Malaria Induces Chronic Bone Loss Even After Cure

Malaria infection can lead to an adverse balance in bone homeostasis, a process usually tightly controlled- by bone forming osteoblasts and bone resorbing osteoclasts, Osaka University researchers have found.

Malaria caused by Plasmodium parasites is a life-threatening infectious disease that kills at least half a million people annually while causing over 200 million new infections.

In some cases, complications can quickly develop such as cerebral malaria, respiratory distress and severe anemia, often leading to death. The majority of patients recover from disease, however, there is increasing evidence to suggest that survivors experience long-term ‘hidden’ pathologies due to infection that are as yet poorly defined.

Professor Cevayir Coban, corresponding author of the study, says:

“Even after a one time malaria infection (it does not matter if the disease is completely cured or chronic low level infection continues), substantial chronic bone loss occurs.”

Malaria Infection By-products

The Laboratory of Malaria Immunology Team at the Immunology Frontier Research Center (IFReC), Osaka University, headed by Dr. Coban, used mouse malaria models to show that robust immune activation and invasion of parasite by-products into the bone marrow during and after malaria infection leads to the adverse bone homeostasis balance.

Michelle Lee, a PhD candidate and the first author of the study explains,

“We found that Plasmodium products continuously accumulate in the bone marrow niche which turns the bone noticeably black in color, and results in it being “eaten-up” by bone resorbing cells known as osteoclasts, eventually disrupting bone homeostasis.

These products, including the major malarial by-product hemozoin, malarial proteins and as yet undefined virulence factors, induce MyD88-dependent inflammatory responses in osteoclast and osteoblast precursors, leading to increased RANKL expression (a key molecule inducing osteoclast differentiation), and over-stimulation of osteoclastogenesis favoring bone resorption”.

malaria boneloss

Credit: Osaka University

The team infected mice with a mutant Plasmodium parasite producing less by-products such as hemozoin, and discovered in this case bone loss did not occur, thereby confirming their findings.

Chronic Inflammation

Dr. Coban explains,

“Although chronic inflammatory conditions are known to facilitate bone disorders, our study -for the first time- shows that malaria can do the same thing, with hallmark “signatures” left in the bone tissue, a very unique feature of malaria infection. One may think that the infection has been completely cured by anti-malarial treatment, and be feeling fully recovered, however, sustained long-term accumulation of parasite by-products leave the bone in a state of chronic inflammation, leading to long term bone loss. This is particularly worrisome in the young of age, where it may cause growth problems and osteoporotic, fragile bones.”

Importantly, the study shows that there is a simple way to reverse the side effects of malaria infection on bone.

Oral supplementation with alfacalcidol, a vitamin D3 analog, could completely prevent bone loss. Therefore, anti-malarials coupled with bone therapy may be beneficial in improving bone health in malaria-infected individuals.

Michelle S. J. Lee, Kenta Maruyama, Yukiko Fujita, Aki Konishi, Patrick M. Lelliott, Sawako Itagaki, Toshihiro Horii, Jing-wen Lin, Shahid M. Khan, Etsushi Kuroda, Shizuo Akira, Ken J. Ishii, Cevayir Coban
Plasmodium products persist in the bone marrow and promote chronic bone loss
Science Immunology 02 Jun 2017: Vol. 2, Issue 12, eaam8093 DOI: 10.1126/sciimmunol.aam8093

Top Image: Ute Frevert; false color by Margaret Shear, CC BY 2.5. Sporozoite of Plasmodium bergei migrating through the cytoplasm of midgut epithelia of an Anopheles stephensi mosquito