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Camila Santos

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Research paper thumbnail of Role of the Trypanosoma brucei natural cysteine peptidase inhibitor ICP in differentiation and virulence

Molecular Microbiology, 2007

ICP is a chagasin-family natural tight binding inhibitor of Clan CA, family C1 cysteine peptidase... more ICP is a chagasin-family natural tight binding inhibitor of Clan CA, family C1 cysteine peptidases (CPs). We investigated the role of ICP in Trypanosoma brucei by generating bloodstream form ICP-deficient mutants (Dicp). A threefold increase in CP activity was detected in lysates of Dicp, which was restored to the levels in wild type parasites by re-expression of the gene in the null mutant. Dicp displayed slower growth in culture and increased resistance to a trypanocidal synthetic CP inhibitor. More efficient exchange of the variant surface glycoprotein (VSG) to procyclin during differentiation from bloodstream to procyclic form was observed in Dicp, a phenotype that was reversed in the presence of synthetic CP inhibitors. Furthermore, we showed that degradation of anti-VSG IgG is abolished when parasites are pretreated with synthetic CP inhibitors, and that parasites lacking ICP degrade IgG more efficiently than wild type. In addition, Dicp reached higher parasitemia than wild type parasites in infected mice, suggesting that ICP modulates parasite infectivity. Taken together, these data suggest that CPs of T. brucei bloodstream form play a role in surface coat exchange during differentiation, in the degradation of internalized IgG and in parasite infectivity, and that their function is regulated by ICP.

Research paper thumbnail of Gene expression profile in long-term non progressor HIV infected patients: In search of potential resistance factors

Molecular Immunology, 2014

Long-term non-progressors (LTNP) represent a minority (1-5%) of HIV-infected individuals characte... more Long-term non-progressors (LTNP) represent a minority (1-5%) of HIV-infected individuals characterized by documented infection for more than 7-10 years, a stable CD4+ T cell count over 500/mm(3) and low viremia in the absence of antiretroviral treatment. Protective factors described so far such as the CCR5delta32 deletion, protective HLA alleles, or defective viruses fail to fully explain the partial protection phenotype. The existence of additional host resistance mechanisms in LTNP patients was investigated here using a whole human genome microarray study comparing gene expression profiles of unstimulated peripheral blood mononuclear cells from LTNP patients, HIV-1 infected patients under antiretroviral therapy with CD4+ T cell levels above 500/mm(3) (ST), as well as healthy individuals. Genes that were up- or downregulated exclusively in LTNP, ST or in both groups in comparison to controls were identified and classified in functional categories using Ingenuity Pathway Analysis. ST and LTNP patient groups revealed distinct genetic profiles, regarding gene number in each category and up- or downregulation of specific genes, which could have a bearing on the outcome of each group. We selected some relevant genes to validate the differential expression using quantitative real-time qRT-PCR. Among others, we found several genes related to the canonical Wnt/beta-catenin signaling pathway. Our results identify new possible host genes and molecules that could be involved in the mechanisms leading to the slower progression to AIDS and sustained CD4+ T cell counts that is peculiar to LTNP patients.

Research paper thumbnail of Role of chagasin-like inhibitors as endogenous regulators of cysteine proteases in parasitic protozoa

Parasitology Research, 2006

Page 1. Parasitol Res (2006) 99: 323–324 DOI 10.1007/s00436-006-0195-y REVIEW Camila C. Santos . ... more Page 1. Parasitol Res (2006) 99: 323–324 DOI 10.1007/s00436-006-0195-y REVIEW Camila C. Santos . Julio Scharfstein . Ana Paula C. de A. Lima Role of chagasin-like inhibitors as endogenous regulators of cysteine proteases in parasitic protozoa ...

Research paper thumbnail of Chagasin, the endogenous cysteine-protease inhibitor of Trypanosoma cruzi, modulates parasite differentiation and invasion of mammalian cells

Journal of Cell Science, 2005

Research paper thumbnail of The role of conserved residues of chagasin in the inhibition of cysteine peptidases

FEBS Letters, 2008

We have evaluated the roles of key amino acids to the action of the natural inhibitor chagasin of... more We have evaluated the roles of key amino acids to the action of the natural inhibitor chagasin of papain-family cysteine peptidases. A W93A substitution decreased inhibitor affinity for human cathepsin L 100-fold, while substitutions of T31 resulted in 10-100-fold increases in the K i for cruzipain of Trypanosoma cruzi. A T31A/T32A double mutant had increased affinity for cathepsin L but not for cruzipain, while the T31-T32 deletion drastically affected inhibition of both human and parasite peptidases. These differential effects reflect the occurrence of direct interactions between chagasin and helix 8 of cathepsin L, interactions that do not occur with cruzipain.

Research paper thumbnail of Role of the Trypanosoma brucei natural cysteine peptidase inhibitor ICP in differentiation and virulence

Molecular Microbiology, 2007

ICP is a chagasin-family natural tight binding inhibitor of Clan CA, family C1 cysteine peptidase... more ICP is a chagasin-family natural tight binding inhibitor of Clan CA, family C1 cysteine peptidases (CPs). We investigated the role of ICP in Trypanosoma brucei by generating bloodstream form ICP-deficient mutants (Dicp). A threefold increase in CP activity was detected in lysates of Dicp, which was restored to the levels in wild type parasites by re-expression of the gene in the null mutant. Dicp displayed slower growth in culture and increased resistance to a trypanocidal synthetic CP inhibitor. More efficient exchange of the variant surface glycoprotein (VSG) to procyclin during differentiation from bloodstream to procyclic form was observed in Dicp, a phenotype that was reversed in the presence of synthetic CP inhibitors. Furthermore, we showed that degradation of anti-VSG IgG is abolished when parasites are pretreated with synthetic CP inhibitors, and that parasites lacking ICP degrade IgG more efficiently than wild type. In addition, Dicp reached higher parasitemia than wild type parasites in infected mice, suggesting that ICP modulates parasite infectivity. Taken together, these data suggest that CPs of T. brucei bloodstream form play a role in surface coat exchange during differentiation, in the degradation of internalized IgG and in parasite infectivity, and that their function is regulated by ICP.

Research paper thumbnail of Gene expression profile in long-term non progressor HIV infected patients: In search of potential resistance factors

Molecular Immunology, 2014

Long-term non-progressors (LTNP) represent a minority (1-5%) of HIV-infected individuals characte... more Long-term non-progressors (LTNP) represent a minority (1-5%) of HIV-infected individuals characterized by documented infection for more than 7-10 years, a stable CD4+ T cell count over 500/mm(3) and low viremia in the absence of antiretroviral treatment. Protective factors described so far such as the CCR5delta32 deletion, protective HLA alleles, or defective viruses fail to fully explain the partial protection phenotype. The existence of additional host resistance mechanisms in LTNP patients was investigated here using a whole human genome microarray study comparing gene expression profiles of unstimulated peripheral blood mononuclear cells from LTNP patients, HIV-1 infected patients under antiretroviral therapy with CD4+ T cell levels above 500/mm(3) (ST), as well as healthy individuals. Genes that were up- or downregulated exclusively in LTNP, ST or in both groups in comparison to controls were identified and classified in functional categories using Ingenuity Pathway Analysis. ST and LTNP patient groups revealed distinct genetic profiles, regarding gene number in each category and up- or downregulation of specific genes, which could have a bearing on the outcome of each group. We selected some relevant genes to validate the differential expression using quantitative real-time qRT-PCR. Among others, we found several genes related to the canonical Wnt/beta-catenin signaling pathway. Our results identify new possible host genes and molecules that could be involved in the mechanisms leading to the slower progression to AIDS and sustained CD4+ T cell counts that is peculiar to LTNP patients.

Research paper thumbnail of Role of chagasin-like inhibitors as endogenous regulators of cysteine proteases in parasitic protozoa

Parasitology Research, 2006

Page 1. Parasitol Res (2006) 99: 323–324 DOI 10.1007/s00436-006-0195-y REVIEW Camila C. Santos . ... more Page 1. Parasitol Res (2006) 99: 323–324 DOI 10.1007/s00436-006-0195-y REVIEW Camila C. Santos . Julio Scharfstein . Ana Paula C. de A. Lima Role of chagasin-like inhibitors as endogenous regulators of cysteine proteases in parasitic protozoa ...

Research paper thumbnail of Chagasin, the endogenous cysteine-protease inhibitor of Trypanosoma cruzi, modulates parasite differentiation and invasion of mammalian cells

Journal of Cell Science, 2005

Research paper thumbnail of The role of conserved residues of chagasin in the inhibition of cysteine peptidases

FEBS Letters, 2008

We have evaluated the roles of key amino acids to the action of the natural inhibitor chagasin of... more We have evaluated the roles of key amino acids to the action of the natural inhibitor chagasin of papain-family cysteine peptidases. A W93A substitution decreased inhibitor affinity for human cathepsin L 100-fold, while substitutions of T31 resulted in 10-100-fold increases in the K i for cruzipain of Trypanosoma cruzi. A T31A/T32A double mutant had increased affinity for cathepsin L but not for cruzipain, while the T31-T32 deletion drastically affected inhibition of both human and parasite peptidases. These differential effects reflect the occurrence of direct interactions between chagasin and helix 8 of cathepsin L, interactions that do not occur with cruzipain.

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