Biology subjects

Lamb, T. J.

Publications and source records attributed to Lamb, T. J..

3 recordsLinked to original sources

bioRxiv2025

Sickle cell status skews malaria parasite genotype at infection

Sickle cell hemoglobin (HbS) confers protection against symptomatic malaria caused by Plasmodium falciparum. HbS carriers with symptomatic malaria harbour parasites enriched for sickle-associated alleles (Pfsa+), which appear to partially overcome HbS-mediated protection, but their role in asymptomatic infections is unclear. Here, we conducted a cross-sectional survey of 2,246 healthy school children in a region of high malaria transmission region in Cameroon. Analysing parasite Pfsa and human HbS genotypes for 1,701 asymptomatic P. falciparum infections confirmed that heterozygous HbS (HbAS) and homozygous non-HbS (HbAA) genotypes have similar rates of asymptomatic infection. However, the HbS genotype is strongly associated with parasites carrying Pfsa+ alleles at Pfsa1 and Pfsa3 loci, indicating a selective advantage for these alleles in HbS carriers. Our findings reveal that the protective effect of HbS is complex, where HbS has a protective effect prior to symptoms against Pfsa- parasites and Pfsa+ alleles may contribute to lower rates of symptomatic disease in HbS carriers. HbS protection against malarial disease should consider both resistance and tolerance and ongoing co-evolution with parasites.

genetics↗

bioRxiv2024

Influenza-induced alveolar macrophages protect against death by malaria-associated acute lung injury (MA-ALI)

Lower respiratory tract infections are common in malaria-endemic areas, and there is some evidence that co-infections between various bacteria/viruses and Plasmodium may affect disease prognosis. In this study, we report the novel finding that co-infection with influenza/A/X31 protects mice from death by Plasmodium berghei NK65-Edinburgh, a model of severe malarial pulmonary leak which underpins malaria-associated acute lung injury (MA-ALI) and malaria-associated acute respiratory distress (MA-ARDS). Co-infected mice exhibit equivalent parasitemia as mice with malaria only, suggesting that the survival phenotype is due to differences in immune kinetics. We demonstrated that the pulmonary leak typical of PbE is attenuated in co-infected mice without alteration in CD8 T cell activation and recruitment to the lung. Upon further examination of the immune response to influenza/A/X31 we identified a population of arginase 1-expressing alveolar macrophages that traffic to the lungs early during infection. In vitro these macrophages inhibit CD8 T cell activation and proliferation better than non-arginase expressing cells. Removal of arginase-1 expressing alveolar macrophages in vivo via administration of the antimetabolite gemcitabine removed the protective effects of influenza/A/X31co-infection on MA-ALI. This study opens a route to better understanding of how to modulate the immunopathology observed in pulmonary leak associated with severe malaria, which must be achieved to rationally design therapeutic interventions for MA-ARDS / MA-ALI.

immunology↗

bioRxiv2019

Multi-omics Integrative Analysis of Acute and Relapsing Malaria in a Non-Human Primate Model of P. vivax infection

Systems-scale analysis of multiple layers of molecular and cellular data has significant potential for providing novel insights into malaria pathology and immunity. We present here a unique longitudinal multi-omics dataset encompassing Macaca mulatta blood and bone marrow responses to infection by Plasmodium cynomolgi, a non-human primate (NHP) parasite species used to model P. vivax malaria acute and relapsing infections in humans. We analyzed relationships across multiple biological layers using a mutual information-based machine learning approach to integrate heterogeneous longitudinal datasets and constructed an atlas of multi-omics relatedness networks (MORNs). Using this technique, we were able to detect signatures that defined both acute and relapsing infections. Importantly, relapse infections could be distinguished from both acutely-infected and uninfected NHP, suggesting that the host-parasite interactions during relapses are unique compared to acute Plasmodium infections. To our knowledge, this is the first report of large-scale, longitudinal multi-omics analysis of malaria in any system. This dataset, along with the method used to analyze it, provides a unique resource for the malaria research community and demonstrates the power of longitudinal infection study designs, NHP model systems and integrative multi-omics analyses.

systems biology↗