Commentary:
Bone loss is another hidden pathology caused by malaria infection
Osaka University Researchers at the Immunology Frontier Research Center (IFReC) havediscovered that malaria infection causes bone loss as a result of chronic bone inflammationinduced by accumulated Plasmodium by-products in bone.

Osaka-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 somecases, 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 isincreasing evidence to suggest that survivors experience long-term ‘hidden’ pathologies due toinfection that are as yet poorly defined.
Now, the Laboratory of Malaria Immunology Team at the Immunology Frontier ResearchCenter (IFReC), Osaka University, headed by Professor Cevayir COBAN, have used mousemalaria models to show that robust immune activation and invasion of parasite by-products into
the bone marrow during and after malaria infection leads to an adverse balance in bonehomeostasis -a process usually tightly controlled- by bone forming osteoblasts and boneresorbing osteoclasts.
“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”, Dr. Coban,
corresponding author of the study, says. Michelle Lee, a PhD candidate and the first author of thestudy explains, “We found that Plasmodium products continuously accumulate in the bone marrowniche which turns the bone noticeably black in color, and results in it being “eaten-up” by boneresorbing cells known as osteoclasts, eventually disrupting bone homeostasis”. These products,
including the major malarial by-product hemozoin, malarial proteins and as yet undefinedvirulence factors, induce MyD88-dependent inflammatory responses in osteoclast and osteoblast
precursors, leading to increased RANKL expression (a key molecule inducing osteoclastdifferentiation), and over-stimulation of osteoclastogenesis favoring bone resorption (Figure 1)”.
The Coban 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 theirfindings.
Dr. Coban explains, “Although chronic inflammatory conditions are known to facilitate bonedisorders, 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 thinkthat 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 ina state of chronic inflammation, leading to long term bone loss. This is particularly worrisome inthe 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 bebeneficial in improving bone health in malaria-infected individuals.

Figure 1. Malaria induces chronic bone loss due to sustained accumulation of Plasmodium
products even after the cure of malaria disease.

Article information:
Title: “Plasmodium products persist in the bone marrow and promote chronic bone loss”
Authors: Michelle S. J. Lee, Kenta Maruyama, Yukiko Fujita, Aki Konishi, Patrick M. Lelliott,
Sawako Itagaka, Toshihiro Horii, Jing-wen Lin, Shahid M. Khan, Etsushi Kuroda, Shizuo Akira,Ken J. Ishii, Cevayir Coban.
Journal: Science Immunology [Sci. Immunol. 2, eaam8093 (2017)]
Funded by: Japan Society for the Promotion of Science