Plasmodium products persist in the bone marrow and promote chronic bone loss

Abstract

Although malaria is a life-threatening disease with severe complications, most people develop partial immunity and suffer from mild symptoms. However, incomplete recovery from infection causes chronic illness, and little is known of the potential outcomes of this chronicity. We found that malaria causes bone loss and growth retardation as a result of chronic bone inflammation induced by products. Acute malaria infection severely suppresses bone homeostasis, but sustained accumulation of products in the bone marrow niche induces MyD88-dependent inflammatory responses in osteoclast and osteoblast precursors, leading to increased RANKL expression and overstimulation of osteoclastogenesis, favoring bone resorption. Infection with a mutant parasite with impaired hemoglobin digestion that produces little hemozoin, a major by-product, did not cause bone loss. Supplementation of alfacalcidol, a vitamin D3 analog, could prevent the bone loss. These results highlight the risk of bone loss in malaria-infected patients and the potential benefits of coupling bone therapy with antimalarial treatment.

Inhibition of heme sequestration of histidine‐rich protein 2 using multiple epitope‐targeted peptides

“…Chronic bone loss has been correlated with the persistence of accumulated hemozoin in bone marrow after P. falciparum infection. The retained hemozoin modulates immune responses and bone homeostasis, so inhibition of heme biocrystallization might reduce disease‐related complications, in addition to being harmful to the parasite …”

“…The retained hemozoin modulates immune responses and bone homeostasis, so inhibition of heme biocrystallization might reduce disease-related complications, in addition to being harmful to the parasite. 7 The biocrystallization of free heme, or heme sequestration, is the target of numerous antimalarial drugs, many of which function through direct interaction with heme itself. 6 One example of a hemozoin-targeted drug is the quinoline-based compound chloroquine (CQ).…”

Vivax-induced thrombocytopenia may be associated with lymphopenia and mild anaemia. Correlation of RBC parameters with WBC and platelet counts – A report of 13 patients with vivax malaria

“…Subsequent introduction of a related species (P. vivax) in susceptible nonimmune population might have resulted in evolution of intracellular hepatic forms of vivax malaria 14 . Further, Plasmodium parasite and its products may be engulfed by osteoclasts, eliciting a strong cytokine-mediated inflammatory response 15 . Persistent release of inflammatory cytokines may affect maturation of haemic cells in bone marrow.…”

Intravital microscopy: Imaging host–parasite interactions in lymphoid organs

“…In Plasmodium‐ infected humans, non‐human primates and mice, both asexual stages and gametocytes of Plasmodium have been found in the bone marrow during blood stages of infection. The presence of parasites and parasite products has been associated with pathology including bone loss (Lee et al, ), anaemia and immune dysregulation (Waseem et al, ).…”

“…However, histology techniques combined with human and animal autopsies have shown that the bone marrow can influence pathology related to parasitic infections and in some cases, is even a key niche for parasite development. Direct and indirect bone marrow involvement in pathology has been suggested for parasites including Plasmodium spp., (Alano, 2017;Baro et al, 2017;De Niz et al, 2018;Duffier et al, 2016;Farfour et al 2012;Joice et al, 2014;Lee et al, 2017;Lee et al, 2018;Mayor & Alano, 2015;Messina et al, 2018;Neveu et al, 2018;Rogers et al, 2000;Smalley et al 1981;Waseem et al, 2016;Wickramasinghe et al, 1987), Toxoplasma gondii (Brouland et al, 1996), Leishmania spp., (Ali & Hussain, 2014;Hellal & Kundu, 2013;Kumar et al, 2007), Schistosoma spp., (Azevedo et al, 2015;Jones & Leday, 2014;Kamal et al 1989) and Trypanosoma spp. (Baena Terán et al, 2012;Bockstal, Guirnalda, et al, 2011;Bockstal, Geurts, & Magez, 2011;Carbajosa et al, 2017;De Diego et al 1998;Felizardo et al, 2018;Habila et al, 2014;Mabbott & Sternberg, 1995;Müller et al, 2018;Obishakin et al 2014;Souza et al, 2014;Stijlemans et al, 2016).…”