Circulating foamy macrophages in the Golden Syrian Hamster model of Leptospirosis

Authors: Putz, Ellie; ANDREASEN, CLAIRE - Iowa State University; Stasko, Judith; FERNANDES, LUIS - Butantan Institute; Palmer, Mitchell; RAUH, MICHAEL - Queen'S University - Canada; Nally, Jarlath

Submitted to: Journal of Comparative Pathology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/15/2021
Publication Date: 11/18/2021
Citation: Putz, E.J., Andreasen, C.B., Stasko, J.A., Fernandes, L.G., Palmer, M.V., Rauh, M.J., Nally, J.E. 2021. Circulating foamy macrophages in the Golden Syrian Hamster model of Leptospirosis. Journal of Comparative Pathology. 189(10):98-109. https://doi.org/10.1016/j.jcpa.2021.10.004.
DOI: https://doi.org/10.1016/j.jcpa.2021.10.004

Interpretive Summary: Leptospirosis is a global zoonotic neglected tropical disease that affects humans, companion animals, and all major livestock species. Leptospira bacteria colonize the kidneys of infected hosts where they are shed in urine and can be subsequently excreted into the environment facilitating indirect exposure, or can be transferred directly to other individuals. Asymptomatic reservoir hosts, such as the rat, are the primary vessel for disease transmission. Vaccines do exist for leptospirosis (vaccination is a common practice for many companion animal and livestock species) but the commercial vaccines available suffer from poor cross protection across the many species and serovars of Leptospira that pose infection risk. While the rat is the most classic asymptomatic carrier of leptospirosis, a high level of species specificity (both bacteria and host) plays a major role in the severity of disease presentation which can vary from asymptomatic to flu-like symptoms to organ failure and death. Research revolving around leptospirosis instead typically relies on the Golden Syrian hamster model as it is susceptible to most species and serovar of pathogenic Leptospira, and thus, better suited to measure parameters of clinical disease. This susceptibility is also utilized for testing leptospirosis vaccine efficacy resulting in all commercial mandatory vaccine testing relying on the hamster model. Despite heavy reliance on the hamster model of leptospirosis, we know remarkably little about the immune response of the hamster to leptospiral disease challenge. In this study, we looked at manual differential cell counts of immune cells in whole blood after challenge with several species and strains Leptospira. During this analysis large lipid filled cells were identified closest in the literature to ‘foamy macrophages’ (FM). After additional characterization using Scanning and Transmission Electron Microscopy (SEM and TEM), pathologists confirmed the FM phenotype. This finding challenges the classic immune dogma dictating that only monocytes are found circulating in blood while macrophages are found in tissues. FM cells are articulated in the literature, found in select tissues after leptospirosis challenge, or best associated with tuberculosis granulomas. Identifying this rare cell type in a circulating blood phenotype offers a unique model for the study and characterization of FM cells. Additionally, the FM appearance in the hamster model of leptospirosis suggests a critical need to evaluate the biological significance in the context of vaccine testing, and suggests a potential diagnostic tool that should be evaluated in alternative animal models.

Technical Abstract: Leptospirosis is world-wide zoonotic disease caused by pathogenic Leptospira. Symptoms can range from asymptomatic, to flu-like, to multi-organ failure and death in severe cases. While species and strain specificity can play a large role in disease presentation, the hamster is susceptible to most leptospiral infections and the model of choice for vaccine efficacy testing. Understanding the pathophysiologic mechanisms of leptospirosis, characterizing the host immune response, the species/serovar/strain specific interactions between host and bacteria, and the mechanisms of pathogen escape from the host immune system are critical to understanding disease pathogenesis and development of prevention and treatment methods. During evaluation of blood smears from hamsters challenged with different species and strains of Leptospira, a circulating population of large, mononuclear, lipid-filled cells, most similar to foamy macrophages (FMs), was identified. FMs were identified by Giemsa stain and verified by scanning and transmission electron microscopy. FMs were found in the circulating blood of all Leptospira challenged hamsters, indicating the finding was not species or strain specific, although higher numbers of FMs did tend to correlate with severity of disease. The unique finding of circulating FMs in the hamster leptospirosis model can yield additional insights into the pathogenesis of leptospirosis and other diseases that induce FMs.