Trypanosoma brucei brucei: Biochemical characterization of ecto-nucleoside triphosphate diphosphohydrolase activities

Leite, Milane de Souza; Thomaz, Rachel; Fonseca, Fabiana Valéria da; Panizzutti, Rogério; Vercesi, Anı́bal E.; Meyer‐Fernandes, José Roberto

doi:10.1016/j.exppara.2006.09.002

Cited by 45 publications

(38 citation statements)

References 51 publications

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“…While the parasite is a purine auxotroph and may utilize some of the adenosine produced for growth, free adenosine may also play a secondary role as a mediator of immune suppression. The trypanosomes Leishmania and S. mansoni have all been shown experimentally to hydrolyze AMP to generate adenosine at the surface of the parasite (13,47,118,132), suggesting a similar role for the enzyme in these organisms. Of particular interest is the observation that C57BL/6 mice are able to control infection by L. braziliensis but develop chronic lesions when infected with L. amazonensis (98).…”

Section: Adenosine Generation By Pathogensmentioning

confidence: 99%

“…One explanation may be that in all three trypanosome species in which NTPDases have been studied, the enzymes hydrolyze ATP preferentially, resulting in liberation of ADP and transient platelet activation. Although preferential ATPase activity would provide ADP for activation of P2Y 1 and P2Y 12 receptors, ADP hydrolysis by these enzymes is nevertheless still relatively efficient (47,57,59). Again, more work is needed to clarify the contribution of NTPDases to platelet responses during infection.…”

Section: Interference With P2 Receptor Signaling By Parasitesmentioning

confidence: 99%

“…The genome of T. brucei encodes a putative secreted NTPDase, and assays using intact parasites demonstrate that T. brucei exhibits Mg 2ϩ -dependent surface-located NTPDase activity that hydrolyzes ATP, GTP, CTP, UTP, and ADP. Interestingly, catalytic activity may be stimulated by other divalent cations, including zinc (47).…”

Section: Trypanosomatidsmentioning

confidence: 99%

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Possible Effects of Microbial Ecto-Nucleoside Triphosphate Diphosphohydrolases on Host-Pathogen Interactions

Sansom

Robson

Hartland

2008

Microbiol Mol Biol Rev

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SUMMARYIn humans, purinergic signaling plays an important role in the modulation of immune responses through specific receptors that recognize nucleoside tri- and diphosphates as signaling molecules. Ecto-nucleoside triphosphate diphosphohydrolases (ecto-NTPDases) have important roles in the regulation of purinergic signaling by controlling levels of extracellular nucleotides. This process is key to pathophysiological protective responses such as hemostasis and inflammation. Ecto-NTPDases are found in all higher eukaryotes, and recently it has become apparent that a number of important parasitic pathogens of humans express surface-located NTPDases that have been linked to virulence. For those parasites that are purine auxotrophs, these enzymes may play an important role in purine scavenging, although they may also influence the host response to infection. Although ecto-NTPDases are rare in bacteria, expression of a secreted NTPDase in Legionella pneumophila was recently described. This ecto-enzyme enhances intracellular growth of the bacterium and potentially affects virulence. This discovery represents an important advance in the understanding of the contribution of other microbial NTPDases to host-pathogen interactions. Here we review other progress made to date in the characterization of ecto-NTPDases from microbial pathogens, how they differ from mammalian enzymes, and their association with organism viability and virulence. In addition, we postulate how ecto-NTPDases may contribute to the host-pathogen interaction by reviewing the effect of selected microbial pathogens on purinergic signaling. Finally, we raise the possibility of targeting ecto-NTPDases in the development of novel anti-infective agents based on potential structural and clear enzymatic differences from the mammalian ecto-NTPDases.

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Section: Adenosine Generation By Pathogensmentioning

confidence: 99%

Section: Interference With P2 Receptor Signaling By Parasitesmentioning

confidence: 99%

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Possible Effects of Microbial Ecto-Nucleoside Triphosphate Diphosphohydrolases on Host-Pathogen Interactions

Sansom

Robson

Hartland

2008

Microbiol Mol Biol Rev

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“…The competitive index (CI) was calculated as the proportion of mutant to wild type bacteria recovered from mice divided by the proportion of mutant to wild type bacteria in the inoculum (41). (28,(42)(43)(44), but Zn 2ϩ has also been shown to stimulate ecto-NTPDase activity of Trypanosoma brucei (27). In contrast, ecto-NTPDase activity of Leishmania spp.…”

Section: ј-Cgcaacagctggtatggcactactaccccaatcac-3јmentioning

confidence: 99%

Enzymatic Properties of an Ecto-nucleoside Triphosphate Diphosphohydrolase from Legionella pneumophila

Sansom

Riedmaier

Newton

et al. 2008

Journal of Biological Chemistry

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Legionella pneumophila is the predominant cause of Legionnaires disease, a severe and potentially fatal form of pneumonia. Recently, we identified an ecto-nucleoside triphosphate diphosphohydrolase (NTPDase) from L. pneumophila, termed Lpg1905, which enhances intracellular replication of L. pneumophila in eukaryotic cells. Lpg1905 is the first prokaryotic member of the CD39/NTPDase1 family of enzymes, which are characterized by the presence of five apyrase conserved regions and the ability to hydrolyze nucleoside tri-and diphosphates. Here we examined the substrate specificity of Lpg1905 and showed that apart from ATP and ADP, the enzyme catalyzed the hydrolysis of GTP and GDP but had limited activity against CTP, CDP, UTP, and UDP. Based on amino acid residues conserved in the apyrase conserved regions of eukaryotic NTPDases, we generated five site-directed mutants, Lpg1905E159A, R122A, N168A, Q193A, and W384A. Although the mutations E159A, R122A, Q193A, and W384A abrogated activity completely, N168A resulted in decreased activity caused by reduced affinity for nucleotides. When introduced into the lpg1905 mutant strain of L. pneumophila, only N168A partially restored the ability of L. pneumophila to replicate in THP-1 macrophages. Following intratracheal inoculation of A/J mice, none of the Lpg1905 mutants was able to restore virulence to an lpg1905 mutant during lung infection, thereby demonstrating the importance of NTPDase activity to L. pneumophila infection. Overall, the kinetic studies undertaken here demonstrated important differences to mammalian NTPDases and different sensitivities to NTPDase inhibitors that may reflect underlying structural variations.Legionella pneumophilia is the major causative agent of Legionnaires disease, a severe systemic disease characterized by acute pneumonia. During infection of the human lung, L. pneumophila is internalized by alveolar macrophages where the bacteria replicate within an intracellular vacuole that evades fusion with the endocytic pathway. Instead the L. pneumophila containing vacuole intercepts early secretory vesicles and following maturation exhibits properties of the endoplasmic reticulum (1-3). Establishment of the unique Legionella vacuole and the ability to replicate within eukaryotic cells requires the Dot/Icm type IV secretion system, which translocates bacterial effector proteins into the cytoplasm of the host cell (4 -7).The ability of L. pneumophila to replicate within mammalian cells appears to be a consequence of its association in the natural environment with free living protozoa. The three sequenced L. pneumophila genomes encode an unusually high number of proteins with similarity to eukaryotic proteins (8 -10), which may interfere with host cell processes by functional mimicry (11). We recently showed that Lpg1905 from L. pneumophila is a secreted member of the CD39/ NTPDase1 family of ecto-nucleoside triphosphate diphosphohydrolases (NTPDases; gene family ENTPD).5 NTPDases are extremely rare in bacteria, and Lpg1905 is the first prokaryotic...

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“…Neospora caninum, also an apicomplexan parasite, expresses a type I nucleoside triphosphate hydrolase [62]. Recently, ecto-ATPases have been identified in diverse trypanosomatids, including T. cruzi [63], T. rangeli [64], and T. brucei brucei [65]. While the physiological significance of some of these ecto-ATPases remains to be shown, virulent Leishmania amazonensis promastigotes can hydrolyze ATP by a Mgdependent ecto-ATPase more efficiently than avirulent promastigotes [66].…”

Section: Other Ectonucleotidases Produced By Parasitesmentioning

confidence: 99%

The P2X7 receptor and intracellular pathogens: a continuing struggle

Coutinho‐Silva

Corrêa

Sater

et al. 2009

Purinergic Signalling

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The purinergic receptor, P2X 7 , has recently emerged as an important component of the innate immune response against microbial infections. Ligation of P2X 7 by ATP can stimulate inflammasome activation and secretion of proinflammatory cytokines, but it can also lead directly to killing of intracellular pathogens in infected macrophages and epithelial cells. Thus, while some intracellular pathogens evade host defense responses by modulating with membrane trafficking or cell signaling in the infected cells, the host cells have also developed mechanisms for inhibiting infection. This review will focus on the effects of P2X 7 on control of infection by intracellular pathogens, microbial virulence factors that interfere with P2X 7 activity, and recent evidence linking polymorphisms in human P2X 7 with susceptibility to infection.

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Trypanosoma brucei brucei: Biochemical characterization of ecto-nucleoside triphosphate diphosphohydrolase activities

Cited by 45 publications

References 51 publications

Possible Effects of Microbial Ecto-Nucleoside Triphosphate Diphosphohydrolases on Host-Pathogen Interactions

Possible Effects of Microbial Ecto-Nucleoside Triphosphate Diphosphohydrolases on Host-Pathogen Interactions

Enzymatic Properties of an Ecto-nucleoside Triphosphate Diphosphohydrolase from Legionella pneumophila

The P2X7 receptor and intracellular pathogens: a continuing struggle

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