Advancing Key Gaps in the Knowledge of Plasmodium vivax Cryptic Infections Using Humanized Mouse Models and Organs-on-Chips

Abstract

Plasmodium vivax is the most widely distributed human malaria parasite representing 36.3% of disease burden in the South-East Asia region and the most predominant species in the region of the Americas. Recent estimates indicate that 3.3 billion of people are under risk of infection with circa 7 million clinical cases reported each year. This burden is certainly underestimated as the vast majority of chronic infections are asymptomatic. For centuries, it has been widely accepted that the only source of cryptic parasites is the liver dormant stages known as hypnozoites. However, recent evidence indicates that niches outside the liver, in particular in the spleen and the bone marrow, can represent a major source of cryptic chronic erythrocytic infections. The origin of such chronic infections is highly controversial as many key knowledge gaps remain unanswered. Yet, as parasites in these niches seem to be sheltered from immune response and antimalarial drugs, research on this area should be reinforced if elimination of malaria is to be achieved. Due to ethical and technical considerations, working with the liver, bone marrow and spleen from natural infections is very difficult. Recent advances in the development of humanized mouse models and organs-on-a-chip models, offer novel technological frontiers to study human diseases, vaccine validation and drug discovery. Here, we review current data of these frontier technologies in malaria, highlighting major challenges ahead to study P. vivax cryptic niches, which perpetuate transmission and burden.

Putative Contribution of 8-Aminoquinolines to Preventing Recrudescence of Malaria

“…The effect of 8-AQ antimalarials on non-circulating asexual stages of P. vivax , such as in the bone marrow [ 106 , 107 ], needs to be investigated, including whether 8-AQs or their partner drugs can induce temporary quiescence of intra-erythrocytic P. vivax parasites, a subject that has been raised elsewhere [ 30 , 63 ]. It is conceivable that the apparently increased in vivo schizontocidal activity in peripheral blood that results when therapy includes both PQ and CQ [ 84 ] also reflects increased inactivation of non-circulating asexual parasites, thereby preventing recrudescences.…”

Summary report of the 1st MOVE symposium in Málaga from 24-27th October 2023 - Foster the European mobility for young scientists in extracellular vesicles research

“…These findings further indicate that the spleen is one of two suspected niches for cryptic infections with P. vivax outside the liver, the second niche being the bone marrow [7] . P. vivax presence was also confirmed in the bone marrow of infected patients, leading to dyserythropoiesis [8] . Finally, Portillo showed exciting unpublished results from organ-on-a-chip models concerning the bone marrow cryptic niche [9] .…”

Transforming the Niche: The Emerging Role of Extracellular Vesicles in Acute Myeloid Leukaemia Progression

“…It can be divided between different types, based on their location: the endosteal niche, within the interior bone or on the endosteum surface, and the vascular/perivascular niche, mostly located in the medullary compartment of the BM. The native endosteal niche extracellular matrix (ECM) is mostly rigid, at 35-40 KPa, and comprises collagen (types I and IV), fibronectin, and osteopontin [95,96]. On the other hand, the vascular niche ECM, which surrounds all the different cells of this niche, is mostly compliant, at 0.1 to 0.3 KPa, comprising laminin, collagen type IV, and fibronectin, and is thus softer than the endosteal niche ECM [95,96].…”

“…The native endosteal niche extracellular matrix (ECM) is mostly rigid, at 35-40 KPa, and comprises collagen (types I and IV), fibronectin, and osteopontin [95,96]. On the other hand, the vascular niche ECM, which surrounds all the different cells of this niche, is mostly compliant, at 0.1 to 0.3 KPa, comprising laminin, collagen type IV, and fibronectin, and is thus softer than the endosteal niche ECM [95,96]. Noteworthy, the extracellular matrix of the different haematopoietic niches-along with their mechanical and chemical properties-have been shown to instruct niche cell phenotypes by modulating their properties, secretome, and function [97].…”