Investigations into the Epidemiology, Diagnostics and Pathogenic mechanisms of Leptospirosis

Schuller, Simone (2018). Investigations into the Epidemiology, Diagnostics and Pathogenic mechanisms of Leptospirosis. (Habilitation, Universität Bern, Vetsuisse Fakutät Bern)

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Leptospirosis is considered one of the most widespread zoonoses worldwide affecting a broad range of warm and cold-blooded animals. It represents a major public health issue in tropical and subtropical countries. While human leptospirosis remains rare in Switzerland, a dramatic increase in the incidence of canine leptospirosis was documented between 2003 and 2012. Moreover, a previously uncommon, severe form of leptospirosis associated with pulmonary haemorrhage emerged during this period and led to high morbidity amongst dogs. This form of leptospirosis also affects many other species and has become the major cause of mortality from leptospirosis in humans. The pathogenic mechanisms of leptospiral pulmonary haemorrhage syndrome (LPHS) are poorly understood hampering the application of efficient treatment strategies.
With the backdrop of these events, an urgent need to better understand the epidemiology of canine leptospirosis, to validate rapid diagnostic tools and to better understand the pathogenic mechanisms leading to pulmonary haemorrhage was identified and collaborations established to tackle these important questions.
The results of these studies are included in this habilitation.
We demonstrated that despite a very high incidence of acute canine leptospirosis in Switzerland, the prevalence of anti-leptospiral antibodies in the overall canine population is in the mid-range (24%) to what has been described in other areas in Europe (6-49%). Dogs in Switzerland rarely showed evidence of urinary shedding of pathogenic Leptospira spp. (0.001%) and thus probably do not significantly contribute to the spread of Leptospria in the environment. In contrast, dogs in Ireland, showed a much higher rate of urinary shedding (7.8%).These studies showed that there are regional differences in the epidemiology leptospirosis even across Europe, and that the role of the dog in the disease transmission may vary depending on the prevailing serovars in any given region.
Early confirmation of acute leptospirosis is important because of its zoonotic potential. Patient side tests to detect anti-leptospiral IgM have recently become commercially available and claim to have a higher sensitivity in early infection than the gold standard microscopic agglutination test (MAT) because of the early occurrence of IgM in patient serum. Demonstrated that the diagnostic accuracy of two commercial patient side tests, is similar to that of the MAT and thus can be helpful tools in the management of patients suspected to have leptospirosis.
An important part of this work was dedicated to establish the dog as a natural disease model for leptospirosis and LPHS and to further elucidate the pathogenic mechanism of LPHS. Initially we investigated the hypothesis that LPHS in in part mediated by the host immune system. Indeed, we were able to demonstrate deposition of IgG and IgM on alveolar walls of canine patients with LPHS in the absence of leptospiral antigens, which suggests that host rather than leptospiral antigens are targeted by the immune response. However, further extensive work to identify potential autoreactive antigens has so far failed to confirm any specific targets. We therefore also applied a top down proteomics approach to generate new hypotheses. Comparative proteomic analysis of LPHS lung tissue of experimentally infected guinea pigs demonstrated a significant decrease in abundance of proteins involved in the cytoskeleton and cellular organisation, many of them being involved in the maintenance of the endothelial barrier function, thus suggesting a role of the endothelium in the pathogenesis of LPHS.
To further investigate the role of endothelial cell activation and dysfunction in LPHS in vivo, we have validated a human ELISA for measurement of canine Angiopoietin-2. Angiopoietin-2 is an important marker of endothelial cell dysfunction and was significantly elevated in a validation population of dogs with sepsis and systemic inflammatory response syndrome. Furthermore, protocols were established to isolate canine aortic endothelial cells, which represents another important research tool to investigate endothelial dysfunction in leptospirosis using the dog as a natural disease model.
With these tools in place we are now able to study endothelial responses during infection with Leptospira spp both in vitro and in vivo and are currently focussing on the role of the endothelial adherence junction in the breakdown of the endothelial barrier function in LPHS.

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