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

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.

Carrion's Disease: the Sound of Silence

“…The transient depression of the cellular immunity that occurs during the acute hematic phase is of note (200), with patients presenting lymphopenia with a decrease in CD4 ϩ and a slight increase of CD8 ϩ T lymphocytes. Recent data support the possibility that this immunosuppression remains long after the end of the acute phase (190). These findings may reflect an immune tolerance (lack of a specific immune response to an antigen) which might be triggered by B. bacilliformis, leading to an immune evasion and installation of persistent bacteremia.…”

“…Significantly elevated IFN-␥ and IL-4 levels were reported in 21 patients in the chronic phase of the disease (187). Interestingly, for healthy preexposed and asymptomatic carriers it was observed that those having elevated IgG levels were more prone to have high eotaxin levels (P ϭ 0.006), while IgG seropositivity was correlated with VEGF levels (P ϭ 0.047), both of which are involved in angiogenic processes (190).…”

“…The elevated IL-10 secretion leads to an immune peripheral tolerance which greatly favors asymptomatic infection and persistent infection (158,188,189). An analysis of up to 30 different cytokines and chemokines from inhabitants of both postoutbreak areas and areas of endemicity showed the presence of significant differences in some cytokine levels related to the presence or absence of asymptomatic bacteremia and immunoglobulin M (IgM) and IgG levels (190). Thus, in asymptomatic carriers, lower levels of hepatocyte growth factor (HGF) (P ϭ 0.005), IL-15 (P ϭ 0.002), IL-6 (P ϭ 0.05), IFN-␥-inducible protein 10 (IP-10) (P ϭ 0.008), MIG (P ϭ 0.03), and MIP-1␣ (P ϭ 0.03) were observed, showing a trend to higher IL-1RA levels (P ϭ 0.059).…”

“…HGF, IL-15, IP-10, MIG, and MIP-1␣ have been shown to be involved in inflammatory processes and T cell and NK cell activation (191)(192)(193). Thus, this cytokine profile leads to attenuation of inflammatory processes as well as a reduction in the immune response (190). In the same study, a multimarker analysis developed to show an association with the presence of markers found that HGF, IL-6, IL-15, and IP-10, as well as granulocyte colonystimulating factor (G-CSF), IFN-␥, MIG, MIP-1␣, and RANTES, were negatively associated with the presence of asymptomatic bacteremia, while IL-2, IL-8, IL-10, MCP-1, MIP-1␤, and tumor necrosis factor (TNF) had a positive association (190).…”

Molecular prevalence of Bartonella, Babesia, and hemotropic Mycoplasma species in dogs with hemangiosarcoma from across the United States

“…In vitro, B. henselae induces angiogenesis and proliferation of endothelial cells in part by stimulating production of VEGF. [23][24][25]31,53,54] It is well established that Bartonella spp. cause the non-neoplastic endothelial proliferative disorders bacillary angiomatosis and peliosis hepatis in humans, and there have also been rare reports of these conditions in dogs infected with Bartonella spp.…”