In Vitro Alterations Do Not Reflect a Requirement for Host Cell Cycle Progression during Plasmodium Liver Stage Infection

Abstract

f 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.

Primaquine–quinoxaline 1,4-di-N-oxide hybrids with action on the exo-erythrocytic forms of Plasmodium induce their effect by the production of reactive oxygen species

“…These phenomena of cell survival can be due to mechanisms of adaptation of the niche of the host cell to their specific needs [36]. This approach is in agreement with the data observed at the cell cycle level, where a progression of the cycle was observed when comparing infected and uninfected cells.…”

“…This fact is consistent with the non-activation of the transcription factor p53 and caspase effector of apoptotic cell death, caspase 3 in infected cells and treated with the hybrids. Moreover, the hybrid 6b showed a negative regulation of p53, which is consistent with a higher probability of infection according to Kaushansky et al [36], since p53 was suppressed during the infection process. This result supports the notion that 6b induces its tissue schizontocidal activity in P. yoelii spp., by other mechanisms, since it is unable to induce the activation of p53 in the host cell.…”

Liver stage malaria infection is controlled by host regulators of lipid peroxidation

“…2a) [23]. We have previously demonstrated that elevated levels of P53 reduce LS burden, independent of the role of P53 in apoptosis, and likely independent of its role in promoting cell cycle arrest [12,13,24,25]. The small molecule Nutlin-3 binds the E3 ubiquitin ligase MDM-2, which under normal conditions acts to degrade P53, thereby increasing P53 protein levels [26].…”

Besnoitia besnoiti–driven endothelial host cell cycle alteration

“…Conversely, L. amazonensis interferes early in cell cycle by G0/G1-phase arrest (Kuzmenok et al 2005 ). In contrast, Plasmodium falciparum infections of HepG2 cells affect mitosis and lead to a binucleated phenotype and a lack of cell division (Hanson et al 2015 ). In the case of T. gondii , available data record different modes of action, on one side, an infection-driven shift from G0/G1 to S phase with an accumulation of host cells in S phase (Molestina et al 2008 ; Lavine and Arrizabalaga 2009 ).…”