Highly adaptive Phenuiviridae with biomedical importance in multiple fields

The newly established virus family Phenuiviridae in Bunyavirales harbors viruses infecting three kingdoms of host organisms (animals, plants, and fungi), which is rare in known virus families. Many phenuiviruses are arboviruses and replicate in two distinct hosts (e.g., insects and humans or rice). Multiple phenuivirid species, such as Dabie bandavirus, Rift Valley fever phlebovirus, and Rice stripe tenuivirus, are highly pathogenic to humans, animals, or plants. They impose heavy global burdens on human health, livestock industry, and agriculture and are research hotspots. In recent years the taxonomy of Phenuiviridae has been expanded greatly, and research on phenuiviruses has made significant progress. With these advances, this review drew a novel panorama regarding the biomedical significance, distribution, morphology, genomics, taxonomy, evolution, replication, transmission, pathogenesis, and control of phenuiviruses, to aid researchers in various fields to recognize this highly adaptive and important virus family and conduct relevant risk analysis.

groups are susceptible to SFTSV infection. Humans and domestic or wild animals can be readily infected with SFTSV during the bloodfeeding of virus-carrying ticks.
The tick-borne Heartland virus (HRT) in Heartland bandavirus (HRTV) was first isolated in 2009 from two patients in the USA, and both patients were with fever, fatigue, anorexia, diarrhea, leukopenia, and thrombocytopenia. 11 HRTV-specific antibodies have been detected in wild animals in 13 eastern and central states. A targeted survey identified 16 patients with acute HRTV disease in seven states with illness onset from April to September. Most reported fatigue, anorexia, nausea, headache, confusion, arthralgia, or myalgia, and 14 cases were hospitalized with two fatalities. 12 The tick-borne Bhanja virus in Bhanja bandavirus has been found in Asia, Africa, and Europe. 13 It infects humans, sheep, goats, cattle, hedgehogs, and squirrels. It causes encephalitis in young ruminants and conjunctivitis or meningoencephalitis in humans with the symptoms of headache, photophobia, vomiting, and paresis. 14 RVF virus (RVFV) in Rift Valley fever phlebovirus causes the mosquito-borne zoonosis of RVF that was first described in Kenya in 1930. 5 RVF has been endemic throughout multiple African countries and the Arabian Peninsula. 15 RVFV primarily infects domestic sheep, goats, and cattle, causing high mortality rates among young animals and "abortion storms," in which nearly all infected pregnant animals abort pregnancies. 16 Human infections result in various clinical symptoms, including fever, headache, backache, vertigo, anorexia, photophobia, miscarriage in pregnant women, and life-threatening hemorrhagic diatheses. Around 1%-2% of human infections result in severe disease, often with high fatalities. [17][18][19] The disease may last several days to a month. Some patients show a reduction of symptoms on the third day and recrudescence 1-3 days later. Outbreaks appeared regularly from the 1950s and started outside Africa after 2000. RVF has led to thousands of human deaths and millions of animal deaths in Africa. 20 Toscana virus (TOSV) in Toscana phlebovirus is prevalent in the countries surrounding the Mediterranean. 21 TOSV has diverged into three distinct lineages roughly corresponding to three overlapping regions. TOSV is found in both the male and female sand flies and can be sexually transmitted between adults and transovarially transmitted to larvae. TOSV infection is prevalent in dogs and other domestic animals. 22 Seroprevalence among humans is around 10% −24%, occasionally reaching 40% in the endemic regions. Although TOSV infection cases are generally self-limiting febrile illnesses, TOSV causes sporadic severe meningitis, meningoencephalitis, and other neuroinvasive diseases. 23 Some other phenuiviruses in the genus Phlebovirus can also infect humans. For instance, viruses in Sicilian phlebovirus (e.g., sandfly fever Sicilian virus) and Naples phlebovirus (e.g., sandfly fever Naples virus) transmitted by sandflies are responsible for most clinically described "sandfly fever." 22 These viruses are endemic in the Mediterranean region and western and central Asia. 24 Symptoms of their infections are often described as 3-day-fever characterized by abrupt onset of fever, headache, muscular pain, photophobia, and nausea. Human infections with the phenuiviruses in Punta Toro phlebovirus (PTV), Cocle phlebovirus, and Chagres phlebovirus have been identified in Panama. 25 The phenuivirus in Buenaventura phlebovirus was identified from a febrile human in Colombia. The phenuiviruses in Candiru phlebovirus and Alenquer phlebovirus were identified from febrile humans in Brazil, and the phenuiviruses in Echarate phlebovirus and Maldonado phlebovirus were identified from febrile humans in Peru. 26 The human febrile illness caused by these phleboviruses is usually nonspecific and self-limited. Moreover, these phleboviruses can also infect domestic animals (e.g., dogs and cats) and various wild animals.
Some other phenuiviruses are also pathogenic to humans or animals. Guertu bandavirus strains can infect humans, as suggested by serological evidence and cell culture. 27 Infection of a Tacheng uukuvirus strain in a febrile human was reported in 2021. 28 A Human tanzavirus strain was identified from a human with fever, headache, back pain, and pollakiuria in 2019 in Tanzania. 29 Infection of a Gouleako goukovirus strain with severe symptoms in swine in South Korea was reported in 2013.
The phenuivirus of rice stripe virus (RSV) in Rice stripe tenuivirus causes one of rice's most destructive viral diseases, which leads to a 30%-40% reduction in rice yield in affected regions. 30 It is widely distributed throughout East Asia, especially in China, Japan, and Korea.
Over 80% of the rice fields in Eastern China and Korea are affected by this disease annually. 31 RSV-infected plants display chlorosis, weakness, necrosis in leaves, abnormal growth, and even complete grain yield loss.
Phenuiviruses have 2−8 single-stranded RNA genomic segments, totally composed of around 10,000−25,000 nucleotides. 34 The numbers and functions of proteins encoded by phenuivirid genomes are different among genera and species (Table 1).
Many vertebrate-infecting phenuiviruses (e.g., RVFV) have three genomic segments which encode at least four structural proteins ( Figure 1). The longest (L) segment encodes an RNAdependent RNA polymerase (RdRp), responsible for the replication and transcription of viral genomic RNA. RdRp of phenuiviruses also has endonuclease functions. 36 The medium (M) segment encodes a precursor polypeptide, cleaved by host signal peptidase into two envelope glycoproteins, Gn and Gc. Gn and Gc are responsible for virion binding to the target cells and penetrating the cytosol, assembling in cytosols. They are also the targets for neutralizing antibodies, making them key targets for vaccine development. 36 Both Gn and Gc contain N-glycosylation sites. 37 Some dipteranborne phenuiviruses (e.g., RVFV) encode another nonstructural protein, NSm, before the coding region of Gn in the M segment.
NSm interacts with the outer mitochondrial membrane, regulates the p38 mitogen-activated protein kinase stress response, and has an antiapoptotic role, which is important for the viral infectivity in dipteran insects. 38,39 The small (S) segment encodes the nucleocapsid protein (N) that encapsulates the genomic RNA. RdRp, N, and genomic RNA constitute the viral ribonucleoproteins (RNPs). The S segment of some phenuiviruses also encodes a nonstructural protein, NSs, which impacts interferon production in host cells and viral virulence. 34,40 For many phenuiviruses, the viral L and M segments are in the negative sense, while the viral S segment is in double senses for encoding proteins (Figure 1). For all ambisense genomic segments of phenuiviruses, there is an untranslated intergenic region in a stable hairpin structure between the two open reading frames encoded in two senses.  p4 is a disease-specific protein whose expression is associated with the severity of RSV symptoms. 47 MP of fungi-infecting phenuiviruses and plant-infecting phenuiviruses is vital for them to spread from infected cells to neighboring cells. 34,48,49 Insertion and deletion of nucleotides occur more frequently in the intergenic regions and the 5′ or 3′ noncoding regions of RSV genomes. 50     The cytoplasmic tail of phlebovirus Gc proteins is short (e.g., only five amino acid residues for UUKV), while the cytoplasmic tail of Gn is much longer (e.g., 81 amino acid residues for UUKV). 37 The extended length is associated with additional biological functions: the Gn cytoplasmic tail contains the Golgi localization signal and initiates the budding process and packaging RNPs into virus particles. 79 Transcription of phenuivirid genomes begins with a capsnatching mechanism, in which host mRNAs are cleaved at a position close to the 5′ cap by RdRp. 88 The short capped fragments ( Like vertebrate-infecting phenuiviruses, the glycoprotein precursor pc2 encoded by the second segment of RSV is cleaved into pc2-N and pc2-C, which are functional homologs of Gn and Gc, but they are nonstructural. pc2-N and pc2-C are required for RSV entrance into the planthopper midgut cells. 91 They interact with RSV RNPs, and pc2-N binds to an unknown receptor. The binding leads to endocytosis followed by internalization of the RNPs/pc2-N/pc2-C complexes into early and late endosomes. 91 Under an acidic condition inside the late endosomes, pc2-C undergoes a conformation change that triggers cell membrane fusion, which releases RSV/pc2-N complexes into the cytosol. 91  Replication of phenuiviruses of plants and fungi is not well known. 34 These viruses likely enter the cytosol of plant or fungi cells due to mechanical wounds, such as those caused by grafting or insect sucking. 42 After that, viral RNPs start to disseminate, followed by the animals, but these vertebrate animals do not develop significant viremia and long viremic periods, suggesting that these animals, like infected humans, are likely accidental hosts. 103 Although the primary infection route to humans is through infected tick bites, human-to-human and animal-to-human transmission cases have been reported. 104,105 Amblyomma americanum ticks are the vector for HRTV, and they are widely distributed across the eastern and central United States. 11,106 Serologic surveys of mammals and birds detected HRTV-specific neutralizing antibodies in a variety of mammals, including raccoons and white-tailed deer, suggesting that various medium-and large-sized mammals may serve as hosts, but experimental infection of mice, rabbits, hamsters, chickens, raccoons, goats, and deer with HRTV failed to produce detectable viremia. 106 RVFV is maintained through vertical transovarial transmission in mosquitos between epidemics. 107  They also induce the production of type I interferon that binds to the interferon-α/β receptor and mediates the activation of STAT1 and STAT2 heterodimers. Transcriptional activation of IFN-stimulated genes is important in the host's innate immune system against viral infection. In host cells, SFTSV NSs forms inclusion bodies that capture multiple host immune molecules, such as RIG-I, STAT1, and STAT2. 116,117 Hence SFTSV NSs aids the virus to evade the host innate immune response and serve as a critical virulence molecule. 100 Similarly, deletion of the NSs gene of RVFV greatly attenuated RVFV. 34,40 In recent years, substantial advances in the pathogenesis of a few plant-infecting phenuiviruses (e.g., RSV and RGSV) have been achieved. 99 acaricides, and behavior-based control tools. 131 Anti-tick vaccines that could be used in humans or animals targeting pathogen transmission are under investigation. 131 Control of severe plant diseases caused by phenuiviruses mainly relies on pesticides to control their vector plant-hoppers. Pesticides are also widely employed to reduce arthropods to control various human and animal arboviruses, including phenuiviruses. However, pesticides are costly and harmful to humans and animals and heavily pollute the environment. 120 Breeding of virus-resistant cultivars is an economical, effective, and environment-friendly measure for controlling severe viral plant diseases. 120,132 One RSV-resistance gene in the rice genome, STV11, has been identified. 31 This gene encodes a sulfotransferase catalyzing the conversion of salicylic acid to sulphonated salicylic acid. Another gene, Stvb-i, is also highly associated with RSV resistance, and rice varieties harboring Stvb-i have shown stable resistance for over 50 years in paddy fields of Japan. 119 However, virus mutants can resume virulence in cultivars introgressed with natural resistance genes. 34,133 The expression of various viral genes has proven effective in preventing or reducing infection by plant viruses through RNA interference (RNAi), also termed RNA silencing. 134

| DISCUSSION
From the panorama of phenuiviruses depicted above, phenuiviruses are highly adaptive with great significance in the health of humans, animals, and plants. In recent years, the taxonomy of Phenuiviridae has been expanded and revised rapidly, and research targeting various aspects of this important virus family has made significant progress.
In the coming years, many research advances of Phenuiviridae can be envisaged. More novel genera or species in Phenuiviridae will be discovered, particularly from novel regions or host species, like novel phenuiviruses from grass, nematodes, and bats reported recently. 64,135,136 Some genomic segments of important known phenuiviruses (e.g., those inTacheng uukuvirus, Dipteran beidivirus, Laurel Lake laulavirus, and some tenuiviruses) shall be sequenced or parsed. 53 The taxonomy of Phenuiviridae shall be further expanded

CONFLICT OF INTERESTS
The authors declare that there are no conflict of interests.

AUTHOR CONTRIBUTIONS
Ming-Hui Sun wrote the parts of the biomedical significance,

DATA AVAILABILITY STATEMENT
The data that supporting the findings of this study are available from the corresponding author upon reasonable request.