Destruction of the hepatocyte junction by intercellular invasion of Leptospira causes jaundice in a hamster model of Weil's disease

Abstract

Weil's disease, the most severe form of leptospirosis, is characterized by jaundice, haemorrhage and renal failure. The mechanisms of jaundice caused by pathogenic Leptospira remain unclear. We therefore aimed to elucidate the mechanisms by integrating histopathological changes with serum biochemical abnormalities during the development of jaundice in a hamster model of Weil's disease. In this work, we obtained three-dimensional images of infected hamster livers using scanning electron microscope together with freeze-cracking and cross-cutting methods for sample preparation. The images displayed the corkscrew-shaped bacteria, which infiltrated the Disse's space, migrated between hepatocytes, detached the intercellular junctions and disrupted the bile canaliculi. Destruction of bile canaliculi coincided with the elevation of conjugated bilirubin, aspartate transaminase and alkaline phosphatase levels in serum, whereas serum alanine transaminase and γ-glutamyl transpeptidase levels increased slightly, but not significantly. We also found in ex vivo experiments that pathogenic, but not non-pathogenic leptospires, tend to adhere to the perijunctional region of hepatocyte couplets isolated from hamsters and initiate invasion of the intercellular junction within 1 h after co-incubation. Our results suggest that pathogenic leptospires invade the intercellular junctions of host hepatocytes, and this invasion contributes in the disruption of the junction. Subsequently, bile leaks from bile canaliculi and jaundice occurs immediately. Our findings revealed not only a novel pathogenicity of leptospires, but also a novel mechanism of jaundice induced by bacterial infection.

Leptospirosis in Humans

“…Immunohistochemistry studies have documented large numbers of leptospires between hepatocytes in animal models. A recent, elegant study has documented leptospiral infiltration of Disse’s space and preferential leptospiral attachment to and invasion of the perijunctional region between hepatocytes (Miyahara et al 2014). Additionally, hepatocyte apoptosis has been documented in leptospirosis (Merien et al 1998).…”

Spirochete Flagella and Motility

“…These results suggest that LPS is responsible for crawling, serving as one of the adhesins anchoring the cell to the surface (Figure 5b-d) [73]. Electron microscopic observation of a hamster liver infected by pathogenic leptospires showed entry of leptospiral cells into the intercellular junction of hepatocytes [100], implying that leptospiral pathogenicity could involve adherence of spirochetes to host cells, followed by crawling (discussed in Section 7).…”

The Spiraling Case of a Yellow Chef: Isolated Hyperbilirubinemia

“…Jaundice in leptospirosis is a unique feature that remains incompletely understood; however intrahepatic cholestasis, duodenitis resulting in ampulla of Vater obstruction, and indirect hyperbilirubinemia from hemorrhage have all been described as causes of jaundice with this condition [13]. In mouse models, Leptospira bacteria have been seen to invade the intercellular junctions of host hepatocytes resulting in disruption of cellular junctions within bile canaliculi [14]. While awareness of the disease and a high clinical suspicion is required to identify this condition in a timely fashion, liver biopsy can be helpful, as this may reveal congested sinusoids, leptospiral attachment to and invasion of the perijunctional region between hepatocytes, and a lack of normal adhesion between hepatocytes with hepatocyte apoptosis.…”