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Determining the interactions between mosquito oogenesis and Plasmodium falciparum survival and transmission

Award Number: R01AI153404
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Determining the interactions between mosquito oogenesis and Plasmodium falciparum survival and transmission - PROJECT ABSTRACT Anopheles gambiae females are the most important vectors of human malaria in sub-Saharan Africa. During their lives, these females feed on blood several times to undergo multiple gonotrophic cycles of egg development and egg laying. These reproductive cycles, largely orchestrated by the steroid hormone 20- hydroxyecdysone (20E), are exploited by Plasmodium falciparum parasites for transmission between human hosts. The time required for parasite development—from ingestion of male and female gametocytes to sporozoite invasion of salivary glands—is called the Extrinsic Incubation Period (EIP) and is a key factor in malaria transmission dynamics, especially when considering the limited lifespan of mosquitoes. Despite its relevance for parasite transmission, the link between parasite development and oogenesis has not been fully explored, and important questions such as whether Plasmodium survival and growth depends on pathways that promote egg development are still largely understudied. In a recent study, we revealed substantial physiological links between P. falciparum development and An. gambiae reproductive processes that shape oogenesis. We have unveiled an unexpected positive correlation between egg and oocyst numbers and have shown that, in instances where 20E function is impaired, reduced oogenesis induces a decrease in parasite intensities. Manipulating egg development by these and other 20E-independent means, however, accelerates Plasmodium growth rates, shortening the EIP and allowing sporozoites to become infectious sooner. Faster growth depends on the accumulation of blood meal-derived midgut lipids trafficked to the ovaries by the lipid transporter Lipophorin (Lp). Our outstanding questions concern the mechanisms by which 20E-regulated oogenetic processes affect parasite numbers, and how the EIP is affected by egg development and Lp-transported lipids in the natural context of multiple gonotrophic cycles. Preliminary evidence suggests that the mis-regulation of 20E signaling may cause parasite death via oxidative stress and/or apoptosis. Moreover, we show that an additional blood meal significantly accelerates parasite growth, while our initial field infections in Burkina Faso suggest the EIP is regulated by parasite genetic determinants. Here we will perform lab and field studies to determine how oogenesis impacts the biology of P. falciparum in the An. gambiae female, from establishment of infection to sporozoite transmission and across multiple reproductive cycles. Specifically, we will: Aim 1) determine the fundamental mechanism by which parasite numbers are reduced when egg development is impaired; Aim 2) analyze how a second gonotrophic cycle affects the EIP and sporozoite infectivity to human hepatocytes; and Aim 3) determine in field infections whether the EIP is regulated by parasite genetic factors. This project will not only fill critical knowledge gaps in mosquito-parasite interactions but will also provide crucial information for control strategies that aim to reduce the reproductive output of mosquito populations.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $693,117 )
2024	2024	HARVARD COLLEGE PRESIDENT & FELLOWS OF	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	5	5/22/2024	NON-COMPETING CONTINUATION	$693,117
														Subtotal = $693,117

Issue Date FY: 2023 ( Subtotal = $740,203 )
2023	2023	HARVARD COLLEGE PRESIDENT & FELLOWS OF	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	4	5/15/2023	NON-COMPETING CONTINUATION	$740,203
														Subtotal = $740,203

Issue Date FY: 2022 ( Subtotal = $768,986 )
2022	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	3	5/17/2022	NON-COMPETING CONTINUATION	$768,986
														Subtotal = $768,986

Issue Date FY: 2021 ( Subtotal = $748,438 )
2021	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	2	5/27/2021	NON-COMPETING CONTINUATION	$748,438
														Subtotal = $748,438

Issue Date FY: 2020 ( Subtotal = $775,395 )
2020	2020	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	1	6/11/2020	NEW	$775,395
														Subtotal = $775,395

Grand Total All Awards = $3,726,139

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Determining the interactions between mosquito oogenesis and Plasmodium falciparum survival and transmission

Award Number: R01AI153404

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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