lpxL in all sequenced Y. pestis isolates leads to increased pathogen evasion of host innate immune defenses.

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