Systematic tracking of altered haematopoiesis during sporozoite-mediated malaria development reveals multiple response points

Abstract

Haematopoiesis is the complex developmental process that maintains the turnover of all blood cell lineages. It critically depends on the correct functioning of rare, quiescent haematopoietic stem cells (HSCs) and more numerous, HSC-derived, highly proliferative and differentiating haematopoietic progenitor cells (HPCs). Infection is known to affect HSCs, with severe and chronic inflammatory stimuli leading to stem cell pool depletion, while acute, non-lethal infections exert transient and even potentiating effects. Both whether this paradigm applies to all infections and whether the HSC response is the dominant driver of the changes observed during stressed haematopoiesis remain open questions. We use a mouse model of malaria, based on natural, sporozoite-driven Plasmodium berghei infection, as an experimental platform to gain a global view of haematopoietic perturbations during infection progression. We observe coordinated responses by the most primitive HSCs and multiple HPCs, some starting before blood parasitaemia is detected. We show that, despite highly variable inter-host responses, primitive HSCs become highly proliferative, but mathematical modelling suggests that this alone is not sufficient to significantly impact the whole haematopoietic cascade. We observe that the dramatic expansion of Sca-1+ progenitors results from combined proliferation of direct HSC progeny and phenotypic changes in downstream populations. We observe that the simultaneous perturbation of HSC/HPC population dynamics is coupled with early signs of anaemia onset. Our data uncover a complex relationship between Plasmodium and its host's haematopoiesis and raise the question whether the variable responses observed may affect the outcome of the infection itself and its long-term consequences on the host.

Malaria-induced remodelling of the bone marrow microenvironment mediates loss of haematopoietic stem cell function

“…In contrast, the proliferation rates of both MPPs and HSCs were only statistically consistent with controls until day 3, before dramatically increasing by day 5 ( Figure 1D). As we previously reported (Vainieri et al, 2016), LK cell numbers were significantly reduced by day 7, while MPP numbers were substantially increased, and the number of HSCs remained essentially unchanged throughout the course of infection ( Figure 1E). The observation that the HSC compartment does not grow in size during infection, even though the proportion of HSCs entering S-phase does, suggests that HSCs produce an increased number of differentiated progeny.…”

“…In parallel with the development of innate and adaptive immune responses, infections and inflammatory cytokines stimulate haematopoietic stem and progenitor cells (HSPCs) to modify the composition of their progeny to cope promptly with the increased demand for mature cells (Essers et al, 2009;Esplin et al, 2011;MacNamara et al, 2011). A range of dramatic HSPC responses have been noted as a result of these insults, including an expansion of the early progenitor compartment (identified as Lineagec-Kit + Sca-1 +, or LKS), and alterations in cycling properties, long-term function and migration patterns of HSCs (Baldridge et al, 2010;Rashidi et al, 2014;Matatall et al, 2016;Vainieri et al, 2016). These phenomena all take place within the bone marrow (BM) microenvironment, yet very little is currently known about the response of HSC niche cells to infection and inflammation, and what their role may be in regulating the observed changes in haematopoietic dynamics.…”

“…Using a murine experimental model based on the natural route of sporozoite-mediated infection, with mice receiving bites from Plasmodium berghei-infected mosquitoes, we previously demonstrated that multiple components of the haematopoietic tree simultaneously respond to P. berghei infection. We uncovered a dramatic increase in the proportion of proliferating HSCs and early progenitors at the advanced stages of blood infection (Vainieri et al, 2016) Here, we combined phenotypic, functional, molecular and intravital microscopy (IVM) analyses to gain insights into the haematopoietic and BM microenvironment responses over the course of infection, investigating causal links between the two. These data established that the entire HSPC compartment is affected and activated by P. berghei infection, with significant changes in HSPC proliferation rate, loss of the transcriptional HSC signature, and loss of HSC long-term function.…”

Blood stem cells: from beginning to end

“…By integrating intravital microscopy, computational analysis of images, flow cytometry and mathematical modelling, Cristina Lo Celso (Imperial College London, UK) addressed how stresses such as infection or leukemia influence normal blood cell generation in situ. Cristina showed that during infection, HSCs become either motile (although not mobilized) or very still, and that the flux through HSC and progenitor (HSPC) populations is likely to be dramatically altered (Vainieri et al, 2016). Furthermore, results presented by Delfim Duarte from her laboratory highlighted the increasing migratory behavior of leukemia cells from early bone marrow infiltration to overt chemoresistance and their relationship with bone marrow niches known to maintain HSCs (Hawkins et al, 2016).…”

Severe Malarial Anemia (SMA) Pathophysiology and the Use of Phytotherapeutics as Treatment Options

“…These parasites continue to shed soluble antigens, hemoglobin metabolites and derivatives that drive various syndromes of malaria like SMA. This may explain the continued decline in hematologic indices despite the evidently low parasitemia and the malarial anemia pathogenesis, which implicates bone marrow dysfunction as displayed by low reticulocytosis [16,17]. When Hb decreases, the normal body physiology upregulates the bone marrow erythroid progenitors and reticulocytes are increased as an indicator of this process.…”