Figure 5. Schematic model to distinguish hypnozoites from other liver stages based on PI4K drug susceptibility.

Malaria liver stage infection begins when infective sporozoites injected by mosquitoes invade host hepatocytes. Within hepatocytes, sporozoites transform into hepatic schizonts for 7–9 days and subsequently, mature schizonts burst and release pathogenic merozoites into blood circulation (Prudêncio et al., 2011). Sporozoite transformation into early liver stage development coincides with LISP2 expression. LISP2 expression marks the beginning of liver stage development at day 3 and its expression increases as liver stage progresses into complete maturation. Sporozoites of relapsing malaria species such as P. vivax and P. cynomolgi can generate dormant hypnozoites (Wells et al., 2010). LISP2- Hz exhibits UIS4 prominence on PVM (shown in green) and grows till day 5 and remains persistent and unchanged from day 5 onwards. LISP2 +Tz display crescent staining pattern (shown in red) which colocalizes with UIS4 protein on PVM. Beyond day 6 post-sporozoite infection, both LISP2- Hz and LISP2+ Tz have identical size and can only be discriminated on the basis of susceptibility to PI4K inhibitor. The shaded areas (in orange) represent the parasite that can be eliminated by both PI4K inhibitors and 8-aminoquinoline drugs. The non-shaded area in the model represents only LISP2- Hz which is resistant to PI4K and can be eliminated only by 8-aminoquinoline drugs. List of supplemental tables.