Taylor, T. E. | bioRxiv Science

bioRxiv2024

Large-scale genotyping and meta-analysis of PIEZO1 short tandem repeat alleles suggest a modest association with malaria susceptibility

PIEZO1 forms a mechanosensitive ion channel involved in regulating calcium levels in red blood cells. E756del, a deletion allele within a short tandem repeat (STR) in PIEZO1, is common in many African populations and has been proposed to be associated with protection from malarial disease, but epidemiological evidence has been inconsistent. Here, we use Illumina sequencing of amplicons covering the PIEZO1 STR to genotype 5,558 severe malaria cases and 8,174 population controls from The Gambia, Kenya, and Malawi. We estimate a modest effect for E756del and meta-analysis with two published studies, for a total of 8,224 cases and 10,103 controls, reveals a consistent protective effect (OR=0.93, 95% CI 0.88-0.99). By comprehensively genotyping the STR, we identify additional, less common alleles, with two (Q745del and E756ins) showing consistent, but also modest, risk effects across studies. Although allele frequency differentiation between African and non-African populations could be consistent with a selective effect, we show that it is not exceptional compared with STR variants genome wide. Thus, our results support a protective effect of E756del against risk of malaria but with a much smaller effect size than initially reported.

genetics↗

bioRxiv2024

Reversible host cell surface remodelling limits immune recognition and maximizes transmission of Plasmodium falciparum gametocytes

Reducing malaria transmission has been a major pillar of control programmes and is considered crucial for achieving malaria elimination. Gametocytes, the transmissible forms of the P. falciparum parasite, arise during the blood stage of the parasite and develop through 5 morphologically distinct stages. Immature gametocytes (stage I-IV) sequester and develop in the extravascular niche of the bone marrow and possibly spleen. Only mature stage V gametocytes re-enter peripheral circulation to be taken up by mosquitoes for successful onward transmission. We have recently shown that immature, but not mature gametocytes are targets of host immune responses and identified putative target surface antigens. We hypothesize that these antigens play a role in gametocyte sequestration and contribute to acquired transmission-reducing immunity. Here we demonstrate that surface antigen expression, serum reactivity by human IgG, and opsonic phagocytosis by macrophages all show similar dynamics during gametocyte maturation, i.e., on in immature and off in mature gametocytes. Moreover, the switch in surface reactivity coincides with reversal in phosphatidylserine (PS) surface exposure, a marker for red blood cell age and clearance. PS is exposed on the surface of immature gametocytes (as well as in late asexual stages) but is removed from the surface in later gametocyte stages (IV-V). Using parasite reverse genetics and drug perturbations, we confirm that parasite protein export into the host cell and phospholipid scramblase activity are required for the observed surface modifications in asexual and sexual P. falciparum stages. These findings suggest that the dynamic surface remodelling allows (i) immature gametocyte sequestration in bone marrow and (ii) mature gametocyte release into peripheral circulation and immune evasion, therefore contributing to mature gametocyte survival in vivo and onward transmission to mosquitoes. Importantly, blocking scramblase activity during gametocyte maturation results in efficient clearance of mature gametocytes, revealing a potential path for transmission blocking interventions. Our studies have important implications for our understanding of parasite biology and form a starting point for novel intervention strategies to simultaneously reduce parasite burden and transmission. IMPORTANTO_LIManuscripts submitted to Review Commons are peer reviewed in a journal-agnostic way. C_LIO_LIUpon transfer of the peer reviewed preprint to a journal, the referee reports will be available in full to the handling editor. C_LIO_LIThe identity of the referees will NOT be communicated to the authors unless the reviewers choose to sign their report. C_LIO_LIThe identity of the referee will be confidentially disclosed to any affiliate journals to which the manuscript is transferred. C_LI GUIDELINESO_LIFor reviewers: https://www.reviewcommons.org/reviewers C_LIO_LIFor authors: https://www.reviewcommons.org/authors C_LI CONTACTThe Review Commons office can be contacted directly at: office@reviewcommons.org

microbiology↗

bioRxiv2020

Multi-Modal Biomarkers of Cerebral Edema in Low Resolution MRI

A central challenge of medical imaging studies is to extract biomarkers that characterize disease pathology or outcomes. Modern automated approaches have found tremendous success in high-resolution, high-quality magnetic resonance images (MRI). These methods, however, may not translate to low resolution images acquired on MRI scanners with lower magnetic field strength. In low-resource settings where low-field scanners are more common and there is a shortage of radiologists to manually interpret MRI scans, it is critical to develop automated methods that can augment or replace manual interpretation, while accommodating reduced image quality. We present a fully automated framework for translating radiological diagnostic criteria into image-based biomarkers, inspired by a project in which children with cerebral malaria were imaged using low-field 0.35 Tesla MRI. We integrate multi-atlas label fusion, which leverages high-resolution images from another sample as prior spatial information, with parametric Gaussian hidden Markov models based on image intensities, to create a robust method for determining ventricular cerebrospinal fluid volume. We also propose normalized image intensity and texture measurements to determine the loss of gray-to-white matter tissue differentiation and sulcal effacement. These integrated biomarkers have excellent classification performance for determining severe brain swelling due to cerebral malaria.

neuroscience↗