TY - JOUR
T1 - Disruption of the plasmodium falciparum liver-stage antigen-1 locus causes a differentiation defect in late liver-stage parasites
AU - Mikolajczak, Sebastian A.
AU - Sacci, John B.
AU - De La Vega, Patricia
AU - Camargo, Nelly
AU - Vanbuskirk, Kelly
AU - Krzych, Urszula
AU - Cao, Jun
AU - Jacobs-Lorena, Marcelo
AU - Cowman, Alan F.
AU - Kappe, Stefan H.I.
PY - 2011/8
Y1 - 2011/8
N2 - The malaria parasite Plasmodium falciparum infects humans and first targets the liver where liver-stage parasites undergo pre-erythrocytic replication. Liver-stage antigen-1 (LSA-1) is currently the only identified P. falciparum protein for which expression is restricted to liver stages. Yet, the importance of LSA-1 for liver-stage parasite development remains unknown. Here we deleted LSA-1 in the NF54 strain of P. falciparum and analysed the lsa-1- parasites throughout their life cycle. lsa-1- sporozoites had normal gliding motility and invasion into hepatocytes. Six days after infection of a hepatocytic cell line, lsa-1- parasites exhibited a moderate phenotype with an∼50% reduction of late liver-stage forms when compared with wild type. Strikingly, lsa-1- parasites growing in SCID/Alb-uPA mice with humanized livers showed a severe defect in late liver-stage differentiation and exo-erythrocytic merozoite formation 7 days after infection, a time point when wild-type parasites develop into mature merozoites. The lsa-1- parasites also showed aberrant liver-stage expression of key parasite proteins apical membrane antigen-1 and circumsporozoite protein. Our data show that LSA-1 plays a critical role during late liver-stage schizogony and is thus important in the parasite transition from the liver to blood. LSA-1 is the first P. falciparum protein identified to be required for this transitional stage of the parasite life cycle.
AB - The malaria parasite Plasmodium falciparum infects humans and first targets the liver where liver-stage parasites undergo pre-erythrocytic replication. Liver-stage antigen-1 (LSA-1) is currently the only identified P. falciparum protein for which expression is restricted to liver stages. Yet, the importance of LSA-1 for liver-stage parasite development remains unknown. Here we deleted LSA-1 in the NF54 strain of P. falciparum and analysed the lsa-1- parasites throughout their life cycle. lsa-1- sporozoites had normal gliding motility and invasion into hepatocytes. Six days after infection of a hepatocytic cell line, lsa-1- parasites exhibited a moderate phenotype with an∼50% reduction of late liver-stage forms when compared with wild type. Strikingly, lsa-1- parasites growing in SCID/Alb-uPA mice with humanized livers showed a severe defect in late liver-stage differentiation and exo-erythrocytic merozoite formation 7 days after infection, a time point when wild-type parasites develop into mature merozoites. The lsa-1- parasites also showed aberrant liver-stage expression of key parasite proteins apical membrane antigen-1 and circumsporozoite protein. Our data show that LSA-1 plays a critical role during late liver-stage schizogony and is thus important in the parasite transition from the liver to blood. LSA-1 is the first P. falciparum protein identified to be required for this transitional stage of the parasite life cycle.
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U2 - 10.1111/j.1462-5822.2011.01617.x
DO - 10.1111/j.1462-5822.2011.01617.x
M3 - Article
C2 - 21569184
AN - SCOPUS:79960423715
SN - 1462-5814
VL - 13
SP - 1250
EP - 1260
JO - Cellular microbiology
JF - Cellular microbiology
IS - 8
ER -