Reduced circulating dendritic cells in acute Plasmodium knowlesi and Plasmodium falciparum malaria despite elevated plasma Flt3 ligand levels

Abstract Background Plasmodium falciparum malaria increases plasma levels of the cytokine Fms-like tyrosine kinase 3 ligand (Flt3L), a haematopoietic factor associated with dendritic cell (DC) expansion. It is unknown if the zoonotic parasite Plasmodium knowlesi impacts Flt3L or DC in human malaria. This study investigated circulating DC and Flt3L associations in adult malaria and in submicroscopic experimental infection. Methods Plasma Flt3L concentration and blood CD141+ DC, CD1c+ DC and plasmacytoid DC (pDC) numbers were assessed in (i) volunteers experimentally infected with P. falciparum and in Malaysian patients with uncomplicated (ii) P. falciparum or (iii) P. knowlesi malaria. Results Plasmodium knowlesi caused a decline in all circulating DC subsets in adults with malaria. Plasma Flt3L was elevated in acute P. falciparum and P. knowlesi malaria with no increase in a subclinical experimental infection. Circulating CD141+ DCs, CD1c+ DCs and pDCs declined in all adults tested, for the first time extending the finding of DC subset decline in acute malaria to the zoonotic parasite P. knowlesi. Conclusions In adults, submicroscopic Plasmodium infection causes no change in plasma Flt3L but does reduce circulating DCs. Plasma Flt3L concentrations increase in acute malaria, yet this increase is insufficient to restore or expand circulating CD141+ DCs, CD1c+ DCs or pDCs. These data imply that haematopoietic factors, yet to be identified and not Flt3L, involved in the sensing/maintenance of circulating DC are impacted by malaria and a submicroscopic infection. The zoonotic P. knowlesi is similar to other Plasmodium spp in compromising DC in adult malaria.

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Global & Temporal Patterns of Submicroscopic Plasmodium falciparum Malaria Infection

10.1101/554311 ◽

2019 ◽

Cited By ~ 1

Author(s):

Charles Whittaker ◽

Hannah Slater ◽

Teun Bousema ◽

Chris Drakeley ◽

Azra Ghani ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Malaria Infection ◽

Molecular Detection ◽

Plasmodium Falciparum Malaria ◽

West African ◽

South American ◽

Cross Sectional ◽

Large Numbers ◽

Current Transmission ◽

Submicroscopic Infection

AbstractMolecular detection of Plasmodium falciparum infection has revealed large numbers of individuals with low-density (yet transmissible) infections undetectable by microscopy. Here we present an updated systematic review of cross-sectional malaria surveys to explore the prevalence and drivers of these submicroscopic infections and define where they are likely to be relevant to malaria control efforts. Our results show that submicroscopic infections predominate in low transmission settings, but also reveal marked geographical variation in their prevalence, being highest in South American surveys and lowest in West African studies. Whilst current transmission levels partly explain these results, we find that historical transmission intensity also represents a crucial determinant of the size of the submicroscopic reservoir. Submicroscopic infection was more likely in adults than children, although we did not observe a statistically significant influence of seasonality. Our results suggest that the contribution of submicroscopic infections to transmission likely varies substantially across settings, potentially warranting different approaches to their targeting in the approach to elimination.

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DNA replication dynamics during erythrocytic schizogony in the malaria parasites Plasmodium falciparum and Plasmodium knowlesi

10.1101/2021.12.20.473505 ◽

2021 ◽

Author(s):

Jennifer McDonald ◽

Catherine J Merrick

Keyword(s):

Plasmodium Falciparum ◽

Plasmodium Knowlesi ◽

Malaria Parasites ◽

Cell Cycles ◽

New Information ◽

Extreme Variability ◽

Single Mass ◽

Parasite Replication ◽

First Time ◽

High Parasite

Malaria parasites are unusual, early-diverging protozoans with non-canonical cell cycles. They do not undergo binary fission, but divide primarily by schizogony. This is a syncytial mode of replication involving asynchronous production of multiple nuclei within the same cytoplasm, culminating in a single mass cytokinesis event. The rate and efficiency of parasite replication is fundamentally important to malarial disease, which tends to be severe in hosts with high parasite loads. Here, we have studied for the first time the dynamics of schizogony in two human malaria parasite species, Plasmodium falciparum and Plasmodium knowlesi. These differ in their cell-cycle length, the number of progeny produced and the genome composition, among other factors. Comparing them could therefore yield new information about the parameters and limitations of schizogony. We report that the dynamics of schizogony differ significantly between these two species, most strikingly in the gap phases between successive nuclear replications, which are longer in P. falciparum and shorter, but more heterogenous, in P. knowlesi. In both species, gaps become longer as schizogony progresses, whereas each period of active replication grows shorter. In both species there is also extreme variability between individual cells, with some schizonts producing many more nuclei than others, and some individual nuclei arresting their replication for many hours while adjacent nuclei continue to replicate. The efficiency of schizogony is probably influenced by a complex set of factors in both the parasite and its host cell.

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Resistance of Melanesian elliptocytes (ovalocytes) to invasion by Plasmodium knowlesi and Plasmodium falciparum malaria parasites in vitro.

Journal of Clinical Investigation ◽

10.1172/jci110827 ◽

1983 ◽

Vol 71 (3) ◽

pp. 780-782 ◽

Cited By ~ 40

Author(s):

T Hadley ◽

A Saul ◽

G Lamont ◽

D E Hudson ◽

L H Miller ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Falciparum Malaria ◽

Plasmodium Knowlesi ◽

Plasmodium Falciparum Malaria ◽

Malaria Parasites

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VAR2CSA and protective immunity against pregnancy-associated Plasmodium falciparum malaria

Parasitology ◽

10.1017/s0031182007000121 ◽

2007 ◽

Vol 134 (13) ◽

pp. 1871-1876 ◽

Cited By ~ 41

Author(s):

L. HVIID ◽

A. SALANTI

Keyword(s):

Immune Response ◽

Plasmodium Falciparum ◽

Pregnant Women ◽

Protective Immunity ◽

Plasmodium Falciparum Malaria ◽

Surface Antigens ◽

Variant Surface Antigens ◽

Important Target ◽

First Time ◽

Stable Transmission

SUMMARYPeople living in areas with stable transmission of P. falciparum parasites acquire protective immunity to malaria over a number of years and following multiple disease episodes. Immunity acquired this way is mediated by IgG with specificity for parasite-encoded, clonally variant surface antigens (VSA) on the surface of infected erythrocytes (IEs). However, women in endemic areas become susceptible to P. falciparum infection when they become pregnant, particularly for the first time, regardless of previously acquired protective immunity. This conundrum was resolved when it was observed that the selective placental accumulation of IEs that characterizes pregnancy-associated malaria (PAM) is caused by an immunologically and functionally unique subset of VSA (VSAPAM) that is only expressed by parasites infecting pregnant women, and that protective immunity to PAM is mediated by IgG with specificity for VSAPAM. In this review we summarize the research leading to the identification of the distinctly structured PfEMP1 variant VAR2CSA as the dominant PAM-type VSA and as the clinically most important target of the protective immune response to placental P. falciparum infection.

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