Human hemoglobin protects the parasite cytoskeleton during Plasmodium falciparum gametocyte development

Transmission of Plasmodium falciparum requires the differentiation of asexual parasites into male and female gametocytes, which undergo extensive cytoskeletal remodeling, assembling a non-canonical subpellicular microtubule (SPMT) network. Using single-particle cryo-electron microscopy, we determined structures of SPMTs isolated from developing gametocytes. Unexpectedly, we identified human hemoglobin as a prominent microtubule-associated factor that binds to P. falciparum SPMTs in a dimeric form rather than the canonical tetramer. Pharmacological perturbation of microtubules and hemoglobin isoform switching experiments demonstrate that this hemoglobin-SPMT association is essential for proper SPMT organization and gametocyte maturation. Together, these findings reveal a strategy by which P. falciparum repurposes a host metabolic protein to stabilize its cytoskeleton, highlight the intimate co-evolution between parasite and host, and suggest avenues to block malaria transmission. Wang et al. apply single particle cryo-EM to developing gametocytes of Plasmodium falciparum, and identify human hemoglobin as a prominent factor that binds to P. falciparum subpellicular microtubule (SPMT) network.