Macrophages and Galectin 3 Control Bacterial Burden in Acute and Subacute Murine Leptospirosis That Determines Chronic Kidney Fibrosis.

María F Ferrer,Jarlath E Nally,Eugenio A Carrera Silva,Ana L Rípodas,Daniela P Montes De Oca,Ricardo Drut,Ricardo M Gómez,Ariel Nagel,Mirta Schattner,Nancy Charo,Emilia Scharrig

doi:10.3389/fcimb.2018.00384

Abstract

Previous studies have suggested that macrophages may contribute to acute Leptospira dissemination, as well as having a major role in kidney fibrosis. Our aim was to characterize the role of macrophages and galectin 3 (Gal-3) on the survival, clinical course, bacterial burden, interstitial nephritis, and chronic kidney fibrosis in Leptospira interrogans serovar Copenhageni (LIC)-induced experimental murine leptospirosis. C57BL/6J mice depleted of macrophages by liposome-encapsulated clodronate treatment and infected with LIC presented a higher bacterial burden, had reduced subacute nephritis and enhanced chronic kidney fibrosis relative to untreated, infected mice. Moreover, LIC infection in mice whose Gal-3 was disrupted (Lgals3−/–) had a higher bacterial burden and enhanced subacute nephritis and chronic kidney fibrosis when compared to C57BL/6J wild-type mice. Chronic fibrosis did not correlate with higher transcription levels of TGF-β1 or IL-13 in the kidneys. Kidney fibrosis was found in chronically infected rats as well as in wild infected rats. On the other hand, human fibroblast cultures exhibited enhanced differentiation to myofibroblasts after treatment with LIC. Our results demonstrate that macrophages and Gal-3 play a critical role in controlling the LIC burden but has a minor role in subsequent fibrosis. Instead, kidney fibrosis was better correlated with bacterial burden. Taken together, our results do not support a role for macrophages to disseminate leptospires during acute infection, nor in chronic kidney fibrosis.

Highlights

Leptospirosis is a global zoonosis caused by pathogenic spirochetes of the genus Leptospira that frequently occurs in tropical areas (Bharti et al, 2003)
The pathological score was further supported by CCL2 mRNA levels, used as an inflammatory marker, since expression levels were significantly lower in L. interrogans serovar Copenhageni (LIC) + liposome encapsulated clodronate (LipClod) treated animals compared to LIC infected animals (Figure 1G, P < 0.05)
We showed that macrophages and galectin 3 (Gal-3) play a major role in controlling the LIC burden and its associated inflammation, but they are not involved in subsequent fibrosis

Summary

Introduction

Leptospirosis is a global zoonosis caused by pathogenic spirochetes of the genus Leptospira that frequently occurs in tropical areas (Bharti et al, 2003). The pathogenesis of leptospirosis is not completely known (Haake and Levett, 2014). Pathogenic Leptospira spp. disseminate during the acute leptospiremic phase of infection that may affect kidney physiology (Wunder et al, 2016). The subacute leptospiruric phase begins 5–12 days later with an increase in specific antibodies that clear the bacteria from blood and other organs. Bacteria are not cleared from the kidneys, where they can chronically persist in the proximal tubules which results in shedding of leptospires into the urine for months producing a chronic inflammation and the host becomes a carrier that contaminates the environment with their urine (Haake and Levett, 2014)

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