Parasitic diseases represent major global health problems of immense proportion. Schistosomiasis, malaria, leishmaniasis, Chagas disease, and African sleeping sickness affect hundreds of millions of people worldwide, cause millions of deaths annually, and present an immense social and economic burden. Recent advances in genomic analysis of several of the major global parasites have revealed key factors involved in the pathogenesis of parasite diseases. Among the major virulence factors identified are parasite-derived proteases. This review focuses on the direct role of proteases in disease pathogenesis. Well-characterized examples of the roles proteases play in pathogenesis include their involvement in invasion of the host by parasite migration through tissue barriers, degradation of hemoglobin and other blood proteins, immune evasion, and activation of inflammation.

Proteases in parasitic diseases

Parasitic protozoa of the genus Leishmania have provided a useful perspective for immunologists in terms of host defense mechanisms critical for the resolution of infection caused by intracellular pathogens. These organisms, which normally reside in a late endosomal, major histocompatibility complex (MHC) class II(+) compartment within host macrophages cells, require CD4(+) T-cell responses for the control of disease. The paradigm for the CD4(+) T-helper 1 (Th1)/Th2 dichotomy is largely based on the curing/non-curing responses, respectively, to Leishmania major infection. However, this genus of parasitic protozoa is evolutionarily diverse, with the cutaneous disease-causing organisms of the Old World (L. major) and New World (Leishmania mexicana/ Leishmania amazonensis) having diverged 40-80 million years ago. Further adaptations to survive within the visceral organs (for Leishmania donovani, Leishmania chagasi, and Leishmania infantum) must have been required. Consequently, significant differences in host-parasite interactions have evolved. Different virulence factors have been identified for distinct Leishmania species, and there are profound differences in the immune mechanisms that mediate susceptibility/resistance to infection and in the pathology associated with disease. These variations not only point to interesting features of the host-pathogen interaction and immunobiology of this genus of parasitic protozoa, but also have important implications for immunotherapy and vaccine development.

Does the Leishmania major paradigm of pathogenesis and protection hold for New World cutaneous leishmaniases or the visceral disease

The major surface protease (MSP or GP63) of Leishmania sp. Biosynthesis, regulation of expression, and function.

Cysteine peptidases as virulence factors of Leishmania

Laminin (Ln) and collagen are multifunctional glycoproteins that play an important role in cellular morphogenesis, cell signalling, tissue repair and cell migration. These proteins are ubiquitously present in tissues as a part of the basement membrane (BM), constitute a protective layer around blood capillaries and are included in the extracellular matrix (ECM). As a component of BMs, both Lns and collagen(s), thus function as major mechanical containment molecules that protect tissues from pathogens. Invasive pathogens breach the basal lamina and degrade ECM proteins of interstitial spaces and connective tissues using various ECM-degrading proteases or surface-bound plasminogen and matrix metalloproteinases recruited from the host. Most pathogens associated with the respiratory, gastrointestinal, or urogenital tracts, as well as with the central nervous system or the skin, have the capacity to bind and degrade Lns and collagen(s) in order to adhere to and invade host tissues. In this review, we focus on the adaptability of various pathogens to utilize these ECM proteins as enhancers for adhesion to host tissues or as a targets for degradation in order to breach the cellular barriers. The major pathogens discussed are Streptococcus, Staphylococcus, Pseudomonas, Salmonella, Yersinia, Treponema, Mycobacterium, Clostridium, Listeria, Porphyromonas and Haemophilus; Candida, Aspergillus, Pneumocystis, Cryptococcus and Coccidioides; Acanthamoeba, Trypanosoma and Trichomonas; retrovirus and papilloma virus.

Human pathogens utilize host extracellular matrix proteins laminin and collagen for adhesion and invasion of the host

Leishmania species engineered to express high levels of the surface metalloprotease gp63 have enhanced capacity of migration through extracellular matrix in vitro. This correlates with gp63 degradation of extracellular matrix components, such as collagen type IV and fibronectin, and suggests an important role for gp63 in the pathogenesis of leishmaniasis.

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Kwang-Poo Chang

Papers

Migration through the Extracellular Matrix by the Parasitic Protozoan Leishmania Is Enhanced by Surface Metalloprotease gp63