22-ICRAD Call 2 Comparative host and species-specific immune responses of macrophages infected with zoonotic Leptospira interrogans

The "One Health" concept recognizes that human, animal, and environment health are closely interrelated. Leptospira interrogans are the
causative bacterial agent of leptospirosis, an emerging zoonotic disease affecting humans and animals, worldwide. Pathogenic leptospires
present in the environment can infect a broad range of hosts and the disease may appear as an acute, even fatal infection in accidental
hosts, such as humans or livestock, or progress into a chronic, mainly asymptomatic infection in its natural hosts, such as mice and rats. In
cattle, leptospirosis is responsible for high economic losses due to reduction in both, dairy and beef industry, and to high abortion rates.To
improve on this, it is imperative to understand the innate immune responses elicited in different hosts, as this is key to understand the
diverse disease outcomes seen in the different hosts. Many immunological experiments conducted in mice have allowed the understanding
of some aspects of the immune responses during leptospirosis. However, our recent work has shown clear differences in the response seen
in other mammalian hosts such as human and cattle. In this proposal we aim to apply a comparative analysis of the innate immune
responses elicited by macrophages from divergent hosts such as bovines, pigs, mice, hamsters, and humans upon infection with various
zoonotic Leptospira strains that were responsible for distinct outcomes of disease. The goal of this project will be to understand differential
and specific immunological processes and pathways. More specifically, we aim to compare some Toll-like receptors recognition of
membrane components of leptospires, using structural, biochemical, genomic, immunological, high content screening confocal microscopy
and computational modelling approaches. This project should help to better understand the innate immune mechanisms driving host
specificities of leptospirosis, and accordingly tailor host directed intervention strategies.

We aim in this innovative project to address the question of host- and species-specificity of leptospirosis, from an innate immunity point of
view. We will test the hypothesis that host adaptation of leptospires relies on the species specificities of both bacterial components and host
innate immune receptors. To the best of our knowledge this hypothesis has never been formulated. Our consortium will study, using
different complementary approaches, these interactions in the context of different hosts and leptospiral serovars. It will expand the
fragmented knowledge, mainly obtained from mice and humans, to bovine, pigs, hamsters, rats and horses, presenting a large array of
clinical symptoms of leptospirosis. Moreover, the known data only emanates from a few emblematic Leptospira strains grown in vitro, all
isolated from human patients and sometimes passaged in hamster. Here, we will expand the study to Argentinian strains retrieved from
cattle. We also aim to get physiologic data, by directly studying at the mRNA expression level, or at a structural level, the bacterial
components in contact of primary macrophages from relevant hosts.
The quality of the consortium relies on previous achievements of the PIs, all internationally recognized experts in their field,
and to our complementarity. We think that this project in line with the "One health" approach will bring novel data on the
relationship of Leptospira with their hosts. We hope that it could also shed light on the diverse symptoms of leptospirosis
observed in various animals. Finally, this project could set the basis of new perspectives of host-directed strategies to
stimulate the innate immune system and fight leptospirosis and overcome the potent strategies of leptospires to escape the
host defenses.