Immunosuppressive and angiogenic cytokine profile associated with Bartonella bacilliformis infection in post-outbreak and endemic areas of Carrion's disease in Peru.

Maria J Pons,Cláudia Gomes,Gemma Moncunill,Diana Barrios,Ruth Aguilar,Carlota Dobaño,Miguel Angel Aguilar-Luis,Juana Del Valle-Mendoza,Joaquim Ruiz,Melissa J Caimano

doi:10.1371/journal.pntd.0005684

Abstract

Analysis of immune responses in Bartonella bacilliformis carriers are needed to understand acquisition of immunity to Carrion’s disease and may allow identifying biomarkers associated with bacterial infection and disease phases. Serum samples from 144 healthy subjects from 5 villages in the North of Peru collected in 2014 were analyzed. Four villages had a Carrion’s disease outbreak in 2013, and the other is a traditionally endemic area. Thirty cytokines, chemokines and growth factors were determined in sera by fluorescent bead-based quantitative suspension array technology, and analyzed in relation to available data on bacteremia quantified by RT-PCR, and IgM and IgG levels measured by ELISA against B. bacilliformis lysates. The presence of bacteremia was associated with low concentrations of HGF (p = 0.005), IL-15 (p = 0.002), IL-6 (p = 0.05), IP-10 (p = 0.008), MIG (p = 0.03) and MIP-1α (p = 0.03). In multi-marker analysis, the same and further TH1-related and pro-inflammatory biomarkers were inversely associated with infection, whereas angiogenic chemokines and IL-10 were positively associated. Only EGF and eotaxin showed a moderate positive correlation with bacteremia. IgM seropositivity, which reflects a recent acute infection, was associated with lower levels of eotaxin (p = 0.05), IL-6 (p = 0.001), and VEGF (p = 0.03). Only GM-CSF and IL-10 concentrations were positively associated with higher levels of IgM (p = 0.01 and p = 0.007). Additionally, IgG seropositivity and levels were associated with high levels of angiogenic markers VEGF (p = 0.047) and eotaxin (p = 0.006), respectively. Our findings suggest that B. bacilliformis infection causes immunosuppression, led in part by overproduction of IL-10. This immunosuppression probably contributes to the chronicity of asymptomatic infections favoring B. bacilliformis persistence in the host, allowing the subsequent transmission to the vector. In addition, angiogenic markers associated with bacteremia and IgG levels may be related to the induction of endothelial cell proliferation in cutaneous lesions during chronic infections, being possible candidate biomarkers of asymptomatic infections.

Highlights

Carrion’s disease (CD) (ORPHANET 64692) is a tropical, neglected poorest-linked illness, endemic in low-income areas of Peru, and affecting specific areas of Ecuador and Colombia, with sporadic cases reported in Bolivia and Chile [1]
This illness consist in two distinct phases, the Oroya fever and Peruvian wart, but exist a high percentage of asymptomatic carriers in endemic areas that should be detected in order to perform correct surveillance and control
This study identified serum biomarkers associated with Carrion’s disease asymptomatic infections

Summary

Introduction

Carrion’s disease (CD) (ORPHANET 64692) is a tropical, neglected poorest-linked illness, endemic in low-income areas of Peru, and affecting specific areas of Ecuador and Colombia, with sporadic cases reported in Bolivia and Chile [1]. B. bacilliformis is an intracellular pathogen that invades mainly erythrocytes and vascular endothelial cells [7]. B. bacilliformis is transmitted by the bite of sand flies (members of the genus Lutzomyia) and no reservoir has been identified other than humans, making it an eradicable disease [1,8]. CD is located in a restricted area, but in this era of globalization a future expansion to other areas cannot be ruled out, as has been described for other neglected diseases [8]. The infection is diagnosed by blood smear but this has several limitations including low sensitivity [9,10] and diagnosis error [11]

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Discussion

Conclusion