Vector-Parasite Interactions and Malaria Transmission

*Nekpen Erhunse and Victor Okomayin*

#### **Abstract**

Malaria remains one of the world's most devastating vector-borne diseases. During the complex sexual development of the malaria parasite in the mosquito, it is faced with physical and physiological barriers which it must surmount before it can be transmitted to a human host. Proof-of-concept studies using RNAi have unearthed several parasite molecules which are important for countering the immunity of its vector. Understanding the counter-adaptations between the parasite and its vector could inform novel public health intervention strategies. For instance, it could guide the transgenic construction of resistant mosquitoes in which mosquito factors that restrict the parasite growth have been enhanced and/or factors promoting parasite growth deleted so as to make them refractory to malaria parasite infection. Such strategies, when deemed feasible, could be combined with conventional vector control methods as well as treatment of infection with effective malaria therapy, to actualize the malaria eradication goal.

**Keywords:** malaria transmission, vector-parasite interactions, transmission-blocking strategies, genetics-based tools, malaria eradication

#### **1. Introduction**

Malaria is one of the world's deadliest parasitic diseases affecting hundreds of millions of people worldwide. In 2020, the World Health Organization (WHO) reported an estimate of 241 million cases as compared to 227 million cases in 2019, with the number of deaths standing at 627,000 [1]. Due to the spread of insecticide-resistant mosquitoes as well as the development of *Plasmodium falciparum* resistant strains, control strategies are no longer as effective as they should. Thus, novel innovative strategies are required to combat this disease. A better understanding of the interactions between the mosquito and the malaria parasite may inform the development of new tools to control the disease. Transmission intervention by way of vaccines or transgenic mosquitoes may offer additional control strategies. Their development will, however, require the identification of valid molecular targets. The effective transmission of malaria requires specific compatibility between vector and parasite genotypes. Even within the susceptible *Anopheles gambiae* species (the most effective vector of the human malaria parasite), while some are resistant to infection, others, though unable to eliminate the infection, are capable of drastically reducing pathogen numbers [2, 3]. The mosquito molecules which interact with the malaria parasite to cause refractoriness in resistant strains have the potential to serve as targets for the development of novel transmission-blocking intervention strategies [4].

## **2. Malaria parasite life cycle stages**

The female anopheles mosquito requires blood to nourish her eggs. As she sucks her victim's blood, she secretes saliva and, if infected, injects sporozoites into the subcutaneous layer of the skin of her victim. The sporozoite travel to the liver where it invades hepatocytes. Here, it replicates asexually (mitotically) producing thousands of merozoites over a period of 6–15 days without causing any symptoms. Thereafter, the merozoites are released from the hepatocytes in the form of vesicles (merozomes). The vesicles disintegrate, releasing merozoites into the bloodstream to begin the erythrocytic stage of the disease. Within RBCs, parasites develop through ring, trophozoite, and schizont stages producing approximately 16 daughter merozoite per schizont. The schizont then ruptures in near synchrony with each other (unlike other human malaria parasites, *P. falciparum* does not exhibit distinct paroxysms) releasing hemozoin (malaria pigment) into the bloodstream of the victim which is responsible for the intermittent fever that accompanies the disease. The released merozoites invade new cells to initiate a new erythrocytic cycle. This cycle can go on and on resulting in host death from anemia unless the individual gets treated by an effective antimalarial therapy or the parasite gets killed by the immune system of the host. With each replication, some merozoites, instead of producing daughter merozoites, develop into male (microgametocyte) and female (macrogametocyte) gametocytes. Once gametocytes are picked up by a mosquito, transmission is initiated. The increased pH, lowered temperature as well as the presence of xanthurenic acid in the mosquito stomach, trigger the formation of the male and female gametes which fuse to form zygotes thereby initiating the sexual cycle [5]. The fusion of the gametes results in the formation of actively moving ookinete that migrates through the mosquito midgut to form oocytes containing thousands of sporozoites. The oocysts eventually burst to release these sporozoites which travel to the salivary gland of the mosquito for onward transmission.
