title: In vitro alterations do not reflect a requirement for host cell cycle progression during Plasmodium liver stage infection.
abstract: Prior to invading nonreplicative erythrocytes, Plasmodium parasites undergo their first obligate step in the mammalian host inside hepatocytes, where each sporozoite replicates to generate thousands of merozoites. While normally quiescent, hepatocytes retain proliferative capacity and can readily reenter the cell cycle in response to diverse stimuli. Many intracellular pathogens, including protozoan parasites, manipulate the cell cycle progression of their host cells for their own benefit, but it is not known whether the hepatocyte cell cycle plays a role during Plasmodium liver stage infection. Here, we show that Plasmodium parasites can be observed in mitotic hepatoma cells throughout liver stage development, where they initially reduce the likelihood of mitosis and ultimately lead to significant acquisition of a binucleate phenotype. However, hepatoma cells pharmacologically arrested in S phase still support robust and complete Plasmodium liver stage development, which thus does not require cell cycle progression in the infected cell in vitro. Furthermore, murine hepatocytes remain quiescent throughout in vivo infection with either Plasmodium berghei or Plasmodium yoelii, as do Plasmodium falciparum-infected primary human hepatocytes, demonstrating that the rapid and prodigious growth of liver stage parasites is accomplished independent of host hepatocyte cell cycle progression during natural infection.
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Kirsten K
authors.initials: KK
authors.lastname: Hanson
authors.affiliation: Health Sciences and Technology/Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: March
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Shengyong
authors.initials: S
authors.lastname: Ng
authors.affiliation: Health Sciences and Technology/Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA Broad Institute, Cambridge, Massachusetts, USA Howard Hughes Medical Institute, Koch Institute, and Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Sangeeta N
authors.initials: SN
authors.lastname: Bhatia
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal mmota@fm.ul.pt.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Mota
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000502:physiology; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology / Q000469:parasitology / Q000502:physiology*; D006790:Host-Parasite Interactions; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008938:Mitosis; D010961:Plasmodium / Q000254:growth & development* / Q000472:pathogenicity; D034101:Sporozoites / Q000502:physiology*