It is a main component in the fertilization process as male gametes with impaired Pfs230 gene are incapable of interacting with red blood cells (RBCs) and forming exflagellation centers (100)

It is a main component in the fertilization process as male gametes with impaired Pfs230 gene are incapable of interacting with red blood cells (RBCs) and forming exflagellation centers (100). referred to as sexual commitment into both male (microgametocyte) and female (macrogametocyte) gametocytes (Physique Trigonelline 1). This process is known as gametocytogenesis (7, 8). Open in a separate windows Physique 1 Life cycle of development in the human host and mosquito vector. (1). Mosquito’s bite and release sporozoites into the human host followed by migration into the liver. (2). Pre-erythrocytic schizogony: contamination of hepatocytes and asexual multiplication of the parasites in the liver. (3). Erythrocytic schizogony: translocation of parasites from the liver into the bloodstream accompanied by asexual multiplication and release of merozoites upon RBC rupture. (4). Gametocyte generation: sexual commitment, sequestration of early gametocytes, maturation in tissues and release of mature gametocytes in blood (ready to be picked up by the vector). (5). Parasite development in the mosquito midgut: exflagellation of male gametocytes prior to fertilization which yields the zygote which undergoes further development into a motile ookinete. (6). Parasite CENPF development in the mosquito salivary gland: oocyst formation, sporozoite development, and release in the mosquito salivary gland (ready to be transmitted to the human host during subsequent mosquito bites). Sexually committed ring stage trophozoites from erythrocytic stages in peripheral circulation (9, 10) progress into gametocyte developmental stages 1 to IV while sequestered in bone marrow compartments (11C14). This constitutes the main reason why only late gametocyte stages are found in peripheral circulation. Early gametocytes are thought to sequester in tissues such as spleen and bone marrow through parasite-host interactions via parasite molecules less elucidated Trigonelline but probably PfEMP1, STEVORS, or RIFINS (14C16). The human host endothelial receptors mediating sequestration of developing gametocytes in the bone marrow and other organs however remain unidentified (17). Differentiation of male and female gametocytes occur during sexual commitment where the asexual precursor, schizont, give rise to either male or female gametocytes (7, 8). After about 10C12 days of sequestered development, mature, male, and female gametocytes emerge and circulate in peripheral blood for a variable amount of time until taken up by mosquitoes (18, 19). Gametocytes do not replicate; however, hemoglobin digestion continues until they reach stage IV (20). In addition, gametocyte-specific mRNAs are produced and a subset of these, important for their stage development in the mosquito, are translationally repressed until gametocytes are taken up by the vector when they go back to Trigonelline peripheral circulation (21). The phenomenon governing the return of mature Trigonelline gametocytes in the peripheral blood is not clearly comprehended. Once ingested, gametocytes rapidly transform into male (microgamete) and female gametes (macrogamete) in response to environmental cues such as a rise in pH, reduction in heat and exposure to xanthurenic acid (22). Exflagellation (male gamete induction) is usually followed by the expression of gamete-specific proteins (23). Fertilization of macrogametocytes by microgametes is usually preceded by 3 rounds of DNA replication by male gametocytes giving rise to 8 motile microgametes resulting in a zygote (Physique 1). The zygote elongates to form an ookinete which crosses the midgut wall to develop into an oocyst. Further cell divisions and development of the oocyst give rise to sporozoites. Following oocyst capsule rupture, thousands of sporozoites emerge and invade the mosquito salivary glands which then render the vector infectious to humans during a bloodmeal, thus completing the transmission cycle (24C26) (Physique 1). The infectiousness and transmission potential of gametocytes is usually influenced by their prevalence and density (27), degree of maturity (28), and both mosquito and human Trigonelline immune responses (29, 30). Furthermore, the efficiency of transmission depends on the generation of sporozoites and therefore level of infectivity or sporozoite dose transmitted (31). Moreover, the sporogonic stages are exposed to the vector’s natural immune responses.