TY - JOUR
T1 - Systemic host inflammation induces stage-specific transcriptomic modification and slower maturation in malaria parasites
AU - Lansink, Lianne I.M.
AU - Skinner, Oliver P.
AU - Engel, Jessica A.
AU - Lee, Hyun Jae
AU - Soon, Megan S.F.
AU - Williams, Cameron G.
AU - SheelaNair, Arya
AU - Pernold, Clara P.S.
AU - Laohamonthonkul, Pawat
AU - Akter, Jasmin
AU - Stoll, Thomas
AU - Hill, Michelle M.
AU - Talman, Arthur M.
AU - Russell, Andrew
AU - Lawniczak, Mara
AU - Jia, Xiaoxiao
AU - Chua, Brendon
AU - Anderson, Dovile
AU - Creek, Darren J.
AU - Davenport, Miles P.
AU - Khoury, David S.
AU - Haque, Ashraful
PY - 2023/8/31
Y1 - 2023/8/31
N2 - Maturation rates of malaria parasites within red blood cells (RBCs) can be influenced by host nutrient status and circadian rhythm; whether host inflammatory responses can also influence maturation remains less clear. Here, we observed that systemic host inflammation induced in mice by an innate immune stimulus, lipopolysaccharide (LPS), or by ongoing acute Plasmodium infection, slowed the progression of a single cohort of parasites from one generation of RBC to the next. Importantly, plasma from LPS-conditioned or acutely infected mice directly inhibited parasite maturation during in vitro culture, which was not rescued by supplementation, suggesting the emergence of inhibitory factors in plasma. Metabolomic assessments confirmed substantial alterations to the plasma of LPS-conditioned and acutely infected mice, and identified a small number of candidate inhibitory metabolites. Finally, we confirmed rapid parasite responses to systemic host inflammation in vivo using parasite scRNA-seq, noting broad impairment in transcriptional activity and translational capacity specifically in trophozoites but not rings or schizonts. Thus, we provide evidence that systemic host inflammation rapidly triggered transcriptional alterations in circulating blood-stage Plasmodium trophozoites and predict candidate inhibitory metabolites in the plasma that may impair parasite maturation in vivo. IMPORTANCE Malaria parasites cyclically invade, multiply, and burst out of red blood cells. We found that a strong inflammatory response can cause changes to the composition of host plasma, which directly slows down parasite maturation. Thus, our work highlights a new mechanism that limits malaria parasite growth in the bloodstream.
AB - Maturation rates of malaria parasites within red blood cells (RBCs) can be influenced by host nutrient status and circadian rhythm; whether host inflammatory responses can also influence maturation remains less clear. Here, we observed that systemic host inflammation induced in mice by an innate immune stimulus, lipopolysaccharide (LPS), or by ongoing acute Plasmodium infection, slowed the progression of a single cohort of parasites from one generation of RBC to the next. Importantly, plasma from LPS-conditioned or acutely infected mice directly inhibited parasite maturation during in vitro culture, which was not rescued by supplementation, suggesting the emergence of inhibitory factors in plasma. Metabolomic assessments confirmed substantial alterations to the plasma of LPS-conditioned and acutely infected mice, and identified a small number of candidate inhibitory metabolites. Finally, we confirmed rapid parasite responses to systemic host inflammation in vivo using parasite scRNA-seq, noting broad impairment in transcriptional activity and translational capacity specifically in trophozoites but not rings or schizonts. Thus, we provide evidence that systemic host inflammation rapidly triggered transcriptional alterations in circulating blood-stage Plasmodium trophozoites and predict candidate inhibitory metabolites in the plasma that may impair parasite maturation in vivo. IMPORTANCE Malaria parasites cyclically invade, multiply, and burst out of red blood cells. We found that a strong inflammatory response can cause changes to the composition of host plasma, which directly slows down parasite maturation. Thus, our work highlights a new mechanism that limits malaria parasite growth in the bloodstream.
KW - host inflammation
KW - host-parasite interaction
KW - malaria
KW - metabolomics
KW - parasite maturation
KW - Plasmodium
KW - single-cell transcriptomics
UR - http://www.scopus.com/inward/record.url?scp=85169504663&partnerID=8YFLogxK
U2 - 10.1128/mbio.01129-23
DO - 10.1128/mbio.01129-23
M3 - Article
C2 - 37449844
AN - SCOPUS:85169504663
SN - 2150-7511
VL - 14
JO - mBio
JF - mBio
IS - 4
M1 - e0112923
ER -