Leptospirosis Hemorrhage Is Tissue Specific and Requires the Localized Presence of the Bacterium

Leptospirosis continues to be a leading zoonotic infection in the world. Although hemorrhage, particularly pulmonary hemorrhage, is recognized as a major and lethal manifestation of severe leptospirosis, its underlying mechanism remains unclear. This study aimed to clarify the controversial role of locally deposited bacteria in leptospirosis hemorrhage employing a systematic animal model study.;Various levels of hemorrhage syndrome in five major organs (lung, heart, kidney, spleen and liver) were measured and compared. From the infection outcomes in the three models (Mongolian gerbil, guinea pig and mouse) infected by several leptospiral strains with difference in their virulence, lung, heart and kidney were pathologically prone for hemorrhage, while spleen and liver were not. We thus designated lung, heart and kidney as leptospirosis hemorrhage-susceptible organ, and spleen and liver as leptospirosis hemorrhage-resistant organ/tissue, hereafter. Then, the level of bleeding sensitivity of the three hemorrhage-susceptible organs was further assessed by quantitative analyses. Taken together, the rank of hemorrhage-susceptibility was lung > heart > kidney > spleen = liver.;As there was no bleeding in liver or spleen, we only explored the relationship of hemorrhage and the bacteria localized in hemorrhage-susceptible organs hereafter. Leptospires were detected in lung, heart and kidney once hemorrhage happened in four rodent models under most of different infection conditions. Furthermore, the level of bleeding in lung, heart and kidney increased or decreased as the number of leptospires increased or decreased in respective organs during the disease progress of gerbil model. The regional number of the bacteria was correlated with the intensity of the hemorrhagic lesions in lung, heart and kidney. These results demonstrated that leptospirosis bleeding was associated with topical leptospires in hemorrhage-susceptible organs.;Based on the bleeding sensitivity of rodent skin, subcutaneous bacterial inoculation was utilized to establish a condition of regional presence of leptospires in skin, and then the bleeding was determined. In guinea pig, gerbil and immuno-inhibited BABL/c mouse model, topical bacterium existence through subcutaneous inoculation of virulent serovar Lai induced localized dermal bleeding. In addition, other pathogenic strains inoculated in guinea pigs showed similar hemorrhage situations in skin to virulent serovar Lai. Furthermore, the bleeding in skin of guinea pigs was diminished when the regional bacterium number was decreased via topical treatment of erythromycin or lincomycin. Therefore, regional leptospires were essential for leptospirosis hemorrhage in skin.;Lung was selected for further evaluation of the essential role of local leptospira presence in hemorrhage using the combination of intraperitoneal and intratracheal routes. In both guinea pigs and BABL/c mice infected with virulent serovar Lai, the overpopulation of leptospires in lung was shown to increase the level of pulmonary hemorrhage in a dose-dependent manner, indicating that the increase of leptospira burden in lung increased the level of pulmonary hemorrhage.;Collectively, the discovery of differences of organs in leptospirosis hemorrhage-susceptibility and the essential requirement of locally existed bacteria for this severe manifestation, not only provided a novel direction for leptospirosis hemorrhage study but also a new insight for more proper and effective intervention of the disease.