Proteases from Entamoeba spp. and Pathogenic Free-Living Amoebae as Virulence Factors

Abstract

The standard reference for pathogenic and nonpathogenic amoebae is the human parasite Entamoeba histolytica; a direct correlation between virulence and protease expression has been demonstrated for this amoeba. Traditionally, proteases are considered virulence factors, including those that produce cytopathic effects in the host or that have been implicated in manipulating the immune response. Here, we expand the scope to other amoebae, including less-pathogenic Entamoeba species and highly pathogenic free-living amoebae. In this paper, proteases that affect mucin, extracellular matrix, immune system components, and diverse tissues and cells are included, based on studies in amoebic cultures and animal models. We also include proteases used by amoebae to degrade iron-containing proteins because iron scavenger capacity is currently considered a virulence factor for pathogens. In addition, proteases that have a role in adhesion and encystation, which are essential for establishing and transmitting infection, are discussed. The study of proteases and their specific inhibitors is relevant to the search for new therapeutic targets and to increase the power of drugs used to treat the diseases caused by these complex microorganisms.

Figure 1

Proteases from E. histolytica as virulence factors during intestinal amoebiasis.

Figure 2

E. histolytica proteases participating during trophozoite transit in blood vessels.

Figure 3

(a) Hamster amoebic liver abscess of eight days of infection (Photo kindly donated by G. Dominguez). (b) Proteases involved in the development of human amoebic liver abscess.

Figure 4

Localization of proteases in E. histolytica.

Figure 5

Proposed scenarios for how EhROM1 regulates parasite adhesion. EhROM1 may process an unknown adhesin (a) or a different substrate that masks the Gal/GalNAc lectin adhesion (b) or EhROM1 may play a role in signaling during the adhesion process by detaching the signaling integrin-like motif present in the cytoplasmic domain from the rest of the Gal/GalNAc lectin (c).

Figure 6

EhPCP5 stimulates NFκB-mediated proinflammatory responses. Attached to E. histolytica surface or secreted, EhPCP5 binds to α(V)β(3) integrin through the RGD motif and triggers PI3K-mediated ILK activation. ILK phosphorylates Akt-473, which binds and induces the ubiquitination of NEMO. This activates the IKKα-IKKβ complex that phosphorylate IκBα. This phosphorylation event signals IκBα ubiquitin-mediated degradation and, thereby, the release of NF-κB into the nucleus, where it activates proinflammatory gene expression.

Figure 7

Host proteins containing iron are internalized and degraded by amoebic proteases for use as iron sources for growth.