An essential role of the basal body protein SAS-6 in Plasmodium male gamete development and malaria transmission.

Sara R Marques,Michael J Delves,Robert E Sinden,Andrew M Blagborough,Arthur M Talman,Raffaella Carzaniga,Chandra Ramakrishnan

doi:10.1111/cmi.12355

Sara R Marques, Michael J Delves + Show 5 more

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https://doi.org/10.1111/cmi.12355

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Abstract

Gametocytes are the sole Plasmodium parasite stages that infect mosquitoes; therefore development of functional gametes is required for malaria transmission. Flagellum assembly of the Plasmodium male gamete differs from that of most other eukaryotes in that it is intracytoplasmic but retains a key conserved feature: axonemes assemble from basal bodies. The centriole/basal body protein SAS-6 normally regulates assembly and duplication of these organelles and its depletion causes severe flagellar/ciliary abnormalities in a diverse array of eukaryotes. Since basal body and flagellum assembly are intimately coupled to male gamete development in Plasmodium, we hypothesized that SAS-6 disruption may cause gametogenesis defects and perturb transmission. We show that Plasmodium berghei sas6 knockouts display severely abnormal male gametogenesis presenting reduced basal body numbers, axonemal assembly defects and abnormal nuclear allocation. The defects in gametogenesis reduce fertilization and render Pbsas6 knockouts less infectious to mosquitoes. Additionally, we show that lack of Pbsas6 blocks transmission from mosquito to vertebrate host, revealing an additional yet undefined role in ookinete to sporulating oocysts transition. These findings underscore the vulnerability of the basal body/SAS-6 to malaria transmission blocking interventions.

Highlights

Plasmodium is the causative agent of malaria, a deadly disease spread by mosquito vectors
Gametocytes are the sole Plasmodium parasite stages that infect mosquitoes; development of functional gametes is required for malaria transmission
Flagellum assembly of the Plasmodium male gamete differs from that of most other eukaryotes in that it is intracytoplasmic but retains a key conserved feature: axonemes assemble from basal bodies

Summary

Introduction

Plasmodium is the causative agent of malaria, a deadly disease spread by mosquito vectors. Gametocytes are the only parasite stages transmitted from the host to the mosquito, where sexual reproduction occurs. When a mosquito bites an infected host, ingested male and female gametocytes are activated to undergo gametogenesis forming dimorphic motile male microgametes and sessile female macrogametes, which fertilize forming ookinetes. Oocysts undergo endomitosis and upon maturation release several thousand sporozoites which invade the salivary glands and can be injected with the mosquito saliva into the skin of naive hosts, perpetuating the life cycle. While facultative for the majority of parasite pathogens, gametogenesis and fertilization are obligate steps of the Plasmodium life cycle (Heitman, 2010), disrupting either process prevents infection of new hosts. Because the focus of malaria studies has been to cure the symptoms of disease which are caused by asexual parasites (Fidock, 2010), the molecular aspects of gametogenesis, which solely cause transmission, remain comparatively poorly understood (Guttery et al, 2012)

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