Severe malaria infections caused by malaria could disrupt hematopoietic processes in mouse models, resulting in faster turnover of hematopoietic stem cells (HSCs) and drastically affecting their function, researchers from Imperial College London and The Francis Crick Institute reported in the November 23, 2020, online issue of Nature Cell Biology.

The researchers also found that, although malaria caused both short- and long-term damage to HSCs in the mice models, some of the damage could be reversed by parathyroid hormone treatment.

Hematopoietic stem cells are cells capable of reconstituting all blood cell lineages. The bone marrow microenvironment in which HSCs reside, known as the "niche", is a critical regulator of HSC function. During severe infection, profound changes in the bone marrow niche increase the production of blood cells, while depleting HSCs.

"HSC response to infection is accompanied and mediated by changes to the bone marrow microenvironment," Lead author Miryam Haltalli told BioWorld Science. "Our hypothesis was that it may be possible to avoid infection-induced HSC exhaustion through interventions directly targeting the bone marrow microenvironment."

Haltalli is a postdoctoral researcher in Professor Cristina Lo Celso's group at Imperial College. Lo Celso's group focuses on the dynamic processes underlying healthy and malignant haematopoiesis.

"This is the first study to tackle the fundamental question of how cell-extrinsic mechanisms regulate the HSC response to severe infections," Haltalli said. "Most importantly, this work strongly suggests that the bone marrow microenvironment is an important mediator of the changes in HSC fate observed during severe infection, and we show that by manipulating the HSC niche we can uncouple stem cell proliferation and function in vivo." The study utilized an interdisciplinary approach combining advanced microscopy technologies at Imperial College and the Crick Institute, RNA analyses led by Professor Berthold Gottgens at Cambridge University, and mathematical modeling led by Professor Ken Duffy at Maynooth University.

Rapid changes in bone marrow following infection

The mice used in the study developed malaria naturally, following bites from mosquitoes carrying Plasmodium berghei sporozoites. The researchers subsequently observed the changes in the bone marrow environment and the effect on HSC function. Within days of infection, blood vessels became leaky and there was a dramatic loss in bone-forming cells called osteoblasts. These changes appeared strongly linked to the decline in the number of HSCs during infection. Haltalli said that they were "surprised at the speed of the changes to the bone marrow microenvironment upon infection with Plasmodium as well as the niche's susceptibility to damage, which was completed unexpected."

The study found that P. berghei-exposed HSCs and bone marrow stromal cells exhibited a strong interferon (IFN) response. The researchers detected a remarkable increase of IFN-gamma in the serum and the bone marrow supernatant of infected animals. The decrease in the number of HSCs appeared to particularly affect the production of neutrophils. In a real-world scenario, this could leave patients vulnerable to further infections, with potentially long-term consequences for the functioning of the immune system. In the long term, if the HSC numbers remain below normal levels, chances of the patient developing blood cancers like leukemia are increased.

Damage control-rescuing HSC numbers and function

The team subsequently tested a way to prevent the infection-mediated HSC damage. The researchers treated HSCs with parathyroid hormone -- a hormone that regulates bone calcium and also counters cellular oxidative stress both before and after infection. This process led to a 10-fold increase in HSC function following infection compared with mice that received no treatment.

The requirement to start the hormone treatment before infection, combined with its need to be refrigerated, make it unviable as a solution, especially in many parts of the world where severe infections like malaria and TB are prevalent.

However, the study provides proof of concept that targeting the niche could be useful in leading to the development of novel treatments that can be easily and widely administered. The findings might also be applied in other infections, like SARS-CoV-2, that are accompanied by a massive release of cytokines.

Haltalli is now looking to validate the findings from this work through analysis of human bone marrow sections. Although the interventions proposed in the current work are not translatable or practical as a solution in many parts of the world where severe infections like malaria and TB are prevalent, she said the researchers feel that they have "opened the door for the development of new treatments that can be widely administered to lessen the impact of these infections on HSC function."