Jackson, C. M. | bioRxiv Science

bioRxiv2022

Development of an Ectopic huLiver Model for Plasmodium Liver Stage Infection

Early Plasmodium falciparum and P. vivax infection requires parasite replication within host hepatocytes, referred to as liver stage (LS). However, limited understanding of infection dynamics in human LS exists due to species-specificity challenges. Reported here is a reproducible, easy-to-manipulate, and moderate-cost in vivo model to study human Plasmodium LS in mice; the ectopic huLiver model. Ectopic huLiver tumors were generated through subcutaneous injection of the HC-04 cell line and shown to be infectible by both freshly dissected sporozoites and through the bite of infected mosquitoes. Evidence for complete LS development was supported by the transition to blood-stage infection in mice engrafted with human erythrocytes. Additionally, this model was successfully evaluated for its utility in testing antimalarial therapeutics, as supported by primaquine acting as a causal prophylactic against P. falciparum. Presented here is a new platform for the study of human Plasmodium infection with the potential to aid in drug discovery.

molecular biology↗

bioRxiv2021

A potent myeloid response is rapidly activated in the lungs of premature Rhesus macaques exposed to intra-uterine inflammation

Intrauterine inflammation/infection (IUI), which is present in up to 40% of premature births, leads to elevated levels of pro-inflammatory mediators and microbial products within the amniotic fluid, which come in close contact to fetal mucosae. Yet, knowledge on the fetal mucosal responses to IUI exposure remains limited. To address these questions, we used a non-human primate model of IUI, in which pregnant Rhesus macaques received intra-amniotic (IA) LPS, compared with IA saline. We found that IA LPS exposure induced a robust and rapid inflammation of the fetal lung, but not the intestine. This inflammatory response was characterized by high levels of pro-inflammatory cytokines in the lung and the alveolar wash, and a potent myeloid cell response, dominated by neutrophils and monocytes/macrophages. scRNAseq analyses of fetal lungs showed that the infiltrating (neutrophils and inflammatory monocytes) and the resident (alveolar and interstitial macrophages) myeloid cells exhibited transcriptional profiles consistent with exposure to TLR ligands, as well as to cytokines, notably IL-1 and TNF. However, blocking IL-1 signaling or TNF, alone or simultaneously by administering inhibitors intra-amniotically and subcutaneously to the dam only partially blunted fetal lung inflammation. Together, our novel data indicate that the fetal innate immune system can mount a rapid multi-factorial mucosal innate response to IUI, responding both to direct signaling by bacterial products and to indirect cytokine-mediated pathways of activation. These data thus provide more mechanistic insights into the association between IUI exposure and the post-natal lung morbidities of the premature infant.

immunology↗