Downloaded from http://perspectivesinmedicine.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press Anopheline Reproductive Biology: Impacts on Vectorial Capacity and Potential Avenues for Malaria Control Sara N. Mitchell and Flaminia Catteruccia Harvard T.H. Chan School of Public Health, Department of Immunology and Infectious Diseases, Boston, Massachusetts 02115 Correspondence: [email protected] Vectorial capacity is a mathematical approximation of the efficiency of vector-borne disease transmission, measured as the number of new infections disseminated per case per day by an insect vector. Multiple elements of mosquito biology govern their vectorial capacity, includ- ing survival, population densities, feeding preferences, and vector competence. Intriguingly, biological pathways essential to mosquito reproductive fitness directly or indirectly influence a number of these elements. Here, we explore this complex interaction, focusing on how the interplay between mating and blood feeding in female Anopheles not only shapes their reproductive success but also influences their ability to sustain Plasmodium parasite devel- opment. Central to malaria transmission, mosquito reproductive biology has recently become the focus of research strategies aimed at malaria control, and we discuss promising new methods based on the manipulation of key reproductive steps. In light of widespread resistance to all public health–approved insecticides targeting mosquito reproduction may prove crucial to the success of malaria-eradication campaigns. PLASMODIUM SPOROGONIC which after 2–3 days will culminate in ovula- DEVELOPMENT: A PROCESS INTIMATELY tion and oviposition. Sporogony and oogenesis TIED TO MOSQUITO REPRODUCTION are, therefore, temporally and physiologically www.perspectivesinmedicine.org coupled in the female mosquito (Fig. 1). ransmission of human Plasmodium para- At the start of sporogonic development, Tsites, the causative agents of malaria, relies male and female gametocytes—the sexual stage on the infectious bite of female Anopheles mos- of the Plasmodium parasite—are ingested and quitoes. In the mosquito midgut, sporogonic enter the mosquito midgut where they imme- development starts within minutes of a female diately form gametes, triggered by a drop in taking a blood meal on an infected vertebrate surrounding temperature and by the presence host. At the same time, nutrients derived from of other mosquito-specific factors (Billker et al. the digestion of the blood meal accumulate in 1997, 1998; McRobert et al. 2008; Kuehn and the ovaries during the process of oogenesis, Pradel 2010). After escaping the enveloping Editors: Dyann F. Wirth and Pedro L. Alonso Additional Perspectives on Malaria: Biology in the Era of Eradication available at www.perspectivesinmedicine.org Copyright # 2017 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a025593 Cite this article as Cold Spring Harb Perspect Med 2017;7:a025593 1 Downloaded from www.perspectivesinmedicine.org http://perspectivesinmedicine.cshlp.org/ S.N. Mitchell and F. Catteruccia 2 Midgut Blood bolus Gametes Fertilization Ookinete Developing oocyst Sporozoites Salivary glands Midgut epithelium onOctober2,2021-PublishedbyColdSpringHarborLaboratoryPress Time (not to scale) Cite this article as 0 h 18–24 h 48 h 72 h 4 d 6 d 8 d 10 d 12 d 14 d Ovaries Cold Spring Harb Perspect Med Oviposition BF BF One gonotrophic cycle (GC) 2 GC 3 GC 4 GC Figure 1. Plasmodium sporogony and anopheline oogenesis are temporally and physiologically tied in the mosquito. When a female Anopheles mosquito takes a blood meal from a malaria-infected host, two processes immediately begin within the midgut: Plasmodium gametogenesis, and digestion of the blood bolus for the production of nutrients vital for oogenesis. Within the first 3 days after feeding, a female will have completed her first gonotrophic cycle (GC) consisting of blood 2017;7:a025593 feeding, egg development, and oviposition. During this same 72-h period, the Plasmodium gametes will have fused to produce first a zygote and, subsequently, a motile ookinete form, which traverses the midgut epithelium before developing into an oocyst. Over the course of the next 10 days, the oocysts will produce transmission-stage sporozoites, whereas the female will undergo additional gonotrophic cycles, potentially becoming infectious on sporozoites reaching her salivary glands. BF, Blood feeding. Downloaded from http://perspectivesinmedicine.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press Anopheline Reproductive Biology and Malaria erythrocyte, male gametocytes rapidly exflagel- regulator, 20E induces the expression of YPPs, late to produce eight motile microgametes, including vitellogenin (Vg) and the lipid trans- which fuse with female macrogametes to form porter lipophorin (Lp), which provision the a diploid zygote. During the next 18–24 h, developing oocytes with lipids. 20E and YPPs as the female digests the blood bolus in her are integral to egg development in the malaria midgut, the Plasmodium zygote will transform vector Anopheles gambiae (Atella et al. 2006; into a motile ookinete, which traverses the peri- Bai et al. 2010), with 20E also fundamental to trophic matrix and midgut epithelium to reach oogenesis in a number of insect species, includ- the basal lamina. Here, the ookinete will encyst, ing the fruit fly (Drosophila melanogaster) and differentiating into an oocyst. The initiation of the silk moth (Bombyx mori) (Swevers and oocyst development coincides with the comple- Iatrou 2003; Belles and Piulachs 2015), suggest- tion of oogenesis in the mosquito ovaries, and if ing conservation of this hormonally controlled inseminated, the female will seek a suitable site process. to oviposit her eggs. Over the next 8–15 days Interestingly, the YPPs that facilitate oogen- (depending on Plasmodium species and extrin- esis also promote Plasmodium development via sic factors), the oocyst undergoes rapid growth mechanisms that include protection from the and cellular division to produce thousands of mosquito’s innate immune response (Vlachou infective sporozoites. After rupture of the oocyst et al. 2005; Mendes et al. 2008; Rono et al. 2010). wall, the mature sporozoites will migrate to and RNAi-based knockdown of YPP Lp in An. gam- invade the salivary glands, ready to be injected biae infected with the rodent parasite Plasmodi- into the host when the female takes her next um berghei resulted in reduced oocyst numbers blood meal. During this period, the female and abolished egg development (Vlachou et al. mosquito may undergo up to three additional 2005). It was subsequently demonstrated that gonotrophic cycles consisting of a blood meal, the expression and combined action of Lp and egg development, and oviposition (Fig. 1). This Vg after a blood meal blocks the parasite killing lengthy sporogonic cycle means that only a action of the complement-like factor thioester- small proportion of female mosquitoes will ac- containing protein 1 (TEP1) (Rono et al. 2010). tually survive long enough in nature to become TEP1 was previously shown to severely impair infective with Plasmodium sporozoites and development of Plasmodium species (Levashina transmit disease (Charlwood et al. 1997; Killeen et al. 2001; Blandin et al. 2004), including the et al. 2000). Therefore, control interventions most deadly human malaria parasite Plasmodi- that target female mosquito life span are partic- um falciparum (Dong et al. 2009; Garver et al. ularly successful in reducing malaria transmis- 2009; Eldering et al. 2016). In the absence of Vg, www.perspectivesinmedicine.org sion in the field (Macdonald 1956; Smith et al. TEP1 binds more efficiently to the surface of 2012). P. berghei ookinetes, resulting in higher killing Our understanding of the processes regulat- efficiency. Similarly, Lp knockdown resulted in ing egg development in the mosquito is largely reduced P. falciparum oocyst load, although the derived from studies in the arboviral vector precise mechanism was not confirmed (Mendes Aedes aegypti (reviewed in Attardo et al. 2005; et al. 2008). Others have shown incorporation of Hansen et al. 2014). Oogenesis starts with Lp loaded with lipids into the Plasmodium oo- the synthesis and secretion of yolk protein cysts in Aedes mosquitoes (Atella et al. 2009) precursors (YPPs) and deposition into the and, although the function of these lipids in developing oocytes. After a blood meal, the the parasite is not known, silencing Lp reduces mosquito brain is triggered to release ovary ec- oocyst size in An. gambiae (Rono et al. 2010). dysteroidogenic hormone that stimulates the Overall, it appears that malaria parasites have ovaries to produce the steroid hormone ecdy- developed a system by which vitellogenic factors sone (E). The latter, in turn, is hydroxylated to produced after a blood meal can be coopted to produce the active 20-hydroxyecdysone (20E) facilitate Plasmodium development within the form in the fat body. A potent transcriptional mosquito. Cite this article as Cold Spring Harb Perspect Med 2017;7:a025593 3 Downloaded from http://perspectivesinmedicine.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press S.N. Mitchell and F. Catteruccia THE COST OF INFECTION: POTENTIAL FOR with P. falciparum showed a 10% decrease in TRADE-OFFS BETWEEN REPRODUCTION egg numbers (Hogg and Hurd 1997). AND IMMUNITY DURING PARASITE Although the potential trade-off between DEVELOPMENT