Stealth Proteins: In Silico Identification of a Novel Protein Family Rendering Bacterial Pathogens Invisible to Host Immune Defense

Abstract

There are a variety of bacterial defense strategies to survive in a hostile environment. Generation of extracellular polysaccharides has proved to be a simple but effective strategy against the host's innate immune system. A comparative genomics approach led us to identify a new protein family termed Stealth, most likely involved in the synthesis of extracellular polysaccharides. This protein family is characterized by a series of domains conserved across phylogeny from bacteria to eukaryotes. In bacteria, Stealth (previously characterized as SacB, XcbA, or WefC) is encoded by subsets of strains mainly colonizing multicellular organisms, with evidence for a protective effect against the host innate immune defense. More specifically, integrating all the available information about Stealth proteins in bacteria, we propose that Stealth is a D-hexose-1-phosphoryl transferase involved in the synthesis of polysaccharides. In the animal kingdom, Stealth is strongly conserved across evolution from social amoebas to simple and complex multicellular organisms, such as Dictyostelium discoideum, hydra, and human. Based on the occurrence of Stealth in most Eukaryotes and a subset of Prokaryotes together with its potential role in extracellular polysaccharide synthesis, we propose that metazoan Stealth functions to regulate the innate immune system. Moreover, there is good reason to speculate that the acquisition and spread of Stealth could be responsible for future epidemic outbreaks of infectious diseases caused by a large variety of eubacterial pathogens. Our in silico identification of a homologous protein in the human host will help to elucidate the causes of Stealth-dependent virulence. At a more basic level, the characterization of the molecular and cellular function of Stealth proteins may shed light on fundamental mechanisms of innate immune defense against microbial invasion. The immune system is a complex and highly developed system of specialized cells and organs that protects an organism against bacterial, parasitic, fungal, and viral infections. Broadly speaking, the different types of immune responses subdivide the immune system into two categories: innate (or nonadaptive) and adaptive immune system. The innate immune system serves as a first line of defense but lacks the ability to recognize certain pathogens and to provide the specific protective immunity that prevents reinfection. Just as metazoans have developed many different defenses against pathogens, so have pathogens evolved elaborate strategies to evade these defenses. Based on a comparative genomics approach and data mining, the authors have discovered a new family of proteins with a striking phylogenetic distribution, occurring in most eukaryotes and in subsets of mostly pathogenic or commensal prokaryotes. While the precise functions of these proteins remain unknown, prokaryotic versions have been implicated in the synthesis of extracellular polysaccharides known to be potent regulators of the innate immune system. This previously unrecognized link hints towards a potentially novel regulatory mechanism of the innate immune system. It remains to be shown if drugs selectively inhibiting Stealth in pathogens will help fight Stealth-mediated infections.