BackgroundMild to severe anaemia is a common complication of malaria that is caused in part by insufficient erythropoiesis in the bone marrow. This study used systems biology to evaluate the transcriptional and alterations in cell populations in the bone marrow during Plasmodium cynomolgi infection of rhesus macaques (a model of Plasmodium vivax malaria) that may affect erythropoiesis.ResultsAn appropriate erythropoietic response did not occur to compensate for anaemia during acute cynomolgi malaria despite an increase in erythropoietin levels. During this period, there were significant perturbations in the bone marrow transcriptome. In contrast, relapses did not induce anaemia and minimal changes in the bone marrow transcriptome were detected. The differentially expressed genes during acute infection were primarily related to ongoing inflammatory responses with significant contributions from Type I and Type II Interferon transcriptional signatures. These were associated with increased frequency of intermediate and non-classical monocytes. Recruitment and/or expansion of these populations was correlated with a decrease in the erythroid progenitor population during acute infection, suggesting that monocyte-associated inflammation may have contributed to anaemia. The decrease in erythroid progenitors was associated with downregulation of genes regulated by GATA1 and GATA2, two master regulators of erythropoiesis, providing a potential molecular basis for these findings.ConclusionsThese data suggest the possibility that malarial anaemia may be driven by monocyte-associated disruption of GATA1/GATA2 function in erythroid progenitors resulting in insufficient erythropoiesis during acute infection.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-017-2029-z) contains supplementary material, which is available to authorized users.

Recruitment of foamy monocytes to inflamed endothelium expressing vascular cell adhesion molecule-1 (VCAM-1) contributes to the development of plaque during atherogenesis. Foamy CD11c+ monocytes arise in the circulation during the onset of hypercholesterolemia and recruit to nascent plaque, but the mechanism of CD11c/CD18 and very late antigen-4 (VLA-4) activation and cooperation in shear resistant cell arrest on VCAM-1 is ill defined. Within one week of the onset of a Western high-fat diet (WD) in apoE-/- mice, an inflammatory subset of foamy monocytes emerged comprising ¼ of the circulating population. These cells expressed ∼3-fold more CD11c/CD18 and 50% higher chemokine receptors than non-foamy monocytes. Recruitment from blood to a VCAM-1 substrate under shear stress was assessed ex-vivo using a unique artery-chip microfluidic assay. It revealed that foamy monocytes from mice on a WD increased their adhesiveness over 5 weeks, rising to twice that of mice on a normal diet (ND) or CD11c-/- fed a WD. Shear resistant capture of foamy human or mouse monocytes was initiated by high affinity CD11c, which directly activated VLA-4 adhesion via phosphorylated spleen tyrosine kinase and paxillin within focal adhesion complexes. Lipid uptake and activation of CD11c are early and critical events in signaling VLA-4 adhesive function on foamy monocytes competent to recruit to VCAM-1 on inflamed arterial endothelium.

Background Kra monkeys (Macaca fascicularis), a natural host of Plasmodium knowlesi, control parasitaemia caused by this parasite species and escape death without treatment. Knowledge of the disease progression and resilience in kra monkeys will aid the effective use of this species to study mechanisms of resilience to malaria. This longitudinal study aimed to define clinical, physiological and pathological changes in kra monkeys infected with P. knowlesi, which could explain their resilient phenotype. Methods Kra monkeys (n = 15, male, young adults) were infected intravenously with cryopreserved P. knowlesi sporozoites and the resulting parasitaemias were monitored daily. Complete blood counts, reticulocyte counts, blood chemistry and physiological telemetry data (n = 7) were acquired as described prior to infection to establish baseline values and then daily after inoculation for up to 50 days. Bone marrow aspirates, plasma samples, and 22 tissue samples were collected at specific time points to evaluate longitudinal clinical, physiological and pathological effects of P. knowlesi infections during acute and chronic infections. Results As expected, the kra monkeys controlled acute infections and remained with low-level, persistent parasitaemias without anti-malarial intervention. Unexpectedly, early in the infection, fevers developed, which ultimately returned to baseline, as well as mild to moderate thrombocytopenia, and moderate to severe anaemia. Mathematical modelling and the reticulocyte production index indicated that the anaemia was largely due to the removal of uninfected erythrocytes and not impaired production of erythrocytes. Mild tissue damage was observed, and tissue parasite load was associated with tissue damage even though parasite accumulation in the tissues was generally low. Conclusions Kra monkeys experimentally infected with P. knowlesi sporozoites presented with multiple clinical signs of malaria that varied in severity among individuals. Overall, the animals shared common mechanisms of resilience characterized by controlling parasitaemia 3–5 days after patency, and controlling fever, coupled with physiological and bone marrow responses to compensate for anaemia. Together, these responses likely minimized tissue damage while supporting the establishment of chronic infections, which may be important for transmission in natural endemic settings. These results provide new foundational insights into malaria pathogenesis and resilience in kra monkeys, which may improve understanding of human infections.

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Intermediate monocytes (iMo; CD14 + CD16 +) increase in number in the circulation of patients with unstable coronary artery disease (CAD), and their recruitment to inflamed arteries is implicated in events leading to mortality following MI. Monocyte recruitment to inflamed coronary arteries is initiated by high affinity b2-integrin (CD11c/CD18) that activates b1-integrin (VLA-4) to bind endothelial VCAM-1. How integrin binding under shear stress mechanosignals a functional shift in iMo toward an inflammatory phenotype associated with CAD progression is unknown. Whole blood samples from patients treated for symptomatic CAD including non-ST elevation MI, along with healthy age-matched subjects, were collected to assess chemokine and integrin receptor levels on monocytes. Recruitment on inflamed human aortic endothelium or rVCAM-1 under fluid shear stress was assessed using a microfluidic-based artery on a chip (A-Chip). Membrane upregulation of high affinity CD11c correlated with concomitant activation of VLA-4 within focal adhesive contacts was required for arrest and diapedesis across inflamed arterial endothelium to a greater extent in non-ST elevation MI compared with stable CAD patients. The subsequent conversion of CD11c from a high to low affinity state under fluid shear activated phospho-Syk-and ADAM17-mediated proteolytic cleavage of CD16. This marked the conversion of iMo to an inflammatory phenotype associated with nuclear translocation of NF-kB and production of IL-1b +. We conclude that CD11c functions as a mechanoregulator that activates an inflammatory state preferentially in a majority of iMo from cardiac patients but not healthy patients.