Shulou(Shulou.com)11/24 Report--

This article comes from the official account of Wechat: back to Park (ID:fanpu2019), by Chen Lu, Liu Jianying, etc.

August 20 is World mosquito Day, which is not for mosquitoes. The main reason for this anniversary is to raise awareness of mosquito-borne diseases such as malaria. Mosquitoes can carry many dangerous pathogens, which can be described as mosquitoes'"hidden weapons", so how do they spread to people? In recent years, scientists have taken great pains to understand the vector efficacy of mosquitoes and have learned a lot about the "secret books" of mosquitoes.

Written by Chen Lu (Department of basic Medicine, School of Medicine, Tsinghua University), Liu Jianying (Institute of Infectious Diseases in Shenzhen Bay Laboratory), Cheng Gong (Department of basic Medicine, School of Medicine, Tsinghua University)

As a common blood-sucking insect, mosquitoes have always been regarded as a nuisance in summer, but the hidden health threats are far more than people realize. Mosquitoes are disseminators of many important diseases, and it is no exaggeration to call them "wings of death". Mosquito-borne diseases refer to diseases transmitted by mosquito bites. Among them, malaria, dengue fever, yellow fever and Zika virus disease are all typical examples that people are familiar with. The number of deaths and diseases caused by these diseases remains high every year, posing a serious threat to global public health and security. In order to raise awareness of mosquito-borne infectious diseases such as malaria, August 20 is designated as World mosquito Day (World Mosquito Day). Just today, let's take a look at how mosquitoes become the "lifelong enemies" of human beings.

Malaria: the oldest mosquito-borne disease malaria is undoubtedly one of the most lethal mosquito-borne diseases to humans. In many countries where malaria is severe, it is the leading cause of illness and death. The typical symptoms are recurrent chills, fatigue, vomiting and headaches. If not treated in time, the symptoms may further develop into jaundice, splenomegaly, anemia, epilepsy and even death. The global mortality rate of malaria is 0.3 per cent, while the mortality rate of severe malaria can reach 30 per cent. The extent and depth of the impact of malaria has become a global health problem. It is estimated that there are 200 million cases of malaria each year, of which hundreds of thousands die. More shockingly, historians speculate that malaria may have killed about 6 billion people since the advent of humans [2].

Malaria is one of the oldest diseases in human history. According to ancient documents, malaria has swept through civilizations from China to Mesopotamia, from Egypt to India. As early as in ancient Greece, it was noticed that people living in swampy areas often had fever and splenomegaly. At that time, it was widely believed that this was caused by breathing the "miasma" produced in the swamp. The word "malaria" of malaria comes from "mala" + "aria" (air).

It was not until the end of the 19th century that scientists began to have a better understanding of the disease. In 1880, Dr. Alphonse Laveland (Charles Louis Alphonse Laveran) discovered a very special organism, the malaria parasite, in the blood of malaria patients (figure 1). He observed that the creature could not only move, but also reproduce in the host, eventually leading to the onset of malaria. Since then, mankind has begun a scientific struggle against malaria.

Figure 1. The malaria parasite drawn by Alphonse Laveland [3]. Image source: reference [3] the transmission mechanism of malaria parasite once puzzled scientists. Although mosquitoes are known to transmit the parasite filariasis, the exact transmission of the malaria parasite remains a mystery. Ronald Ross, a military doctor based in India, examined thousands of mosquitoes in areas with a high incidence of malaria, but failed to find traces of the parasite. However, when he tried to feed the blood of malaria patients to different kinds of mosquitoes, he found the sporozoites of the malaria parasite in some kind of Anopheles mosquito. In 1899, Ross successfully used Anopheles vivax-infected Anopheles vivax to infect his medical student son and a volunteer, confirming that Anopheles was a malaria vector [4]. Later, he called the day when he discovered the spores of the malaria parasite, August 20, 1897, "Mosquito Day." Now this day is known as World Mosquito Day, and people will always remember Ross's contribution.

It was also found that malaria could only be transmitted by mosquitoes, and it was not until 1957 that the life cycle of the parasite in the human body was fully understood. When an Anopheles mosquito infected with the malaria parasite bites a human, the sporozoite of the malaria parasite in its salivary gland enters the body along with the saliva. Sporozoites are then quickly transferred to the liver through blood circulation, infecting hepatocytes, where they mature and reproduce. This stage is regarded as the incubation period without any clinical symptoms. Once the malaria parasite completes proliferation and replication, a large number of merozoites (merozoites) are released from infected liver cells and invade red blood cells. at this time, the infected person will begin to produce clinical symptoms and even lead to death [5].

The two key antimalarial drugs currently in use come from two important plants: artemisinin from Artemisia and quinine from cinchona. Quinine and artemisinin are the most effective antimalarial drugs today. At this point, the story of human exploration of malaria parasite is finally basically complete. In the more than 120 years since the establishment of the Nobel Prize, malaria-related research has won four prizes: Ronald Ross in 1902 for confirming that Anopheles mosquitoes are malaria vectors and elucidating the history of the development of the malaria parasite; Alphonse Laveland in 1907 for the discovery of Plasmodium in blood cells; and Robert Burns Woodward in 1965 for the first synthetic quinine. And awarded to Tu Youyou in 2015 for the isolation of a new antimalarial drug, artemisinin. In the long course of human struggle against malaria, they have played a landmark role in the history of medicine.

Yellow fever: the earliest mosquito-borne viral diseases in addition to parasites, viruses are also a key factor in mosquito-borne diseases. The yellow fever virus is the first virus confirmed to be transmitted by mosquitoes. Historical data show that outbreaks of yellow fever were recorded in Mexico as early as 1648. Over the next 200 years, yellow fever was one of the deadliest and most frightening infectious diseases, causing mass casualties in Africa and the Americas [6].

Yellow fever virus infection has different clinical features, such as self-limited diseases such as fever, muscle pain, headache, nausea and vomiting, which in most cases disappear after three to four days. However, a small number of patients enter a second more toxic phase within 24 hours, during which patients may have a relapse of high fever, bleeding, jaundice, blackening of urine, hepatorenal failure, and so on. Half of the patients with recurrence died within 7-10 days [7] (figure 2).

Figure 2. Four clinical stages of yellow fever drawn in the 19th century. Photo: Etienne Pariset and Andre Mazet. 1820. Four illustrations showing the progression of yellow fever. Until the 19th century, people did not know the etiology and mode of transmission of yellow fever, until 1881 Cuban doctor Carlos Finley (Carlos Juan Finlay) put forward the "mosquito hypothesis" that mosquitoes may transmit yellow fever, which laid the foundation for the follow-up scientific research of yellow fever. In 1901, Walter Reed conducted a study using mosquito bites on human volunteers and confirmed that Aedes albopictus was the main vector of yellow fever. Subsequent mosquito-borne interventions in Cuba did control the incidence of yellow fever. In addition, Reid observed that yellow fever is caused by substances in the patient's blood that can pass through tiny filters, suggesting that the pathogen of yellow fever is much smaller than bacteria. But it was not until 1927 that the yellow fever virus was isolated and became the first human virus to be isolated in history. Later, Max Theiler found that the virulence of the yellow fever virus gradually diminished after many passages in animals. After years of experiments, Tyrell finally isolated an attenuated strain called 17D. 17D is very low virulent, but can cause protective immune response, so Tyrell developed a yellow fever vaccine, which lasts for 30-35 years after vaccination, and is considered to be one of the most effective vaccines in history [9]. Max Tyrell won the Nobel Prize in 1951 for this.

Dengue fever: a potential killer in the tropics dengue fever is an acute tropical viral disease caused by the dengue virus, which has four serotypes. It spreads mainly through the bites of Aedes aegypti and Aedes albopictus. The disease is widely spread in tropical and subtropical areas. Dengue fever has been reported in Guangdong, Fujian, Yunnan and Taiwan. Most people infected with dengue virus are asymptomatic, while symptomatic infections often show flu symptoms, such as high fever, headache, muscle and joint pain, rash and so on. In severe cases, it can lead to bleeding and shock, or even death [10].

In 2019, the World Health Organization (WHO) listed dengue fever as one of the top 10 potentially threatening diseases, with about 3.5 billion people at risk of being infected with dengue virus worldwide. It is estimated that cases of dengue fever increased by 600 per cent between 1999 and 2019 [11]. Due to the global movement of population, climate change and the continued expansion of urbanization, the epidemic of dengue disease will continue to expand. In July 2023, the WHO warned that the number of dengue infections worldwide could reach an all-time high this year as global warming facilitates mosquito growth and the spread of mosquito-borne diseases.

Japanese Encephalitis: unlike dengue viruses in Asia, Japanese encephalitis virus (JEV) is usually transmitted by Culex pipiens mosquitoes and its natural circulation involves a variety of vertebrate hosts. Pigs and waterfowl are considered to be the two most important JEV amplification hosts. Although they are usually asymptomatic after infection, they produce high viremia enough to transmit the virus to mosquitoes. Humans and horses are regarded as accidental hosts of JEV, not an important source of mosquito infection with JEV. Humans develop only low levels and transient viremia after being infected with JEV, but less than 1% of those infected show symptoms of fatal encephalitis [12]. JEV is prevalent in Asia, including China, South Korea, Japan and Thailand, and is the main cause of viral encephalitis in these countries. JEV can cause serious neurological diseases. Symptoms in the acute encephalitis phase may include neck ankylosis, hemiplegia, convulsions and high fever, which is a very serious disease with a fatality rate of up to 30%. Between 30% and 50% of survivors may have permanent intellectual, behavioral or neurological disorders, such as deafness, paralysis, inability to speak, etc. [13].

Zika virus disease: the new public health threat Zika virus was first isolated from a sentinel macaque in Uganda's Zika forest in 1947. Before 2007, Zika had been quietly prevalent in many parts of Africa and Asia, but it did not cause serious disease or large-scale outbreaks. Most people infected with Zika have relatively mild symptoms, which may include fever, joint pain, rash and conjunctivitis. However, between 2015 and 2016, Zika virus caused widespread concern around the world. In 2015 alone, Brazil reported millions of cases of Zika infection. Although Zika infection is rarely directly fatal, it can lead to a rare immune disease, Guillain-Barre syndrome. If the infected person is pregnant, the virus may also cause congenital microcephaly and miscarriage in the fetus [14,15].

Study on the transmission mechanism of mosquito-borne virus it is well known that mosquitoes transmit pathogens to animals while sucking blood, so how on earth does the virus work in mosquitoes?

In the field of mosquito-borne diseases, this problem is mainly focused on mosquito vector effectiveness (vector competence), that is, the ability of mosquitoes to acquire, maintain and transmit arboviruses. First of all, we should understand that only some species of female mosquitoes need to absorb blood for nutrition during the egg incubation cycle, while most mosquitoes feed on nectar and plant juices.

It was found that after feeding on the blood containing the virus, the virus entered the midgut and established stable replication in the midgut epithelial cells of the mosquito, and then the virus was released into the mosquito's hemolymph and spread to the mosquito's whole body tissue. such as fat body, blood lymphocytes, muscles, salivary glands and nerve tissue. The virus is then enriched in the salivary glands, and during the next feeding process, the pathogen enters the next host along with the anticoagulant and allergenic substances in the saliva (figure 3). Mosquito saliva has been identified to promote the transmission of mosquito-borne viruses to hosts and is associated with the development of related diseases.

Figure 3. The process by which mosquitoes infect and spread the virus. Source: Snodgrass, Robert Evans. 1959. "The anatomical life of the mosquito." Smithsonian Miscellaneous Collections, 139, (8), 1-87. Obviously, mosquitoes can only get the virus when they feed on the infected and continue to spread, so why can mosquitoes find infected people easily? Human odor is a key factor in regulating mosquito behavior. Dengue virus and Zika virus can regulate the skin microbes of infected people, reshape the smell of infected people, and then affect the sense of smell of mosquitoes. Mosquitoes can efficiently locate infected people and suck blood with the virus [16].

Recent studies have found that components in the host blood, such as iron ion [17] and secreted viral non-structural protein NS1 [18], can regulate mosquitoes to acquire virus. In addition to the blood components of the host, the intestinal symbionts of mosquitoes also play an important role in virus acquisition. There are rich species and large number of intestinal microflora in the intestinal tract of mosquitoes. It has been found that there is a kind of Serratia marcescens in the intestines of Aedes albopictus, which can assist the virus to infect the intestines of mosquitoes and significantly enhance the susceptibility of Aedes albopictus to mosquito-borne viruses [19]. In recent studies, researchers have found that a saliva protein can significantly enhance the infection of mammalian immune cells by Zika and dengue viruses, proving that it is a key factor in assisting mosquito-borne virus transmission [20]. These studies not only reveal the interaction among host, vector mosquito and virus, but also provide new intervention targets and ideas for important mosquito-borne virus prevention and control.

In recent years, the progress made in the field of mosquito-borne virus infection and transmission is exciting, and a large number of studies have revealed the complex relationship among hosts, vectors, mosquitoes and viruses. Although researchers' understanding of the interaction between mosquitoes, viruses and hosts has expanded rapidly, there are still many puzzling mysteries that need to be further studied, such as how mosquitoes tolerate viral replication without producing serious pathological responses; why different viruses prefer different mosquito species for transmission; and how genetic background and environmental differences affect mosquito vector efficiency. After hundreds of millions of years of evolution, mosquitoes have always been accompanied by human evolution, and it can be predicted that they will continue to affect our survival. Therefore, how to effectively reduce the threat of mosquitoes to human beings and how to coexist peacefully with mosquitoes will be an important topic for us to continue to explore in the future. We need to further explore the interaction mechanism between mosquitoes and pathogens in order to develop more effective control and prevention strategies. In addition, strengthening public health education and raising people's awareness of mosquito-borne virus transmission are also the key to prevention. Scientists, doctors and all sectors of society play an important role in facing these challenges. Cooperation and innovation will be the key to solving these problems. Through joint efforts, we are expected to establish a more harmonious coexistence relationship with mosquitoes while protecting human health.

reference

[1] Organization, W. H. (2022). World malaria report 2022 (World Health Organization).

[2] Whitfield, J. (2002). Portrait of a serial killer. Nature 3.

Bruce-Chwatt, L.J. (1981). Alphonse Laveran's discovery 100 years ago and today's global fight against malaria. Journal of the Royal Society of Medicine 74,531-536.

Cox, F.E. (2010). History of the discovery of the malaria parasites and their vectors. Parasites & vectors 3, 1-9.

[5] Varo, R., Chaccour, C., and Bassat, Q. (2020). Update on malaria. Medicina Cl í nica (English Edition) 155395-402.

[6] Barrett, A.D., and Higgs, S. (2007). Yellow fever: a disease that has yet to be conquered. Annu. Rev. Entomol. 52209-229.

[7] Douam, F., and Ploss, A. (2018). Yellow fever virus: knowledge gaps impeding the fight against an old foe. Trends in microbiology 26,913,928.

Staples, J.E., and Monath, T.P. (2008). Yellow fever: 100 years of discovery. Jama 300,960,962.

Monath, T.P. (2005). Yellow fever vaccine. Expert review of vaccines 4,553-574.

Pierson, T.C., and Diamond, M.S. (2020). The continued threat of emerging flaviviruses. Nature microbiology 5796-812.

[11] Organization, W. H. (2022). Virtual Meeting of Regional Technical Advisory Group for dengue and other arbovirus diseases, New Delhi, India, 4-6 October 2021. World Health Organization. Regional Office for South-East Asia.

Misra, U.K., and Kalita, J. (2010). Overview: japanese encephalitis. Progress in neurobiology 91,108-120.

[13] Campbell, G.L., Hills, S.L., Fischer, M., Jacobson, J.A., Hoke, C.H., Hombach, J.M., Marfin, A.A., Solomon, T.A., Tsai, T.F., and Tsu, V.D. (2011). Estimated global incidence of Japanese encephalitis: a systematic review. Bulletin of the World Health Organization 89,766-774.

[14] Mlakar, J.A., Korva, M.S., Tul, N.A., Popovi Austria, M.A., Polj ak-Prijatelj, M.A., Mraz, J.S., Kolenc, M.D., Resman Rus, K.A., Vesnaver Vipotnik, T.S., and Fabjan Vodu Mr. ek, V. (2016). Zika virus associated with microcephaly. New England Journal of Medicine 374,951-958.

[15] Musso, D., Ko, A.I., and Baud, D. (2019). Zika virus infection-after the pandemic. New England Journal of Medicine 381,1444-1457.

[16] Zhang, H., Zhu, Y., Liu, Z., Peng, Y., Peng, W., Tong, L.A., Wang, J., Liu, Q., Wang, P., and Cheng, G. (2022). A volatile from the skin microbiota of flavivirus-infected hosts promotes mosquito attractiveness. Cell 185,2510-2522. E2516.

[17] Zhu, Y.A., Tong, L.A., Nie, K., Wiwatanaratanabutr, I., Sun, P., Li, Q., Yu, X., Wu, P., Wu, T., and Yu, C. (2019). Host serum iron modulates dengue virus acquisition by mosquitoes. Nature Microbiology 4, 2405-2415.

[18] Liu, J., Liu, Y., Nie, K., Du, S.A., Qiu, J., Pang, X., Wang, P., and Cheng, G. (2016). Flavivirus NS1 protein in infected host sera enhances viral acquisition by mosquitoes. Nat Microbiol 1, 16087. 10.1038/nmicrobiol.2016.87.

[19] Wu, P.A., Sun, P., Nie, K., Zhu, Y., Shi, M., Xiao, C., Liu, H., Liu, Q., Zhao, T.S., and Chen, X. (2019). A gut commensal bacterium promotes mosquito permissiveness to arboviruses. Cell host & microbe 25,101-112. E105.

[20] Sun, P.A., Nie, K.S., Zhu, Y., Liu, Y., Wu, P., Liu, Z., Du, S.A., Fan, H., Chen, C.M. H., and Zhang, R. (2020). A mosquito salivary protein promotes flavivirus transmission by activation of autophagy. Nature communications 11, 260.

Welcome to subscribe "Shulou Technology Information " to get latest news, interesting things and hot topics in the IT industry, and controls the hottest and latest Internet news, technology news and IT industry trends.