The Posttranslocation Chaperone PrsA2 Contributes to Multiple Facets ofListeria monocytogenesPathogenesis

Abstract

Listeria monocytogenes is an intracellular bacterial pathogen whose virulence depends on the regulated expression of numerous secreted bacterial factors. As for other gram-positive bacteria, many proteins secreted by L. monocytogenes are translocated across the bacterial membrane in an unfolded state to the compartment existing between the membrane and the cell wall. This compartment presents a challenging environment for protein folding due to its high density of negative charge, high concentrations of cations, and low pH. We recently identified PrsA2 as a gene product required for L. monocytogenes virulence. PrsA2 was identified based on its increased secretion by strains containing a mutationally activated form of prfA, the key regulator of L. monocytogenes virulence gene expression. The prsA2 gene product is one of at least two predicted peptidyl-prolyl cis/trans-isomerases encoded by L. monocytogenes; these proteins function as posttranslocation protein chaperones and/or foldases. In this study, we demonstrate that PrsA2 plays a unique and important role in L. monocytogenes pathogenesis by promoting the activity and stability of at least two critical secreted virulence factors: listeriolysin O (LLO) and a broad-specificity phospholipase. Loss of PrsA2 activity severely attenuated virulence in mice and impaired bacterial cell-to-cell spread in host cells. In contrast, mutants lacking prsA1 resembled wild-type bacteria with respect to intracellular growth and cell-to-cell spread as well as virulence in mice. PrsA2 is thus distinct from PrsA1 in its unique requirement for the stability and full activity of L. monocytogenes-secreted factors that contribute to host infection.

An Intracellular Peptidyl-Prolyl cis / trans Isomerase Is Required for Folding and Activity of the Staphylococcus aureus Secreted Virulence Factor Nuclease

“…Previous studies have demonstrated that Nuc requires PPIase activity for optimal protein folding (3,4). Based on this observation and the fact that PPIase-mediated folding is required for subsequent activity of secreted virulence factors in a number of bacterial pathogens (8)(9)(10)(11)(27)(28)(29)(30), we hypothesized that a staphylococcal PPIase may be required for the activity of Nuc. To begin to investigate this, we examined the genome of the community-associated methicillin-resistant S. aureus (MRSA) isolate USA300 for genes that encode PPIase enzymes.…”

“…It is thought to assist in the refolding of proteins as they are exported from the bacterial cell. PrsA has been well studied in two bacterial pathogens, Listeria monocytogenes and Streptococcus pyogenes, where alteration of prsA levels (either increased or decreased) leads to defects in protein secretion and/or virulence of the organism (7)(8)(9)(10). The cyclophilins are by far the least-studied and least well understood group of PPIases in bacteria.…”

The arsenal of virulence factors deployed byListeria monocytogenesto promote its cell infection cycle

“…PrsA2 was shown to be important for L. monocytogenes pathogenesis by stimulating the activity and assuring the stability of LLO and PC-PLC. 139 Absence of PrsA2 induces significant virulence attenuation in the mouse model and deficient bacterial cell-to-cell spread in host cell lines. PrsA2 is thus required for the stabilization and optimal activity of L. monocytogenes-secreted factors involved in vacuole escape.…”

FKBPs in bacterial infections

“…As chaperones and foldases PPIases are involved in diverse protein-protein interactions that are short lived, difficult to entangle, and pleiotropic in their biological impact on bacterial physiology. Hence, it is not surprising that PPIases also very often correlate with virulence in pathogenic bacteria (Alonzo et al, 2009;Behrens-Kneip, 2010;Moro et al, 1995;Obi et al, 2011). This has become even more evident since the identification of macrophage infectivity potentiator (Mip) of Legionella pneumophila, as the first virulence-associated PPIase, and has opened the way to the analysis of bacterial FKBPs under the aspect infections with implications in alternative drug design strategies Fischer et al, 1992Fischer et al, , Ünal et al, 2011Ünal and Steinert, 2014).…”