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Differential Gene Expression and Infection Profiles of Cutaneous and Mucosal Leishmania braziliensis Isolates from the Same Patient

Differential Gene Expression and Infection Profiles of Cutaneous and Mucosal Leishmania braziliensis Isolates from the Same Patient

Authors :
Ángelez López-Gonzálvez
Manoel Barral-Netto
Patrícia de Cássia Ruy
Viviane Boaventura
Arthur Henrique Cavalcante de Oliveira
Tiago R. Ferreira
Angela K. Cruz
José César Rosa
Aldina Barral
Coral Barbas
Eliza V. C. Alves-Ferreira
Ramon de Freitas Santos
Camila F. Pinzan
Juliano Simões de Toledo
David Rojo
Source :
PLoS Neglected Tropical Diseases, Vol 9, Iss 9, p e0004018 (2015), Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual), Universidade de São Paulo (USP), instacron:USP, PLoS Neglected Tropical Diseases
Publication Year :
2015
Publisher :
Public Library of Science (PLoS), 2015.

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. Methodology/Principal Findings 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/Significance 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.<br />Author Summary Leishmaniasis is a critical public health problem worldwide. The clinical outcome of leishmaniasis depends on the infecting parasite species, host genetics and immune response and insect species. Leishmania braziliensis is a major etiological agent of cutaneous and mucosal leishmaniasis in Brazil. Fewer than 10% of L. braziliensis-infected patients with CL develop the mucosal form (a severe clinical manifestation). The small number of parasites in the mucosae increases the difficulty of obtaining clinical isolates, and parasite samples are frequently derived from individuals with different genetic backgrounds. Therefore, clinical isolates from cutaneous and mucosal sites from the same patient represent unique tools to understand parasite factors that contribute to disease outcome and pathogenesis. In this study, we investigated parasite factors involved in disease progression using two pairs of L. (V.) braziliensis isolates from mucosal (LbrM) and cutaneous (LbrC) sites of the same patient. In conclusion, the murine infection and proteome and metabolome data suggest that the differences between the cutaneous and mucosal isolates are mainly related to inflammation and chemotaxis. Our data also suggest that the LbrPGF2S protein plays a role in parasite virulence in the mammalian host.

Details

Language :
English
ISSN :
19352735 and 19352727
Volume :
9
Issue :
9
Database :
OpenAIRE
Journal :
PLoS Neglected Tropical Diseases
Accession number :
edsair.doi.dedup.....bf3cd131290f58ac78d7ae3be8dbcc98