A cryptic cycle in haematopoietic niches promotes initiation of malaria transmission and evasion of chemotherapy

Abstract

Blood stage human malaria parasites may exploit erythropoietic tissue niches and colonise erythroid progenitors; however, the precise influence of the erythropoietic environment on fundamental parasite biology remains unknown. Here we use quantitative approaches to enumerate Plasmodium infected erythropoietic precursor cells using an in vivo rodent model of Plasmodium berghei. We show that parasitised early reticulocytes (ER) in the major sites of haematopoiesis establish a cryptic asexual cycle. Moreover, this cycle is characterised by early preferential commitment to gametocytogenesis, which occurs in sufficient numbers to generate almost all of the initial population of circulating, mature gametocytes. In addition, we show that P. berghei is less sensitive to artemisinin in splenic ER than in blood, which suggests that haematopoietic tissues may enable origins of recrudescent infection and emerging resistance to antimalarials. Continuous propagation in these sites may also provide a mechanism for continuous transmission and infection in malaria endemic regions.

Experimentally engineered mutations in a ubiquitin hydrolase, UBP-1, modulatein vivoresistance to artemisinin and chloroquine inPlasmodium berghei

“…These data confirm that 280 the V2721F mutation confers ART resistance while the V2752F mutation mediates resistance 281 primarily to CQ and to some extent to ARTs. The recrudescence of the wildtype 820 and G1808 V2721F 282 at 45mg/kg ART is also in agreement with our previous findings, that P. berghei is less sensitive to 283 ARTs, especially in the spleen and bone marrow which could be the source of recrudescent infection 284 at relatively lower doses (Lee et al, 2018). 285 286…”

Regulation of sexual differentiation is linked to invasion in malaria parasites

“…In support of the first possibility, it has long been known that gametocytogenesis is increased when parasites are grown in the presence of reticulocytes 42,43 , and this is notable because of the presence of reticulocytes in the bone marrow where gametocytes accumulate 6,7 . In line with this, work in P. berghei has shown there is preferential formation of gametocytes in early reticulocytes within bone marrow 44 . The committed merozoite may have a preference for invasion of reticulocytes that is directed by PfAP2-G which could account for this propensity to develop in the bone marrow.…”

Intravital microscopy: Imaging host–parasite interactions in lymphoid organs

“…While Plasmodium gametocyte maturation dynamics had previously not been addressed in detail using animal models, three important advances were achieved over the last 3 years: (i) the use of humanised mouse models to study P. falciparum gametocyte dynamics (Duffier et al, ); (ii) the demonstration that organs involved in erythropoiesis, including the bone marrow are an important reservoir for rodent malaria gametocytes (De Niz et al, ; Lee et al, ); and (iii) the use of IVM to study the dynamics of gametocyte maturation including extravasation, maturation and egress (De Niz et al, ). The IVM study showed that bone locations enriched with red marrow were preferentially colonised by P. berghei , and that bone marrow sinusoids are key sites for sequestration and invasion.…”

“…The spleen has recently gained great interest in the context of malaria transmission. Studies in humanised mice infected with P. falciparum (Duffier et al, ), and rodent models of malaria infected with P. berghei (Lee et al, ), have consistently shown increased numbers of immature gametocytes in the spleen. The relevance of this organ for host‐to‐vector transmission, as well as its study in the context of transmission‐blocking drugs, remains to be fully explored, and IVM could be an extremely relevant tool for this purpose.…”

“…However, histology techniques combined with human and animal autopsies have shown that the bone marrow can influence pathology related to parasitic infections and in some cases, is even a key niche for parasite development. Direct and indirect bone marrow involvement in pathology has been suggested for parasites including Plasmodium spp., (Alano, 2017;Baro et al, 2017;De Niz et al, 2018;Duffier et al, 2016;Farfour et al 2012;Joice et al, 2014;Lee et al, 2017;Lee et al, 2018;Mayor & Alano, 2015;Messina et al, 2018;Neveu et al, 2018;Rogers et al, 2000;Smalley et al 1981;Waseem et al, 2016;Wickramasinghe et al, 1987), Toxoplasma gondii (Brouland et al, 1996), Leishmania spp., (Ali & Hussain, 2014;Hellal & Kundu, 2013;Kumar et al, 2007), Schistosoma spp., (Azevedo et al, 2015;Jones & Leday, 2014;Kamal et al 1989) and Trypanosoma spp. (Baena Terán et al, 2012;Bockstal, Guirnalda, et al, 2011;Bockstal, Geurts, & Magez, 2011;Carbajosa et al, 2017;De Diego et al 1998;Felizardo et al, 2018;Habila et al, 2014;Mabbott & Sternberg, 1995;Müller et al, 2018;Obishakin et al 2014;Souza et al, 2014;Stijlemans et al, 2016).…”