Parasitic protozoa are among the most important pathogens worldwide. Diseases such as malaria, leishmaniasis, amoebiasis, giardiasis, trichomoniasis, and trypanosomiasis affect millions of people. Humans are constantly threatened by infections caused by these pathogens. Parasites engage a plethora of surface and secreted molecules to attach to and enter mammalian cells. The secretion of lytic enzymes by parasites into host organs mediates critical interactions because of the invasion and destruction of interstitial tissues, enabling parasite migration to other sites within the hosts. Extracellular matrix is a complex, cross-linked structure that holds cells together in an organized assembly and that forms the basement membrane lining (basal lamina). The extracellular matrix represents a major barrier to parasites. Therefore, the evolution of mechanisms for connective-tissue degradation may be of great importance for parasite survival. Recent advances have been achieved in our understanding of the biochemistry and molecular biology of proteases from parasitic protozoa. The focus of this paper is to discuss the role of protozoan parasitic proteases in the degradation of host ECM proteins and the participation of these molecules as virulence factors. We divide the paper into two sections, extracellular and intracellular protozoa.
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.
Iron is an essential nutrient for the survival of pathogens inside a host. As a general strategy against microbes, mammals have evolved complex iron-withholding systems for efficiently decreasing the iron accessible to invaders. Pathogens that inhabit the respiratory, intestinal and genitourinary tracts encounter an iron-deficient environment on the mucosal surface, where ferric iron is chelated by lactoferrin, an extracellular glycoprotein of the innate immune system. However, parasitic protozoa have developed several mechanisms to obtain iron from host holo-lactoferrin. Tritrichomonas fetus, Trichomonas vaginalis, Toxoplasma gondii and Entamoeba histolytica express lactoferrin-binding proteins and use holo-lactoferrin as an iron source for growth in vitro; in some species, these binding proteins are immunogenic and, therefore, may serve as potential vaccine targets. Another mechanism to acquire lactoferrin iron has been reported in Leishmania spp. promastigotes, which use a surface reductase to recognize and reduce ferric iron to the accessible ferrous form. Cysteine proteases that cleave lactoferrin have been reported in E. histolytica. This review summarizes the available information on how parasites uptake and use the iron from lactoferrin to survive in hostile host environments.
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