A study of cutaneous lesions caused by Leishmania mexicana in plasminogen-deficient mice

Maldonado, Jesús; Calcagno, Marina; Puig, Juan; Maizo, Zulay; Avilán, Luisana

doi:10.1016/j.yexmp.2005.06.005

Cited by 32 publications

(21 citation statements)

References 31 publications

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“…In fact, in Leishmania, surface-associated enolase was previously documented and shown to bind host plasminogen (44). In addition, Leishmania was found to be less infectious in plasminogen knock-out mice, supporting a role for enolase-plasminogen interactions in Leishmania virulence (16).…”

Section: Discussionmentioning

confidence: 85%

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The Oligopeptidase B of Leishmania Regulates Parasite Enolase and Immune Evasion

Swenerton¹,

Zhang²,

Sajid

et al. 2011

Journal of Biological Chemistry

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Proteases are a ubiquitous group of enzymes that play key roles in the life cycle of parasites, in the host-parasite relationship, and in the pathogenesis of parasitic diseases. Furthermore, proteases are targets for the development of new antiparasitic therapy. Protozoan parasites like Leishmania predominantly express Clan CA cysteine proteases for key life cycle functions. It was therefore unexpected to find a high level of serine protease activity expressed by Leishmania donovani. Purification of this activity followed by mass spectrometry identified oligopeptidase B (OPB; Clan SC, family S9A) as the responsible enzyme. This was confirmed by gene knock-out of OPB, which resulted in the disappearance of the detected serine protease activity of Leishmania extracts. To delineate the specific role of OPB in parasite physiology, proteomic analysis was carried out on OPB(؊/؊) versus wild type parasites. Four protein species were significantly elevated in OPB(؊/؊) parasites, and all four were identified by mass spectrometry as enolase. This increased enolase was enzymatically inactive and associated with the parasite membrane. Aside from its classic role in carbohydrate metabolism, enolase was recently found to localize to membranes, where it binds host plasminogen and functions as a virulence factor for several pathogens. As expected, there was a striking alteration in macrophage responses to Leishmania when OPB was deleted. Whereas wild type parasites elicited little, if any, response from infected macrophages, OPB(؊/؊) parasites induced a massive up-regulation in gene transcription. Additionally, these OPB(؊/؊) parasites displayed decreased virulence in the murine footpad infection model.Proteases are a ubiquitous group of enzymes functioning in nearly all biological phenomena. In protozoan parasites, proteases play key roles in life cycle transition, host invasion, parasite immune evasion, and the pathogenesis of parasitic diseases (1, 2). At least 50 cysteine proteases and twenty serine proteases are known to exist in the Leishmania genome (3-5).The molecular evolution of proteases shows a striking dichotomy between the predominant Clan CA cysteine proteases of protozoa and primitive metazoa and the dominant trypsin family (S1A) serine proteases of vertebrates (6). It was therefore unexpected to find that Leishmania donovani, Leishmania major, and Leishmania mexicana (but not the related kinetoplastid parasite, Trypanosoma cruzi) express high levels of serine protease activity, relative to cysteine protease activity in parasite extracts.To delineate the character of this serine protease activity, it was purified from Leishmania extracts and identified as Clan SC, family S9A oligopeptidase B by mass spectrometry. Oligopeptidase B (OPB) 2 has been identified in other protozoa, including T. cruzi, Trypanosoma brucei, and Trypanosoma evansi (7-9). These enzymes represent a subfamily of potential chemotherapeutic targets (10) because their inhibitors have been shown to be trypanocidal (4,11,12). OPB of T. cruzi is i...

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Section: Discussionmentioning

confidence: 85%

“…Enolase is present on the cell surface of several parasites, including Leishmania, where it has been shown to bind host plasminogen (14). It may therefore have a role in macrophage entry via plasminogen receptors and parasite dissemination from the sand fly bite site (15,16).…”

mentioning

confidence: 99%

The Oligopeptidase B of Leishmania Regulates Parasite Enolase and Immune Evasion

Swenerton¹,

Zhang²,

Sajid

et al. 2011

Journal of Biological Chemistry

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“…In particular, Plg binding by Pseudomonas aeruginosa resulted in formation of surface-associated plasmin that enhanced bacterial invasiveness [7]. More recently, Plg binding was shown to be essential for the development of cutaneous lesions by Leishmania mexicana [12].…”

Section: Introductionmentioning

confidence: 99%

Interaction with human plasminogen system turns on proteolytic activity in Streptococcus agalactiae and enhances its virulence in a mouse model

Magalhães

Veiga-Malta²,

Almeida³

et al. 2007

Microbes and Infection

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Interactions of several microbial pathogens with the plasminogen system increase their invasive potential. In this study, we show that Streptococcus agalactiae binds human plasminogen which can be subsequently activated to plasmin, thus generating a proteolytic bacterium. S. agalactiae binds plasminogen via the direct pathway, using plasminogen receptors, and via the indirect pathway through fibrinogen receptors. The glyceraldehyde-3-phosphate dehydrogenase is one of the S. agalactiae proteins that bind plasminogen. Presence of exogenous activators such as uPA and tPA are required to activate bound plasminogen. Results from competitive inhibition assays indicate that binding is partially mediated through the lysine binding sites of plasminogen. Following plasminogen binding and activation, S. agalactiae is able to degrade in vitro fibronectin, one of the host extracellular matrix proteins. Moreover, incubation of S. agalactiae with either plasminogen alone, or plasminogen plus fibrinogen, in the presence of tPA enhanced its virulence in C57BL/6 mice, suggesting that acquisition of plasmin-like activity by the bacteria increase their invasiveness.

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“…50,51 (The functional significance of plasminogen binding with respect to Leishmania pathogenesis has not been established definitively. 52 ) Proteomic analysis indicates that . LLO is represented as small hook-shaped symbols, the long arm of which being the membrane-insinuating region, containing the cholesterol-binding motif.…”

Section: Apoptotic Mimicrymentioning

confidence: 99%

Exploiting death: apoptotic immunity in microbial pathogenesis

Ucker

2016

Cell Death Differ

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Innate immunity typically is responsible for initial host responses against infections. Independently, nucleated cells that die normally as part of the physiological process of homeostasis in mammals (including humans) suppress immunity. Specifically, the physiological process of cell death (apoptosis) generates cells that are recognized specifically by viable cells of all types and elicit a profound transient suppression of host immunity (termed 'innate apoptotic immunity' (IAI)). IAI appears to be important normally for the maintenance of self-tolerance and for the resolution of inflammation. In addition, pathogens are able to take advantage of IAI through a variety of distinct mechanisms, to enable their proliferation within the host and enhance pathogenicity. For example, the protist pathogen Leishmania amazonensis, at its infective stage, mimics apoptotic cells by expressing apoptotic-like protein determinants on the cell surface, triggering immunosuppression directly. In contrast, the pathogenic bacterium Listeria monocytogenes triggers cell death in host lymphocytes, relying on those apoptotic cells to suppress host immune control and facilitate bacterial expansion. Finally, although the inhibition of apoptotic cell death is a common attribute of many viruses which facilitates their extended replication, it is clear that adenoviruses also reprogram the non-apoptotic dead cells that arise subsequently to manifest apoptotic-like immunosuppressive properties. These three instances represent diverse strategies used by microbial pathogens to exploit IAI, focusing attention on the potency of this facet of host immune control. Further examination of these cases will be revealing both of varied mechanisms of pathogenesis and the processes involved in IAI control.

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A study of cutaneous lesions caused by Leishmania mexicana in plasminogen-deficient mice

Cited by 32 publications

References 31 publications

The Oligopeptidase B of Leishmania Regulates Parasite Enolase and Immune Evasion

The Oligopeptidase B of Leishmania Regulates Parasite Enolase and Immune Evasion

Interaction with human plasminogen system turns on proteolytic activity in Streptococcus agalactiae and enhances its virulence in a mouse model

Exploiting death: apoptotic immunity in microbial pathogenesis

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