Immune Evasion in Mosquitoes

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This entry is adapted from the peer-reviewed paper 10.3390/pathogens12050635

In recent decades, mosquito-borne illnesses have emerged as a major health burden in many tropical regions. These diseases, such as malaria, dengue fever, chikungunya, yellow fever, Zika virus infection, Rift Valley fever, Japanese encephalitis, and West Nile virus infection, are transmitted through the bite of infected mosquitoes. These pathogens have been shown to interfere with the host’s immune system through adaptive and innate immune mechanisms, as well as the human circulatory system. Crucial immune checkpoints such as antigen presentation, T cell activation, differentiation, and proinflammatory response play a vital role in the host cell’s response to pathogenic infection. Furthermore, these immune evasions have the potential to stimulate the human immune system, resulting in other associated non-communicable diseases.

mosquito-borne diseases malaria dengue

1. Introduction

Vector-borne diseases are a major public health concern worldwide, accounting for a substantial proportion of the global disease burden. As per a World Health Organization (WHO) report, nearly 700,000 deaths are caused annually by vector-borne contagious diseases ^[1]. Mosquitoes are a potential vector for disease transmission and can disproportionately impact impoverished communities, particularly children. Regardless of acquiring centuries of control strategies, mosquito-borne diseases are burgeoning. These conditions are responsible for enormous mortality and morbidity worldwide ^[2] (Figure 1).

Figure 1. Different pathogens involved in mosquito-borne diseases include Plasmodium, dengue virus, chikungunya virus, yellow fever virus, Zika virus, Rift Valley fever virus, Japanese encephalitis virus, and West Nile virus.

Among mosquito-borne diseases, malaria is a potentially fatal disease caused by Plasmodium parasites and transmitted by hitherto infected female anopheles mosquito bites. When the vector mosquito feeds on an infected person’s blood, Plasmodium parasites get ingested along with the blood meal. Subsequent bites to a healthy person may transmit the parasite, which leads to malaria. Its symptoms begin with the first liver schizont rupture and merozoite release in the peripheral circulation ^[3]. Five species of the malarial parasite have been reported, Plasmodium falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi, leading to clinical symptoms in humans. P. falciparum is the most lethal species associated with the majority of malaria-related deaths worldwide. Apart from its ability to impair neuro-cognitive functions, this species is known to develop resistance to anti-malarial drugs. P. vivax, the most widely distributed species, is responsible for a significant proportion of malaria cases worldwide. Other Plasmodium species, namely P. ovale, differ in the latency period and resemble P. vivax clinically ^[3]. P. malariae is a relatively rare species but has distinct clinical outcomes. Compared to other malaria types, the number of merozoites produced with each schizont rupture is lower; thus, the parasitemias are lower in these patients ^[4]. Because of the longer parasite life cycle, patients experience fever every 72 h during an infection. P. knowlesi, despite its limited distribution, shows a higher severity rate than other common strains ^[5].

Mosquitoes can also harbor viral pathogens and cycle them between the human population. Among mosquito-borne viral infections, dengue is the most common disease caused by dengue virus 1–4 (DENV 1–4). DENVs are most commonly spread through the bite of an infected female Aedes sp. mosquito. A person infected with a particular dengue virus serotype can sometimes induce short-term cross-reactivity with other serotypes as well. Although the majority of dengue virus infections are asymptomatic or only cause mild disease, severe disease can occur and is characterized by plasma leakage, a pathophysiologic process in which the protein-rich fluid component of blood leaks into the surrounding tissue, resulting in extravascular fluid accumulation and shock, coagulopathy, and end-organ impairment ^[6].

Chikungunya virus (CHIKV), a Togaviridae with a single-stranded, positive-sense RNA genome, is transmitted mainly by the mosquito vector Aedes aegypti and, to some extent, A. albopictus, mainly in regions of Paraguay, Bolivia, Argentina, and Thailand ^[7]. Patients infected with CHIKV generally encounter intense asthenia, myalgia, headache, and arthralgia. Unlike other acute infections, CHIKV infection is dedicated to attacking the skeletal muscles, joints, and myotendinous insertions ^[8].

Yellow fever virus (YFV), a flavivirus causing yellow fever, has been considered one of the deadliest infectious diseases. Endemic to the tropics and sub-tropics, this virus is transmitted via Haemogogus janthinomys, H. leucocelaenus, Sabethe, and Aedes mosquitoes. Naturally, YFV circulated between mosquitoes and non-human primates in a sylvatic cycle. Following urbanization, YFV has entered the urban cycle, infecting humans and resulting in human-to-human circulation ^[9]. A. africanus maintains a sylvatic cycle in the rainforest, whereas A. bromelia was found to serve as a vector mediating urban cycles. The subsequent return of sick individuals to non-endemic, more densely populated places can set off an urban cycle perpetuated by A. aegypti mosquitoes ^[10]. Individuals typically experience an incubation period of 3 to 6 days after being bitten by an infected mosquito, followed by flu-like symptoms before a remission period of 1 to 2 days. Following remission, some patients (20–60%) progress to a more toxic phase of the disease, characterized by hemorrhagic fever, jaundice, thrombocytopenia, and liver and renal failure ^[11].

Zika virus (ZIKV) is an arbovirus that usually causes asymptomatic infections in the human host, but several neurological impairments have been reported in several cases. ZIKV is transmitted in the human population mainly through bites of anthropophilic mosquitoes such as A. aegypti, A. albopictus, and A. hensilii. Its urban cycle uses humans as reservoirs and continuously multiplies in them. Apart from this cycle, a sylvatic transmission cycle operates between non-human primates and arboreal canopy-dwelling mosquitoes. ZIKV can persist in mosquito eggs, leading to transovarial transmission, where the virus infects ovarian tissues, and transegg transmission, where the virus infects its host during fertilization ^[12]. Besides the direct human-to-human transmission, ZIKV has also been found to travel to fetuses from infected mothers (in utero).

Other mosquito-transmitted viruses, including the Rift Valley fever virus (RVFV) and Japanese encephalitis virus (JEV), follow the epizootic transmission cycle, where the virus amplifies in domesticated animals before infecting humans. Rift Valley fever is an emerging zoonotic viral disease caused by the RVFV of the Bunyaviridae family. Cattle, sheep, goats, and camels are especially vulnerable to RVF and serve as viral amplification hotspots. Infection of domestic animals is initiated by female Aedes mosquitoes (the primary mosquito vectors) with a disseminated salivary gland with an RVFV infection during probing or blood-feeding. After the primary infection, Culex and Mansonia sp. can channel RVFV between viremic domestic animals and humans ^[13]. JEV, the causative agent of human encephalitis, is primarily transmitted by Culex tritaeniorhynchus and C. annulirostris. C. pipiens and A. japonicus could be considered potentially important vectors in the case of JEV introduction in new regions ^[14].

West Nile virus (WNV), another emerging neurotropic flavivirus, is predominantly found to cycle between mosquitoes and birds. Culex pipens and C. quinqifasciatus serve as WNV vectors in major parts of Asia, Africa, and America, whereas C. australicus and C. globcoxitus have been found to be predominant in Australia. While feeding on infected viraemic birds, female Culex spp. mosquitoes pick up WNV. The virus replicates in the mosquito’s midgut epithelial cells and spreads to the salivary glands and other organs via hemolymph ^[15]. The pathogenesis of WNV includes an initial infectivity period followed by viral amplification and, finally, neuro-invasion in the central nervous system ^[16].

From the mosquito perspective, A. aegypti is distributed worldwide and found in most tropical countries. A. albopictus, on the other hand, is an opportunistic daytime and outdoor feeder that prefers humans and can be found feeding and resting indoors. Vertical transmission (VT) of viral pathogens is common in mosquito hosts. Similarly, viruses can also spread among mosquito populations through venereal transmission, which involves viral transfer during mosquito mating. Males cannot contract the virus through a blood meal, but they can contract it through venereal transmission from an infected female partner. Transmission by different species depends on some specific alterations in their non-structural proteins. Aedes aegypti was found to be more prone to ZIKV infection owing to a mutation in its non-structural protein 1 (NS1), whereas A. triseriatus and A. taeniorhynchus were not susceptible ^[17]^[18]. Other Aedes species, such as A. furcifer, were found to transmit DENV to humans, whereas Aedes luteocephalus transmit DENV and YFV in non-human primates ^[19]. In this context, several cases of co-infection were reported where patients were positive for both CHIKV and DENV ^[20]. In the genus Culex, C. quinquefasciatus, the most abundant species in tropical Africa, serves as a vector for the transmission of CHIKV and Japanese encephalitis virus (JEV). Meanwhile, C. antennatus is speculated to play an essential role as an epizootic vector of WNV ^[21]. The Anopheles genera support the transmission of Plasmodium sp. and certain nematodes but do not support arboviral transmission ^[22].

2. Immune Evasion in Mosquitoes

Mosquito midgut tissues are the first to be infected ^[23] and therefore have been the primary area of focus for studying the immune responses of the vector. Researchers aim to identify the molecules and pathways involved in the infection process of mosquito-borne pathogens. The major innate immune pathways involved in vector immune responses are the toll pathway, IMD pathway, JAK-STAT pathway, RNAi pathway (mi-RNA and pi-RNA pathways), and the interferon-mediated antiviral response. Mosquito-borne pathogens can shut down all these defense mechanisms by downregulating the responsible genes for these pathways ^[24]^[25]. According to a transcriptome study, the toll pathway plays a role in restricting the mosquito’s capacity for infection. Toll, Rel1A, and Spätzle (Spz) are the genes responsible for Toll activation, whereas cactus is the negative regulator.

In the mosquito, the anti-plasmodial response in Anopheles is enacted by the circulating thioester-containing protein 1 (TEP 1) responsible for humoral immunity at the ookinete stage. Apart from this, Enterobacter, Pseudomonas, Asaia, and Panteoa induce the secretion of antimicrobial peptides (AMPs) against the invading Plasmodium ^[26]. The innate immune system of Anopheles controls pathogen invasion by regulating three signaling cascades: the immune deficiency, the Toll, and the JAK-STAT pathways ^[27]. Immune evasion by Plasmodium includes the activation of the Pfs47 gene, which allows the parasite to inhibit several caspases responsible for the Jun-N-terminal-kinase-mediated activation of mid-gut apoptosis ^[28]. Furthermore, Pfs47 inhibits midgut nitration responses, which are required to activate the complement-like system ^[29].

Arboviruses can inhibit the antibacterial and antiparasitic activity of the IMD pathway in Aedes aegypti, leading to enhanced viral replication ^[30]. Functional studies have revealed that genes involved in the JAK-STAT pathway are essential to the vector’s immune system. This pathway is upregulated as an early response to arbovirus infection ^[31]. However, DENV and other mosquito-borne pathogens have evolved mechanisms to downregulate the JAK-STAT immune response ^[24]. Interfering RNA is one of the most successful antiviral defense mechanisms in mosquitoes ^[32]. Different viral proteins/factors can inhibit the vector’s RNAi processing pathways to prevent the degradation of their genomic material. The cytokine-like element named Vago establishes coordination between an IFN-like antiviral immunity pathway and the canonical innate immunity pathway (JAK-STAT) in culex mosquitoes ^[33].

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1. Introduction

2. Immune Evasion in Mosquitoes

References