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Different distribution of malaria parasite in left and right extremities of vertebrate hosts translates into differences in parasite transmission.

ABSTRACT: Malaria, a vector-borne disease caused by Plasmodium spp., remains a major global cause of mortality. Optimization of disease control strategies requires a thorough understanding of the processes underlying parasite transmission. While the number of transmissible stages (gametocytes) of Plasmodium in blood is frequently used as an indicator of host-to-mosquito transmission potential, this relationship is not always clear. Significant effort has been made in developing molecular tools that improve gametocyte density estimation and therefore prediction of mosquito infection rates. However a significant level of uncertainty around estimates remains. The weakness in the relationship between gametocyte burden, measured from a blood sample, and the mosquito infection rate could be explained by a non-homogeneous distribution of gametocytes in the bloodstream. The estimated gametocyte density would then only be a single snapshot that does not reflect the host infectivity. This aspect of Plasmodium infection, however, remains largely neglected. In both humans and birds, we found here that the gametocyte densities differed depending on which side of the body the sample was taken, suggesting that gametocytes are not homogeneously distributed within the vertebrate host. We observed a fluctuating asymmetry, in other words, the extremity of the body with the highest density of parasites is not always the same from one individual to another. An estimation of gametocyte density from only one blood sample, as is commonly measured, could, therefore, over- or underestimated the infectivity of gametocyte carriers. This might have important consequences on the epidemiology of the disease since we show that this variation influences host-to-mosquito transmission. Vectors fed on the least infected body part had a lower parasite burden than those fed on the most infected part. The heterogeneous distribution of gametocytes in bloodstream should be considered to improve diagnosis and test new malaria control strategies.

SUBMITTER: Pigeault R

PROVIDER: S-EPMC7311528 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Different distribution of malaria parasite in left and right extremities of vertebrate hosts translates into differences in parasite transmission.

Pigeault Romain R Isaïa Julie J Yerbanga Rakiswendé S RS Dabiré Kounbobr R KR Ouédraogo Jean-Bosco JB Cohuet Anna A Lefèvre Thierry T Christe Philippe P

Scientific reports 20200623 1

Malaria, a vector-borne disease caused by Plasmodium spp., remains a major global cause of mortality. Optimization of disease control strategies requires a thorough understanding of the processes underlying parasite transmission. While the number of transmissible stages (gametocytes) of Plasmodium in blood is frequently used as an indicator of host-to-mosquito transmission potential, this relationship is not always clear. Significant effort has been made in developing molecular tools that improv ...[more]

PMID: 32576924

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Project description:BackgroundMalaria parasites reproduce asexually, leading to the production of large numbers of genetically identical parasites, here termed a clonal line or clone. Infected hosts may harbor one or more clones, and the number of clones in a host is termed multiplicity of infection (MOI). Understanding the distribution of parasite clones among hosts can shed light on the processes shaping this distribution and is important for modeling MOI. Here, I determine whether the distribution of clones of the lizard malaria parasite Plasmodium mexicanum differ significantly from statistical distributions commonly used to model MOI and logical extensions of these models.MethodsThe number of clones per infection was assessed using four microsatellite loci with the maximum number of alleles at any one locus used as a simple estimate of MOI for each infection. I fit statistical models (Poisson, negative binomial, zero-inflated models) to data from four individual sites to determine a best fit model. I also simulated the number of alleles per locus using an unbiased estimate of MOI to determine whether the simple (but potentially biased) method I used to estimate MOI influenced model fit.ResultsThe distribution of clones among hosts at individual sites differed significantly from traditional Poisson and negative binomial distributions, but not from zero-inflated modifications of these distributions. A consistent excess of two-clone infections and shortage of one-clone infections relative to all fit distributions was also observed. Any bias introduced by the simple method for estimating of MOI did not appear to qualitatively alter the results.ConclusionsThe statistical distributions used to model MOI are typically zero-truncated; truncating the Poisson or zero-inflated Poisson yield the same distribution, so the reasonable fit of the zero-inflated Poisson to the data suggests that the use of the zero-truncated Poisson in modeling is adequate. The improved fit of zero-inflated distributions relative to standard distributions may suggest that only a portion of the host population is located in areas suitable for transmission even at small sites (<1 ha). Collective transmission of clones and premunition may also contribute to deviations from standard distributions.

Project description:BackgroundConsistent asymmetry of the left-right (LR) axis is a crucial aspect of vertebrate embryogenesis. Asymmetric gene expression of the TGFβ superfamily member Nodal related 1 (Nr1) in the left lateral mesoderm plate is a highly conserved step regulating the situs of the heart and viscera. In Xenopus, movement of maternal serotonin (5HT) through gap-junctional paths at cleavage stages dictates asymmetry upstream of Nr1. However, the mechanisms linking earlier biophysical asymmetries with this transcriptional control point are not known.ResultsTo understand how an early physiological gradient is transduced into a late, stable pattern of Nr1 expression we investigated epigenetic regulation during LR patterning. Embryos injected with mRNA encoding a dominant-negative of Histone Deacetylase (HDAC) lacked Nr1 expression and exhibited randomized sidedness of the heart and viscera (heterotaxia) at stage 45. Timing analysis using pharmacological blockade of HDACs implicated cleavage stages as the active period. Inhibition during these early stages was correlated with an absence of Nr1 expression at stage 21, high levels of heterotaxia at stage 45, and the deposition of the epigenetic marker H3K4me2 on the Nr1 gene. To link the epigenetic machinery to the 5HT signaling pathway, we performed a high-throughput proteomic screen for novel cytoplasmic 5HT partners associated with the epigenetic machinery. The data identified the known HDAC partner protein Mad3 as a 5HT-binding regulator. While Mad3 overexpression led to an absence of Nr1 transcription and randomized the LR axis, a mutant form of Mad3 lacking 5HT binding sites was not able to induce heterotaxia, showing that Mad3's biological activity is dependent on 5HT binding.ConclusionHDAC activity is a new LR determinant controlling the epigenetic state of Nr1 from early developmental stages. The HDAC binding partner Mad3 may be a new serotonin-dependent regulator of asymmetry linking early physiological asymmetries to stable changes in gene expression during organogenesis.

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Different distribution of malaria parasite in left and right extremities of vertebrate hosts translates into differences in parasite transmission.

Publications

Different distribution of malaria parasite in left and right extremities of vertebrate hosts translates into differences in parasite transmission.

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