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Chronic Systemic Infection of Mice with Leishmania infantum Leads to Increased Bone Mass
Chaobo Lai1,2, Jennifer Heinemann1, Ulrike Schleicher1,3
1Mikrobiologisches Institut-Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany.
Abstract:
Vector-borne infections of humans with the protozoan parasite Leishmania (L.) infantum can cause a systemic and potentially lethal disease termed visceral leishmaniasis. In the corresponding mouse model, an intravenous infection with L. infantum leads to the persistence of parasites in various organs, including bone marrow (BM). Considering the anatomical proximity between the BM and the cortical bone, we investigated whether a chronic infection with L. infantum affected bone homeostasis. Unexpectedly, chronic infection with L. infantum caused an increase in bone mass in mice. In vivo, an increased number of osteoblasts and osteocytes and a decreased maturation of osteoclasts characterized the phenotype. Confocal laser scanning fluorescence microscopy confirmed the infection of BM macrophages but also revealed the presence of parasites in osteoclasts. In vitro, mature osteoclasts took up L. infantum parasites. However, infection of osteoclast progenitors abolished their differentiation and function. In addition, secretory products of infected BM-derived macrophages inhibited the maturation of osteoclasts. Both in vitro and in vivo, infected macrophages and osteoclasts showed an enhanced expression of the anti-osteoclastogenic chemokine CCL5 (RANTES). Neutralization of CCL5 prevented the inhibition of osteoclast generation seen in the presence of culture supernatants from L. infantum-infected macrophages. Altogether, our study shows that chronic infection with Leishmania increases bone mass by inducing bone formation and impairing osteoclast differentiation and function. © 2022 American Society for Bone and Mineral Research (ASBMR).
Insights
Chronic Leishmania infantum infection unexpectedly increases bone mass in mice. This occurs by boosting bone formation and hindering osteoclast development and function, impacting bone homeostasis.
Area of Science:
- Immunology
- Infectious Diseases
- Bone Biology
Background:
- Visceral leishmaniasis, caused by Leishmania (L.) infantum, is a severe systemic infection.
- L. infantum infection in mice leads to parasite persistence in organs like the bone marrow (BM).
- The impact of chronic L. infantum infection on bone homeostasis, particularly near the BM, was unexplored.
Purpose of the Study:
- To investigate the effects of chronic Leishmania (L.) infantum infection on bone homeostasis.
- To determine if L. infantum infection influences bone formation and resorption processes.
- To elucidate the mechanisms by which L. infantum might affect bone cells.
Main Methods:
- In vivo mouse models of chronic L. infantum infection.
- Confocal laser scanning fluorescence microscopy to detect parasites in bone cells.
- In vitro studies using osteoclast progenitors and bone marrow-derived macrophages.
- Analysis of osteoblast and osteoclast numbers and function.
- Assessment of chemokine CCL5 (RANTES) expression and function.
Main Results:
- Chronic L. infantum infection led to a significant increase in bone mass in mice.
- Increased numbers of osteoblasts and osteocytes were observed, alongside decreased osteoclast maturation.
- Parasites were found in osteoclasts and BM macrophages; infected osteoclast progenitors showed impaired differentiation.
- Secretory products from infected macrophages inhibited osteoclast maturation.
- Enhanced CCL5 (RANTES) expression in infected macrophages and osteoclasts was linked to impaired osteoclastogenesis.
Conclusions:
- Chronic Leishmania infection paradoxically increases bone mass by stimulating bone formation.
- The parasite impairs osteoclast differentiation and function, contributing to increased bone density.
- CCL5 plays a crucial role in mediating the anti-osteoclastogenic effects of infected macrophages.
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