Cryptic erythrocytic infections in Plasmodium vivax, another challenge to its elimination

Fernández-Becerra, Carmen; Aparici-Herraiz, Iris; Portillo, Hernando A. del

doi:10.1016/j.parint.2021.102527

Cited by 11 publications

(16 citation statements)

References 74 publications

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“…A caveat for studying the cellular dynamics within the immune system while relying solely on peripheral blood or bone marrow is that not all immune cell types of interest, or their specific activated phenotypes, are necessarily circulating in the blood or present in the bone marrow. Moreover, a subset of iRBCs can become sequestered or concealed in various tissues and organs [ 24 , 112 , 151 , 152 , 267 , 268 , 274 , 277 ], so that peripheral blood parasitaemia counts do not necessarily reflect the true parasite load in the host (reviewed in [ 24 , 97 , 110 , 196 ]). Tissue samples other than peripheral blood can seldom be obtained from humans.…”

Section: Discussionmentioning

confidence: 99%

“…In these cases, other types of host–parasite interactions must account for the removal of subpopulations from circulation and possible associated disease manifestations. Above all, what has become clear, is that for all Plasmodium species, the circulating iRBCs represented in blood smear parasitaemias, do not necessarily represent the entire parasite load, or parasite burden in infected individuals (reviewed in [ 24 , 97 , 110 , 196 ]). First, there can be multiple broods of parasites in an individual, each in different stages of the life cycle.…”

Section: Twenty-first Century—turning Point In Malaria Researchmentioning

confidence: 99%

“…In the early stages of infection, P. falciparum gametocytes have been found in the bone marrow, where their maturation takes place [ 258 – 261 ], and the bone marrow has also been recognized as a development niche or reservoir for P. vivax gametocytes [ 262 ]. Surprisingly, the spleen has also become recognized as a biologically relevant tissue site for P. vivax iRBCs in humans [ 263 – 265 ], presumptively to support reticulocyte host cell invasion and the asexual blood-stage development cycle (reviewed in [ 110 ]). Aotus and Saimiri monkey NHP infection studies have demonstrated and quantified the burden of P. vivax iRBCs in these tissues relative to others [ 151 , 152 , 266 ].…”

Section: Twenty-first Century—turning Point In Malaria Researchmentioning

confidence: 99%

“…A study based on Aotus monkey infections has also indicated that the spleen influenced transcription of 67 P. vivax genes [ 109 ]. Moreover, the spleen has become recognized as a niche for a subpopulation of P. vivax iRBCs, possibly to promote their invasion and replication in host reticulocytes (reviewed in [ 110 ]) . Interestingly in this regard, P. cynomolgi infections became attenuated when passaged in splenectomized rhesus [ 111 ].…”

Section: Introductionmentioning

confidence: 99%

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Systems biology of malaria explored with nonhuman primates

Galinski

2022

Malar J

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Abstract“The Primate Malarias” book has been a uniquely important resource for multiple generations of scientists, since its debut in 1971, and remains pertinent to the present day. Indeed, nonhuman primates (NHPs) have been instrumental for major breakthroughs in basic and pre-clinical research on malaria for over 50 years. Research involving NHPs have provided critical insights and data that have been essential for malaria research on many parasite species, drugs, vaccines, pathogenesis, and transmission, leading to improved clinical care and advancing research goals for malaria control, elimination, and eradication. Whilst most malaria scientists over the decades have been studying Plasmodium falciparum, with NHP infections, in clinical studies with humans, or using in vitro culture or rodent model systems, others have been dedicated to advancing research on Plasmodium vivax, as well as on phylogenetically related simian species, including Plasmodium cynomolgi, Plasmodium coatneyi, and Plasmodium knowlesi. In-depth study of these four phylogenetically related species over the years has spawned the design of NHP longitudinal infection strategies for gathering information about ongoing infections, which can be related to human infections. These Plasmodium-NHP infection model systems are reviewed here, with emphasis on modern systems biological approaches to studying longitudinal infections, pathogenesis, immunity, and vaccines. Recent discoveries capitalizing on NHP longitudinal infections include an advanced understanding of chronic infections, relapses, anaemia, and immune memory. With quickly emerging new technological advances, more in-depth research and mechanistic discoveries can be anticipated on these and additional critical topics, including hypnozoite biology, antigenic variation, gametocyte transmission, bone marrow dysfunction, and loss of uninfected RBCs. New strategies and insights published by the Malaria Host–Pathogen Interaction Center (MaHPIC) are recapped here along with a vision that stresses the importance of educating future experts well trained in utilizing NHP infection model systems for the pursuit of innovative, effective interventions against malaria.

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Section: Discussionmentioning

confidence: 99%

Section: Twenty-first Century—turning Point In Malaria Researchmentioning

confidence: 99%

Section: Twenty-first Century—turning Point In Malaria Researchmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Systems biology of malaria explored with nonhuman primates

Galinski

2022

Malar J

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“…Clearly, as is known for P. knowlesi and most species of Plasmodium where all blood-stage forms circulate, avoidance of the spleen does not fit as the main function of potentially adhesive surface-exposed proteins. In fact, all other Plasmodium species known to infect humans do not have comparable var/SICAvar genes ( P. vivax , P. malariae , P. ovale , P. cynomolgi ) ( Tachibana et al., 2012 ; Rutledge et al., 2017 ; Imwong et al., 2018 ) and all their iRBC developmental life cycle stages circulate, seemingly unaffected by passage through the spleen (or potentially even benefiting from intra-splenic interactions (reviewed in Kho et al., 2021 ; Fernandez-Becerra et al., 2022 ). All iRBC developmental forms of these species circulate despite P. malariae and P. ovale sharing knobby iRBC surface phenotypes ( Matsumoto et al., 1986 ; Li et al., 2010 ) that are morphologically similar to those in P. falciparum infections ( Gruenberg et al., 1983 ; Aikawa et al., 1996 ).…”

Section: Discussionmentioning

confidence: 99%

Plasmodium knowlesi Cytoadhesion Involves SICA Variant Proteins

Peterson

Joyner²,

Lapp³

et al. 2022

Front. Cell. Infect. Microbiol.

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Plasmodium knowlesi poses a health threat throughout Southeast Asian communities and currently causes most cases of malaria in Malaysia. This zoonotic parasite species has been studied in Macaca mulatta (rhesus monkeys) as a model for severe malarial infections, chronicity, and antigenic variation. The phenomenon of Plasmodium antigenic variation was first recognized during rhesus monkey infections. Plasmodium-encoded variant proteins were first discovered in this species and found to be expressed at the surface of infected erythrocytes, and then named the Schizont-Infected Cell Agglutination (SICA) antigens. SICA expression was shown to be spleen dependent, as SICA expression is lost after P. knowlesi is passaged in splenectomized rhesus. Here we present data from longitudinal P. knowlesi infections in rhesus with the most comprehensive analysis to date of clinical parameters and infected red blood cell sequestration in the vasculature of tissues from 22 organs. Based on the histopathological analysis of 22 tissue types from 11 rhesus monkeys, we show a comparative distribution of parasitized erythrocytes and the degree of margination of the infected erythrocytes with the endothelium. Interestingly, there was a significantly higher burden of parasites in the gastrointestinal tissues, and extensive margination of the parasites along the endothelium, which may help explain gastrointestinal symptoms frequently reported by patients with P. knowlesi malarial infections. Moreover, this margination was not observed in splenectomized rhesus that were infected with parasites not expressing the SICA proteins. This work provides data that directly supports the view that a subpopulation of P. knowlesi parasites cytoadheres and sequesters, likely via SICA variant antigens acting as ligands. This process is akin to the cytoadhesive function of the related variant antigen proteins, namely Erythrocyte Membrane Protein-1, expressed by Plasmodium falciparum.

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