Research progress and prospects of arenavirus

LI You‑you, WANG Gao‑yu, HUANG Yi, PENG Ruo‑yan, TANG Chuan‑ning,LU Gang, YIN Fei‑fei, DU Jiang

1.Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Medical University, Haikou 571199, China

2.Hainan Medical University‑The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, Hainan Medical University, Haikou 571199, China

3.Department of Pathogen Biology, Hainan Medical University, Haikou 571199, China

4.NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China

Keywords:

ABSTRACT Arenaviruses belong to the family of RNA viruses that can infect humans in various ways and cause different degrees of mortality.Rodents is the mainly hosts.Human pathogenic arenaviruses include lymphocytic choroid meningitis, Lassa virus group and Takarib virus group, which cause human lymphocytic choriomeningitis and human hemorrhagic diseases.Rodents account for about 43% of mammalian species.At present, more than 30 highly pathogenic viruses have been found in rodents, including arenaviruses.The arenaviridae that infects rodents are mainly mammalian arenaviruses.This article reviews the etiology,clinicopathology, epidemiology, prevention and control of arenavirus, and provides references for the research and prevention of arenavirus.

1.Introduction

Arenoviridae is a single‑stranded negative‑strand segmented RNA.Arenavirus is mainly circulating in West Africa and South America.It can spread across species barriers from its rodent host to humans and cause diseases and symptoms.Manifestations range from mild flu‑like syndrome to severe and fatal zoonotic hemorrhagic fever.In 2008, Bolivia declared a “health emergency” for the whole country.The cause was the detected infection of an arena virus called Chapare virus, which caused 3 deaths and resulted in[1].Lassa fever virus, which is the most harmful of arenaviruses, is raging in West Africa, and its high outbreak rate and death rate have brought major risks to the country’s public health and safety, social stability and economic development.The regulation of arenavirus is mainly related to nucleoprotein (NP) and matrix protein (matrix, Z).These two proteins control the antiviral immune response by targeting and regulating a variety of cellular metabolic pathways, so they are antiviral drugs.Develop an important target in the process of neutralizing virus infection[2].

Rodents (Rodentia) belong to the order of rodents in the Mammalidae, which includes 5 suborders.And murine suborder[3].At present, there are 35 families, 389 genera, and about 2,700 species of rodents in the world, accounting for 43% of the total number of mammals, making it the largest mammalian population on earth[4].Rodents have a wide distribution, many species, strong reproductive ability, and multi‑group migration, which provide them with many opportunities to interact with humans, such as direct contact with animal bodies and animal feces, or indirect methods,such as contact with rodents.The source of water, such two close contact methods, direct and indirect, lead to the spread of diseases.Researchers at home and abroad have identified more than 30 viruses that exist in rodents and can infect humans[5, 6].The research results show that arenavirus is one of the most harmful and far‑reaching pathogens.

2.Arenavirus genome structure and characteristics

Arenavirus is a spherical virus particle with a diameter of 50‑300nm.Its envelope protein contains dense lipids.The arenavirus genome contains at least 2 single negative‑sense strand RNA fragments, and the entire genome is about 10.5kb[7].The S segment encodes NP nucleoprotein and glycoprotein precursors, which are further cleaved into G1 and G2 envelope proteins.The L segment encodes the viral RNA‑dependent RNA polymerase L protein and the Z protein with transcriptional regulatory functions[7].In addition,the amphibian arena virus genome also contains M segments, but lacks the Z protein encoding gene[8].Arenavirus has five structural proteins, mainly the nucleoprotein N, G1 protein, G2 protein, L protein and Z protein.Each protein is regulated by its coding gene.The most abundant nucleoprotein N is regulated by the S segment and can form a compact structure.The nucleoprotein complex[9].

3.Arenavirus classification and related diseases

ICTV updated the virus classification report at the 2020 meeting,in which the arenavirus family is classified into the Bunyavirales(Bunyavirales).There are 50 kinds of viruses in the arenaviridae family, including the following 4 genera, namely Antennavirus,Mammarenavirus, Harmanivirus and Reptile Arenavirus(Reptarenavirus), the main host of infection is different for each genera.Antennavirus mainly infects fish, Hartmanivirus and Reptarenavirus mainly infect snakes, and Mammarenavirus mainly infects rodents[10].Current research has found that the arenaviruses that cause human infection with arenaviruses are mainly divided into two groups, namely lymphocytic choroid meningitis‑Lassa virus group (LCMV‑LASV Complex, formerly known as Continental Arenavirus) and Tacaribe Complex (known as New World Arenavirus), the former mainly includes Lassa virus (LASV),lymphocytic choriomeningitis virus (LCMV), which cause human leaching.Lassa fever and lymphocytic choroid meningitis.The latter mainly includes Junin virus (JUNV), Guanarito virus (GTOV),Machupo virus (MACV), etc.The group can Causes human hemorrhagic diseases[11].Rodent hosts carry the virus for a long time after infection, which can contaminate water and food or form aerosols through feces to spread, infect humans and other primate mammals, and usually cause serious outbreaks of infectious diseases[12].

4.Arenavirus pathogenic mechanism and epidemiological background

4.1 The main pathogenic mechanism of arena virus

NP and Z virus proteins are the main factors that form the host’s antiviral mechanism.Arenavirus uses host cell mechanisms to counter host defenses.The viral proteins NP and Z, which have significant functions, have evolved different synergistic mechanisms to escape the antiviral state induced by viral infection.Both of these proteins can resist transferrin receptor 1 (RIG‑I) mediation.Leading the production of type I interferon (Interferon, IFN1), thereby inhibiting protein expression, thereby inhibiting the innate immune response[2]; and can use its flexible conformation and complex interactions between proteins to expand the ability of the virus to bind Host range, thus forming their escape strategy, so it is very important to develop specific antiviral drugs for viral proteins NP and Z, and to study the function of these two proteins when the virus produces an escape mechanism for the host[2].

4.2 Epidemiological characteristics of diseases caused by arenavirus

Because the natural host of arenavirus is mainly rodents, the local ecological characteristics of rodents, such as distribution, population dynamics, such as population structure, are closely related to the prevalence of diseases caused by arenavirus[11].At present, except for the Takarib virus which is found in the leaf‑mouthed bat and Ixodes lone star ticks, the natural hosts of other viruses in the arenaviridae family are rodents[13].

From 2012 to 2016, the Lassa fever outbreak in Nigeria caused a total of 5051 infections and 3891 deaths[14].The natural host of the pathogen LASV is a multi‑suckling mouse distributed in a large area south of the Sahara Desert.This kind of mouse has a high rate of carrying the virus.At the same time, Lassa fever is highly contagious, so this area has become a high‑risk area of Lassa fever[15]; The host and source of infection of LCMV, Mus musculus, are all over the world.Therefore, LCMV is the only world‑wide species in the arenaviridae.Mus musculus carrying LCMV can mainly cause human infection with lymphatic choroid meningitis.China LCMV has only serological results and few cases of this disease.Sporadic cases have been reported in Harbin and Beijing[15]; JUNV was discovered in Argentina in 1958, causing viral hemorrhagic fever in humans; Sabie caused Brazilian hemorrhagic fever in 1990 , But its host has not been determined; it was the Luyo mammalian arena virus that caused Luyo hemorrhagic fever in 2008,and 4 of the 5 cases died, with a case fatality rate of 80%[16].

5.Clinicopathology and prevention and control of diseases caused by arenavirus

The clinical manifestations of diseases caused by different arenaviruses are different.The common symptoms are persistent fever, headache, myalgia, fatigue, and dullness, and then different diseases have different symptoms.LCMV infection is usually a recessive infection, mainly including influenza type and aseptic meningitis type.The flu type mainly manifests as a series of flu‑like symptoms, such as fever, loss of appetite, fatigue, headache,myalgia, etc.The meningitis type can last for several weeks and is similar to flu‑like symptoms at first, but is accompanied by vomiting and meningitis[17].Argentine haemorrhagic fever caused by JUNV is more common in men, and Bolivian haemorrhagic fever caused by MACV has similar symptoms, and the MACV fatality rate is 10‑20%[18].Lassa fever is mainly prevalent in West Africa.The disease is a common symptom of arenavirus infection.In severe cases,hemorrhage and shock may occur.[19] The host animal and human are transmitted in the form of aerosol.Stool, urine, saliva and other secretions in contact with mucous membranes or damaged skin can also cause human infections.The detection of arena virus requires pathogenic examination.In the acute phase of viral infection,indirect immunofluorescence is mainly used to detect viral antigens in urine, blood, and sputum.Early detection of IgM antibodies in blood is helpful for early diagnosis.In the past, the treatment plan for diseases caused by arenavirus mainly focused on symptomatic treatment.Studies have shown that favipiravir has a good antiviral effect on a variety of viruses in the arenaviridae, but it has not been used in clinical practice[20].

Currently, there is a lack of approved vaccines against arenavirus.In 2014, ZAPATA et al.tested vaccines against LASV in guinea pigs and monkeys and showed 100% immune protection.The SRNA of LASV Josiah strain was constructed by recombination,but due to its undetermined safety, it has not been put into use[21].Controlling the source of infection, such as rodent control, is the main method to prevent arenavirus infection.The people who are in contact with the arenavirus host and infected patients are high‑risk groups, such as rodent breeders, medical staff, etc., should be protected to avoid contact Direct contact with the virus.The natural host of lymphocytic choroid meningitis, Lassa fever and Bolivian hemorrhagic fever is the house mouse.Community disease control should take appropriate prevention and control measures.

6.The current status of arenavirus research at home and abroad

A variety of arenaviridae viruses are related to human diseases worldwide, but China only has a rodent host carrying Wenzhou virus(WENV) and individual reports of human infection with LCMV[19].LCMV infection is only serological Test results.When arenavirus infects its natural host, it usually does not cause host disease, but when it is transmitted to humans through an animal host, it can cause serious and fatal human diseases, such as LASV in West Africa[22],JUNV[23 ], GTOV[24], Brazilian hemorrhagic fever Sabia virus(SABV)[25], MACV[26], which is prevalent in Brazil and the United States, and Dandenong virus (DANV) identified in Australia’s organ transplant infection deaths in 2008, etc.[27].Although LCMV has only serological results in China, cases of LCMV infection have been reported in the United States, the United Kingdom, France, etc.[28].

The arenaviruses related to human pathogenicity are mainly mammalian arenaviruses.The genus currently includes 35 species,except for the TCRV (Tacaribe Complex) in the leaf‑mouthed bat and the lone star tick.In addition to being found in the virus, the natural hosts of other viruses are rodents.In 2014, Ashley Malmlov et al.found that the lone star tick of the Atipus bat was the main carrier of TCRV in 9 areas of central Florida.Separate TCRVs with different viruses, and Ashley Malmlov studied in Trinidad and found serological evidence of arenavirus transmission in fruit‑eating bats,but no virus was isolated and no viral RNA was detected in bats[29].Through serological screening, Morita C et al.found that in China’s Fujian, Harbin, Beijing and other regions, the sera of a variety of murine rodents were positive for LCMV antibodies[28].In 2014,the Chinese Center for Disease Control and Prevention conducted virus screening on 8 rodents in some areas of Zhejiang Province and found a new arenavirus group[30], which was named Wenzhou virus (WENV).In 2019, a yellow‑breasted mouse (R.tanezumi)in Yunnan Province detected and isolated Wenzhou mammalian savirus[31], which was confirmed to cause human flu‑like symptoms in Laos in 2016.In 2020, Yin Feifei and others discovered a variant of WENV in Rattus norvegicus in Daoke Village, Haikou.The new arenaviruses discovered by Du Jiang and others in the genus of Mus musculus in Yunnan, Zhejiang, and Hunan have more than 87%homology with the WENV virus variants that cause fever in humans in Southeast Asia.This new cluster is similar to other sand particles.The virus homology is less than 29%.At the same time, the team reported the first LCMV virus genome in China, and the arena virus was found in the jumper for the first time[32].

In 2016, Kim R Blasdell et al.found genetic variants of WENV in a variety of rodents in Southeast Asia[30], Thailand and Eastern Cambodia.Ogbu O et al.reported that the number of clinical infections in West Africa is about 100,000 to 300,000 each year, and about 5,000 people die[33].From January 1 to February 10, 2019,due to Lassa fever virus infection, a total of 327 cases of Lassa outbreak occurred in Nigeria, with 72 deaths.The case fatality rate reached 22%, causing serious damage to Nigeria[34].Relative diagnostic methods have been established for arenavirus infection,but due to the lack of specificity of clinical manifestations after arenavirus infection, and the diversity of Lassa virus sequences, the diagnostic methods are limited, and there are still huge challenges in the establishment of diagnostic methods.

In 2020, Hadas Cohen-Dvashi studied tfr’s derivative 1sAD(combined with pathogenic mammary virus glycoprotein) to neutralize the arenavirus GP1 domain experiment, and named the glycoprotein Arenacept.Arenacept neutralized all four kinds of carbohydrates.The mimetic viruses of protein complexes (GPCs)have become promising reagents that can neutralize a variety of TfR1‑tropic mammalian viruses[35].In 2018, TJ Okwor et al.reported 33 imported LASV cases returned from 7 West African countries and 9 other countries from 1969 to 2016.A total of 39%of the 3 patients with known prognosis were found to have died[36].In 2020, Sebastien Kenmoe et al.conducted a meta‑analysis.From 1969 to 2020, there were 291 LASA epidemic records from 25 countries.The total human case fatality rate was 29.7%.The combined prevalence of LASV infection in humans was 8.7%.It is 3.2% in animals and 0.7% in other mammals[37].

7.Conclusion and outlook

From various research results, we know that there is a certain understanding and research on the arenavirus genome structure,pathogenicity, pathogenic mechanism, and epidemiological characteristics at home and abroad, but the characteristics of arenavirus transmission in animal hosts and The mechanism of interaction with humans still needs to be further understood.With the rapid development of laboratory testing technology, new arenaviruses are constantly being discovered.With the continuous changes in the epidemiological characteristics of global infectious diseases, a variety of arenaviruses with unclear pathogenicity and public health significance have also caused people.s concern.Rodents often come in close contact with humans, but they cannot grasp and control the unknown pathogens in wild mice in time.At the same time,the ecological environment has been deteriorating in recent years,new arenaviruses and fatal infectious diseases have appeared, and the types of arenaviruses have increased.The outbreak of various diseases has prompted the need to clearly understand this disease and make prevention and control research as soon as possible.With the development of society, virus detection technology has become more and more mature.Lin Shanshan and others established a real‑time fluorescent quantitative RT‑PCR detection method for the newly discovered arenaviruses in the mammalian arenavirus genus Ryukyu virus, Solvezi virus, and Surris virus, which can effectively expand Increasing the detection of viral RNA targets is helpful for rapid screening and testing after a suspected outbreak occurs[38].

In terms of treatment, immunoadhesin is a promising therapeutic agent, which has been successfully used in clinical treatment of various non‑viral pathological diseases.This method of using host‑derived receptor therapy may be effective against other zoonotic viruses, so it has become a general method for constructing broad‑spectrum and potent immunotherapy drugs.Therefore, we will carry out systematic screening and analysis of the domestic arena virus carrying situation, clarify the epidemiological and clinical significance, grasp its etiology and epidemiological characteristics,and carry out sudden infectious diseases related to arenavirus.It is very important to lay the foundation for early warning and traceability.

Author conflict of interest statement:

All authors declare that there is no conflict of interest between them.