Protein sociology of ProA, Mip and other secreted virulence factors at the Legionella pneumophila surface

Abstract

The pathogenicity of L. pneumophila, the causative agent of Legionnaires’ disease, depends on an arsenal of interacting proteins. Here we describe how surface-associated and secreted virulence factors of this pathogen interact with each other or target extra- and intracellular host proteins resulting in host cell manipulation and tissue colonization. Since progress of computational methods like AlphaFold, molecular dynamics simulation, and docking allows to predict, analyze and evaluate experimental proteomic and interactomic data, we describe how the combination of these approaches generated new insights into the multifaceted “protein sociology” of the zinc metalloprotease ProA and the peptidyl-prolyl cis/trans isomerase Mip (macrophage infectivity potentiator). Both virulence factors of L. pneumophila interact with numerous proteins including bacterial flagellin (FlaA) and host collagen, and play important roles in virulence regulation, host tissue degradation and immune evasion. The recent progress in protein-ligand analyses of virulence factors suggests that machine learning will also have a beneficial impact in early stages of drug discovery.

Severe Legionnaires’ disease

“…Several virulence factors involved at different stages of pathogenesis have been described in the literature [ 34 ]. In a recent review focusing on surface-associated and secreted virulence factors, the authors highlighted the role of zinc metalloprotease (ProA), macrophage infectivity potentiator (Mip) and flagellin (FlaA) in virulence regulation, host tissue degradation and immune evasion [ 38 ]. In particular, ProA may contribute to bacterial proliferation and dissemination in the human lung, as well as to the formation and progression of lung damage, through a protease extracellular activity against the host lung tissue.…”

Evaluation of Genetic Diversity and Virulence Potential of Legionella pneumophila Isolated from Water Supply Systems of Residential Buildings in Latvia

“…Proteins and effectors that provide Legionella with their natural ability to infect protozoa also provide the pathogen with the ability to infect mammalian cells. Through horizontal gene transfer from the host amoebae, Legionella has acquired numerous eukaryotic-like genes that regulate the infection process [ 15 ]. Some of the bacterial effectors can perform parallel functions in different organisms, and some of the effectors can overlap or replace each other in pathogenic and nonpathogenic species [ 16 ].…”