Orthohantavirus
Orthohantavirus is a genus of viruses that includes all hantaviruses that cause disease in humans. Orthohantaviruses, hereafter referred to as hantaviruses, are naturally found primarily in rodents. In general, each hantavirus is carried by one rodent species and each rodent that carries a hantavirus carries one hantavirus species. Hantaviruses in their natural reservoirs usually cause an asymptomatic, persistent infection. In humans, however, hantaviruses cause two diseases: hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. HFRS is mainly caused by hantaviruses in Africa, Asia, and Europe, called Old World hantaviruses, and HPS is usually caused by hantaviruses in the Americas, called New World hantaviruses.
Hantaviruses are transmitted mainly through aerosols and droplets that contain rodent excretions, as well as through contaminated food, bites, and scratches. Environmental factors such as rainfall, temperature, and humidity influence transmission. Human-to-human transmission does not occur. HFRS is marked by kidney disease with kidney swelling, excess protein in urine, and blood in urine. The case fatality rate of HFRS varies from less than 1% to 15% depending on the virus. A mild form of HFRS often called nephropathia epidemica is often caused by Puumala virus and Dobrava-Belgrade virus. For HPS, initial symptoms are flu-like, with fever, headache, and muscle pain, followed by sudden respiratory failure. HPS has a higher case fatality rate than HFRS, at 30–60%. For both HFRS and HPS, illness is the result of increased vascular permeability, decreased platelet count, and overreaction of the immune system.
The hantavirus genome consists of three single-stranded negative-sense RNA segments that encode one protein each: an RNA-dependent RNA polymerase, a spike glycoprotein precursor, and the N protein. Segments are encased in N proteins to form ribonucleoprotein complexes that each have a copy of RdRp attached. RNP complexes are surrounded by a lipid envelope that has spike proteins emanating from its surface. Replication begins when spikes attach to the surface of cells. After entering the cell, the envelope fuses with endosomes and lysosomes, which empties RNPs into the cytoplasm. RdRp then transcribes the genome to produce messenger RNA for translation by host ribosomes to produce viral proteins and replicates the genome for progeny viruses. Old World hantaviruses assemble in the Golgi apparatus and obtain their envelope from it, before being transported to the cell membrane to leave the cell via exocytosis. New World hantaviruses assemble near the cell membrane and obtain their envelope from it as they leave the cell by budding from its surface.
Hantaviruses were first discovered following the Korean War. During the war, HFRS was a common ailment in soldiers stationed near the Hantan river. In 1978 in South Korea, the first hantavirus was isolated, Hantaan virus, and was shown to be responsible for the outbreak during the war. Within a few years, other hantaviruses that cause HFRS were discovered throughout Eurasia. In 1982, the World Health Organization gave HFRS its name, and in 1987, hantaviruses were classified for the first time. They collectively bear the name of Hantaan virus and the Hantan river. In 1993, an outbreak of HPS occurred in the Four Corners region in the United States, which led to the discovery of pathogenic New World hantaviruses and the second disease caused by hantaviruses. Since then, hantaviruses have been found not just in rodents but also moles, shrews, and bats.
Disease
Hantaviruses are sorted into Old World hantaviruses, which typically cause hemorrhagic fever with renal syndrome in Africa, Asia, and Europe, and New World hantaviruses which are associated with hantavirus pulmonary syndrome in the Americas. The case fatality rate of HFRS ranges from less than 1% to 15%, while for HPS it is 30–60%. The severity of symptoms of HFRS varies depending on the virus: Hantaan virus causes severe HFRS, Seoul virus moderate HFRS, Puumala virus mild HFRS, and Dobrava-Belgrade virus infection varies from mild to severe depending on genotype. The mild form of HFRS caused by Puumala virus and Dobrava-Belgrade virus is often called nephropathia epidemica. Repeated infections of hantaviruses have not been observed, so recovering from infection likely grants life-long immunity.HFRS is characterized by five phases: febrile, hypotensive, low urine production, high urine production, and recovery. Symptoms usually occur 12–16 days after exposure to the virus. Acute kidney disease occurs with kidney swelling, excess protein in urine, and blood in urine. Other symptoms include headache, lower back pain, nausea, vomiting, diarrhea, bloody stool, the appearance of spots on the skin, and hemorrhaging in the respiratory tract. Renal failure leads oliguria, and restoration of kidney health comes with polyuria. Recovery typically takes a few months. In more mild cases, the different phases of HFRS may be hard to distinguish, or some phases may be absent, while in more severe cases, the phases may overlap.
HPS is mainly caused by two viruses: Andes virus and Sin Nombre virus. The disease has three phases: prodromal, cardiopulmonary, and recovery. Symptoms occur about 1–8 weeks after exposure to the virus. Early symptoms include fever, headache, muscle pain, shortness of breath, and low platelet count. During the cardiopulmonary phase, there is elevated heart rate, irregular heartbeats, and cardiogenic shock. Pulmonary capillary leakage can lead to acute respiratory distress syndrome, buildup of fluids in the lungs, hypotension, and buildup of fluid in the chest cavity. These symptoms can cause sudden death. After the cardiopulmonary phase is resolved, polyuria occurs while recovery takes months. While HFRS is associated with renal disease and HPS with cardiopulmonary disease, HFRS may sometimes include cardiopulmonary symptoms associated with HPS and HPS may sometimes include renal symptoms associated with HFRS.
Transmission
Hantaviruses that cause illness in humans are mainly transmitted by rodents. In rodents, hantaviruses usually cause an asymptomatic, persistent infection. Infected animals can spread the virus to uninfected animals through aerosols or droplets from their feces, urine, saliva, and blood, through consumption of contaminated food, from virus particles shed from skin or fur, via grooming, or through biting and scratching. Hantaviruses can also spread through the fecal-oral route and across the placenta during pregnancy from mother to child. They can survive for 10 days at room temperature, 15 days in a temperate environment, and more than 18 days at 4 degrees Celsius, which aids in the transmission of the virus. Environmental conditions favorable to the reproduction and spread of rodents are known to increase disease transmission. Living in a rural environment, in unhygienic settings, and interacting with environments shared with hosts are the biggest risk factors for infection, especially among people who are hikers, farmers, and forestry workers, as well as those in mining, the military, and zoology.Rodents can transmit hantaviruses to humans through aerosols or droplets from the excretions and through consumption of contaminated food. Rodent bites and scratches are also an important means of transmission to humans. The prevalence of hantavirus among rodent breeders and rodent pet owners is up to 80%. In one outbreak in North America in 2017, Seoul virus infected 31 people through contact with pet rats. Andes virus has often been claimed by researchers to be the only hantavirus known to be spread from person to person, usually after coming into close contact with an infected person. It can also reportedly spread through human saliva, airborne droplets from coughing and sneezing, and to newborns through breast milk and the placenta. A 2021 systematic review, however, found human-to-human transmission of the Andes virus to not be strongly supported by evidence but nonetheless possible in limited circumstances, especially between close household contacts such as sexual partners. There is also suspicion that Puumala virus can spread from person to person through blood and platelet transfusions.
Hantaviruses that cause HFRS can be transmitted through the bites of mites and ticks. Research has also shown that pigs can be infected with Hantaan virus without severe symptoms and sows can transmit the virus to offspring through the placenta. Pig-to-human transmission may also be possible, as one swine breeder was infected with hantavirus with no contact with rodents or mites. Hantaan virus and Puumala virus have been detected in cattle, deer, and rabbits, and antibodies to Seoul virus have been detected in cats and dogs, but the role of these hosts for hantaviruses is unknown. Infection in these other animals can potentially facilitate the evolution of hantaviruses by genome reassortment. In addition to rodents, some hantaviruses are found in small insectivorous mammals, such as moles, shrews, and bats. Hantavirus antigen has also been detected in a variety of bird species, indicative of infection.
Human built environments are important in hantavirus transmission. Deforestation and excess agriculture may destroy rodents' natural habitat. The expansion of agricultural land is associated with a decline in predator populations, which enables hantavirus host species to use farm monocultures as nesting and foraging sites. Agricultural sites built in close proximity to rodents' natural habitats can facilitate the proliferation of rodents as they may be attracted to animal feed. Sewers and stormwater drainage systems may be inhabited by rodents, especially in areas with poor solid waste management. Maritime trade and travel have also been implicated in the spread of hantaviruses. Research results are inconsistent on whether urban living increases or decreases hantavirus incidence. Seroprevalence, which shows past infection to hantavirus, is consistently higher in occupations and areas that have greater exposure to rodents. Poor living conditions on battlefields, in military camps, and in refugee camps make soldiers and refugees at great risk of exposure as well.