title: Differential Gene Expression and Infection Profiles of Cutaneous and Mucosal Leishmania braziliensis Isolates from the Same Patient.
abstract: BACKGROUND
  Leishmaniasis is a complex disease in which clinical outcome depends on factors such as parasite species, host genetics and immunity and vector species. In Brazil, Leishmania (Viannia) braziliensis is a major etiological agent of cutaneous (CL) and mucosal leishmaniasis (MCL), a disfiguring form of the disease, which occurs in ~10% of L. braziliensis-infected patients. Thus, clinical isolates from patients with CL and MCL may be a relevant source of information to uncover parasite factors contributing to pathogenesis. In this study, we investigated two pairs of L. (V.) braziliensis isolates from mucosal (LbrM) and cutaneous (LbrC) sites of the same patient to identify factors distinguishing parasites that migrate from those that remain at the primary site of infection.
  
  
  RESULTS
  We observed no major genomic divergences among the clinical isolates by molecular karyotype and genomic sequencing. RT-PCR revealed that the isolates lacked Leishmania RNA virus (LRV). However, the isolates exhibited distinct in vivo pathogenesis in BALB/c mice; the LbrC isolates were more virulent than the LbrM isolates. Metabolomic analysis revealed significantly increased levels of 14 metabolites in LbrC parasites and 31 metabolites in LbrM parasites that were mainly related to inflammation and chemotaxis. A proteome comparative analysis revealed the overexpression of LbrPGF2S (prostaglandin f2-alpha synthase) and HSP70 in both LbrC isolates. Overexpression of LbrPGF2S in LbrC and LbrM promastigotes led to an increase in infected macrophages and the number of amastigotes per cell at 24-48 h post-infection (p.i.).
  
  
  CONCLUSIONS
  Despite sharing high similarity at the genome structure and ploidy levels, the parasites exhibited divergent expressed genomes. The proteome and metabolome results indicated differential profiles between the cutaneous and mucosal isolates, primarily related to inflammation and chemotaxis. BALB/c infection revealed that the cutaneous isolates were more virulent than the mucosal parasites. Furthermore, our data suggest that the LbrPGF2S protein is a candidate to contribute to parasite virulence profiles in the mammalian host.
authors.affiliation: Departamento de Biologia Celular e Molecular e Bioagentes Patogênicos, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brasil.
authors.forename: Eliza V C
authors.initials: EV
authors.lastname: Alves-Ferreira
authors.affiliation: Departamento de Biologia Celular e Molecular e Bioagentes Patogênicos, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brasil; Centro de Metabolómica y Bioanálisis (CEMBIO), Interacciones y Bioanálisis (UMIB), Universidad CEU San Pablo, Boadilla del Monte, Madrid, Spain.
authors.forename: Juliano S
authors.initials: JS
authors.lastname: Toledo
authors.affiliation: Departamento de Biologia Celular e Molecular e Bioagentes Patogênicos, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brasil; Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brasil.
authors.forename: Arthur H C
authors.initials: AH
authors.lastname: De Oliveira
authors.affiliation: Departamento de Biologia Celular e Molecular e Bioagentes Patogênicos, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brasil.
authors.forename: Tiago R
authors.initials: TR
authors.lastname: Ferreira
authors.affiliation: Departamento de Biologia Celular e Molecular e Bioagentes Patogênicos, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brasil.
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Ruy
authors.affiliation: Departamento de Biologia Celular e Molecular e Bioagentes Patogênicos, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brasil.
authors.forename: Camila F
authors.initials: CF
authors.lastname: Pinzan
authors.affiliation: Departamento de Biologia Celular e Molecular e Bioagentes Patogênicos, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brasil.
authors.forename: Ramon F
authors.initials: RF
authors.lastname: Santos
authors.affiliation: Centro de Pesquisas Gonçalo Moniz (CPqGM)-Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Bahia, Brasil; Faculdade de Medicina da Universidade Federal da Bahia, Salvador, Bahia, Brasil.
authors.forename: Viviane
authors.initials: V
authors.lastname: Boaventura
authors.affiliation: Centro de Metabolómica y Bioanálisis (CEMBIO), Interacciones y Bioanálisis (UMIB), Universidad CEU San Pablo, Boadilla del Monte, Madrid, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Rojo
authors.affiliation: Centro de Metabolómica y Bioanálisis (CEMBIO), Interacciones y Bioanálisis (UMIB), Universidad CEU San Pablo, Boadilla del Monte, Madrid, Spain.
authors.forename: Ángelez
authors.initials: Á
authors.lastname: López-Gonzálvez
authors.affiliation: Departamento de Biologia Celular e Molecular e Bioagentes Patogênicos, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brasil.
authors.forename: Jose C
authors.initials: JC
authors.lastname: Rosa
authors.affiliation: Centro de Metabolómica y Bioanálisis (CEMBIO), Interacciones y Bioanálisis (UMIB), Universidad CEU San Pablo, Boadilla del Monte, Madrid, Spain.
authors.forename: Coral
authors.initials: C
authors.lastname: Barbas
authors.affiliation: Centro de Pesquisas Gonçalo Moniz (CPqGM)-Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Bahia, Brasil; Faculdade de Medicina da Universidade Federal da Bahia, Salvador, Bahia, Brasil.
authors.forename: Manoel
authors.initials: M
authors.lastname: Barral-Netto
authors.affiliation: Centro de Pesquisas Gonçalo Moniz (CPqGM)-Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Bahia, Brasil; Faculdade de Medicina da Universidade Federal da Bahia, Salvador, Bahia, Brasil.
authors.forename: Aldina
authors.initials: A
authors.lastname: Barral
authors.affiliation: Departamento de Biologia Celular e Molecular e Bioagentes Patogênicos, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brasil.
authors.forename: Angela K
authors.initials: AK
authors.lastname: Cruz
mesh_terms: D000818:Animals; D001938:Brazil; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D006801:Humans; D007892:Leishmania braziliensis / Q000235:genetics* / Q000302:isolation & purification*; D007897:Leishmaniasis, Mucocutaneous / Q000382:microbiology* / Q000473:pathology; D055442:Metabolome; D008807:Mice, Inbred BALB C; D009092:Mucous Membrane / Q000382:microbiology* / Q000473:pathology; D020543:Proteome; D012867:Skin / Q000382:microbiology* / Q000473:pathology
chemical_list: D020543:Proteome