Hanta Virus- An Overview

Hantavirus is a type of virus that belongs to the Bunyaviridae family, which consists of five genera: bunyavirus, phlebovirus, nairovirus, tospovirus, and hantavirus. All these genera are composed of negative-sense, single-stranded RNA viruses that are transmitted by arthropods, except for hantavirus, which is carried by rodents. Hantavirus can cause two potentially fatal diseases in humans: hantavirus pulmonary syndrome (HPS) and hemorrhagic fever with renal syndrome (HFRS), which are characterized by defects in vascular permeability and platelet function.

Hantavirus has a spherical or pleomorphic shape with a diameter of about 120-160 nm . The virus has a lipid envelope that surrounds three nucleocapsids and has surface projections that form a grid-like structure . The envelope is embedded with two glycoproteins, Gn and Gc, which are involved in attachment to host receptors and membrane fusion . The nucleocapsids are helical and contain the viral genome, which consists of three segments: S (small), M (medium), and L (large) . The S segment encodes the nucleocapsid (N) protein, which protects the viral RNA and forms the ribonucleoprotein complex . The M segment encodes a polyprotein that is cleaved into the Gn and Gc glycoproteins . The L segment encodes the L protein, which functions as the viral transcriptase/replicase and has an endonuclease activity that cleaves cellular mRNAs for capping viral mRNAs .

Hantavirus is a member of the Bunyaviridae family of viruses, which are enveloped viruses with a single-stranded, negative-sense RNA genome. The genome of hantavirus consists of three segments: small (S), medium (M), and large (L), which range in size from 1 to 12 kb.

The S segment encodes the nucleocapsid (N) protein, which forms a helical ribonucleoprotein complex with the genomic RNA and protects it from degradation. The N protein also plays a role in viral transcription, replication, and assembly. Some hantaviruses also encode a nonstructural protein (NSs) on their S segment, which may have an anti-interferon function.

The M segment encodes a polyprotein that is co-translationally cleaved into two envelope glycoproteins: Gn and Gc. These glycoproteins are responsible for binding to host cell receptors and mediating viral entry by membrane fusion. They also elicit neutralizing antibodies and cellular immune responses in the host.

The L segment encodes the L protein, which functions as the viral RNA-dependent RNA polymerase (RdRp). The L protein initiates transcription by using a "cap-snatching" mechanism, in which it cleaves cellular mRNAs and uses their caps as primers for viral mRNA synthesis. The L protein also produces antigenomic and genomic RNAs by replication via positive-sense intermediates.

The genome segments of hantavirus have conserved terminal sequences that are complementary to each other, allowing circularization of the nucleocapsids and efficient transcription and replication. The genome segments also have different copy numbers within virions, with the S segment being the most abundant, followed by the M and L segments.

Hantavirus replicates exclusively in the cytoplasm of infected cells, mainly in endothelial cells and macrophages. The virus enters the cell by receptor-mediated endocytosis and releases its nucleocapsids into the cytoplasm by fusion with the endosomal membrane. The nucleocapsids then serve as templates for viral transcription and replication, which occur in association with cellular membranes such as the endoplasmic reticulum and the Golgi apparatus. The newly synthesized glycoproteins are transported to the Golgi apparatus, where they form heterodimers and acquire their final glycosylation. The nucleocapsids then bud into the Golgi cisternae, acquiring an envelope with glycoprotein spikes. The mature virions are then released from the cell by exocytosis.

Hantavirus is a zoonotic virus that is transmitted to humans by rodents that carry the virus in their urine, droppings, and saliva. The virus can cause two potentially fatal diseases: hantavirus pulmonary syndrome (HPS) and hemorrhagic fever with renal syndrome (HFRS).

Geographic Distribution

Hantavirus infections have been reported in various regions of the world, with different rodent species serving as reservoirs and different hantavirus strains causing different clinical syndromes.

• In the Americas, HPS is caused mainly by Sin Nombre virus (SNV), which is carried by the deer mouse (Peromyscus maniculatus). SNV is responsible for most cases of HPS in the United States and Canada. Other hantaviruses that cause HPS in the Americas include New York virus, Black Creek Canal virus, Bayou virus, Andes virus (ANDV), Laguna Negra virus, Juquitiba virus, Araraquara virus, and Choclo virus. These viruses are carried by various rodent species such as the white-footed mouse, the cotton rat, the rice rat, the long-tailed pygmy rice rat, and the red-backed vole. HPS cases have been reported in Argentina, Bolivia, Brazil, Canada, Chile, Colombia, Ecuador, Mexico, Panama, Paraguay, Peru, Uruguay, Venezuela and the United States .

• In Eurasia and Africa, HFRS is caused mainly by Hantaan virus (HTNV), Seoul virus (SEOV), Puumala virus (PUUV), and Dobrava-Belgrade virus (DOBV). These viruses are carried by various rodent species such as the striped field mouse, the Norway rat, the bank vole, and the yellow-necked mouse. HFRS cases have been reported in China, Russia, Korea, Japan, Finland, Sweden, Norway, Germany, France, Belgium, Spain, Greece, Romania, Bulgaria, Hungary, Slovenia, Croatia and several African countries .

Modes of Transmission

The primary mode of transmission of hantavirus to humans is through inhalation of aerosols or dust particles contaminated with rodent urine, droppings or saliva. This can occur when people disturb or inhabit rodent-infested areas such as houses, barns or sheds . The virus can also enter the body through mucous membranes or skin breaks if people touch contaminated surfaces or materials. In rare cases, hantavirus can be transmitted by rodent bites. The risk of infection is higher when there is a high density of infected rodents in a given area.

The secondary mode of transmission of hantavirus to humans is through person-to-person contact. This has been documented only for ANDV in Chile and Argentina. ANDV can be transmitted from an infected person to a close contact through respiratory droplets or direct contact with body fluids such as blood or saliva . The risk of person-to-person transmission is higher when there is close and prolonged contact with a symptomatic patient.

Risk Factors for Infection

Anyone who comes into contact with rodents that carry hantavirus is at risk of infection. However, some factors may increase the likelihood or severity of infection. These include:

• Living or working in rural areas where rodents are abundant
• Entering rarely opened or seasonally closed buildings that may harbor rodents
• Cleaning or disturbing rodent nests or droppings
• Having a compromised immune system
• Having a genetic predisposition to severe disease
• Having concurrent infections such as influenza
• Being pregnant
• Being male
• Being older than 40 years .

Hantaviruses replicate exclusively in the host cell cytoplasm. The first step of the replication cycle is the attachment of the virus to the host cell receptors through the Gn-Gc glycoprotein dimer on the viral envelope. The virus then enters the cell by endocytosis, which can occur via different pathways, such as clathrin-mediated, caveolin-mediated or clathrin- and caveolin-independent endocytosis. The fusion of the viral envelope with the endosomal membrane releases the nucleocapsids into the cytoplasm .

The viral RNA-dependent RNA polymerase (RdRp) complex binds to the leader sequence at the 3′ end of each genomic segment and initiates transcription. The viral mRNAs are capped in the cytoplasm by a unique mechanism called “cap snatching”, in which the RdRp cleaves cellular mRNAs and uses their 5′ ends as primers . The viral mRNAs are translated by host ribosomes into three structural proteins: nucleocapsid (N) protein, Gn and Gc glycoproteins and RdRp. Some hantaviruses also encode a non-structural protein (NSs) on their S segment, which may have a role in modulating host immune responses.

Replication of the viral genome occurs when enough N protein is present to encapsidate newly synthesized antigenomes and genomes. The RdRp produces positive-sense RNA intermediates from the negative-sense genomic segments, which are then used as templates for generating more negative-sense RNA copies . The N protein binds to both positive- and negative-sense RNA molecules and forms helical ribonucleoproteins (RNPs).

The assembly and budding of new virions take place at the Golgi apparatus . The Gn and Gc glycoproteins form heterodimers and are transported from the endoplasmic reticulum to the Golgi complex, where they undergo further glycosylation and acquire their mature conformation. The RNPs associate with the glycoproteins embedded in the Golgi membrane and bud into the Golgi cisternae . The newly formed virions are then transported in secretory vesicles to the plasma membrane and released by exocytosis .

Hantavirus infection in humans occurs mainly through inhalation of aerosolized virus-contaminated rodent excreta. The exposure risk is usually determined by the population dynamics of the reservoir species. The incubation period of hantavirus is relatively long: 2‒4 weeks for HPS and 1‒8 weeks for HFRS.

The virus initially targets the respiratory epithelium, which acts as a barrier against inhaled pathogens. However, hantavirus infection does not cause cytopathic effects or disrupt the tight junction integrity of the epithelial cells. The virus can infect and secrete from both the apical and basolateral membranes of the epithelial cells, facilitating its dissemination to the lung endothelium and other organs.

The main target cells of hantavirus are the vascular endothelial cells, which line the inner surface of blood vessels and regulate vascular permeability and platelet function. Hantavirus infection of endothelial cells induces cellular activation, inflammation, and apoptosis. The virus also infects macrophages and dendritic cells, which produce pro-inflammatory cytokines and chemokines that attract immune cells to the site of infection.

The immune response to hantavirus infection is characterized by a strong Th1 polarization, with elevated levels of IFN-γ, TNF-α, IL-12, and TNF-β. These cytokines can enhance the antiviral activity of immune cells, but also cause immunopathology by increasing vascular permeability and tissue damage. In addition, hantavirus infection can impair the function of natural killer cells and cytotoxic T cells, which are important for viral clearance.

The pathogenesis of HPS and HFRS differs in the tropism and distribution of hantavirus in the body. HPS-causing hantaviruses have a preference for lung endothelial cells, resulting in pulmonary edema and respiratory failure. HFRS-causing hantaviruses have a preference for kidney endothelial cells, resulting in renal dysfunction and hemorrhage. However, both diseases share common features such as capillary leakage syndrome, thrombocytopenia, and shock.

The exact mechanisms underlying the pathogenesis of hantavirus infections are not fully understood. It is unclear how the virus causes increased vascular permeability without disrupting the endothelial barrier or causing significant viremia. It is also unclear how the virus evades the host immune system and persists in the reservoir hosts without causing disease. Further research is needed to uncover the mysteries of hantavirus infections and develop effective treatments and vaccines.

Hantavirus infections can cause two potentially fatal diseases in humans: hantavirus pulmonary syndrome (HPS) and hemorrhagic fever with renal syndrome (HFRS). Both diseases are characterized by defects in vascular permeability and platelet function, leading to fluid accumulation in the lungs or kidneys, respectively.

Hantavirus Pulmonary Syndrome (HPS)

HPS is a severe respiratory disease that occurs mainly in the Americas. It is caused by several hantavirus species that are transmitted by rodents, such as deer mice, cotton rats, rice rats and white-footed mice.

The incubation period of HPS is estimated to range from 1 to 8 weeks after exposure to rodent excreta or saliva. The disease progresses through two stages: a prodromal stage and a cardiopulmonary stage.

The prodromal stage lasts for 3 to 5 days and is characterized by nonspecific symptoms, such as:

• Fever
• Chills
• Muscle aches, especially in the thighs, hips, back and shoulders
• Headache
• Dizziness
• Nausea
• Vomiting
• Diarrhea
• Abdominal pain
• Cough
• Malaise

The diagnosis of HPS is often missed at this stage, as the symptoms are similar to those of other viral or bacterial infections.

The cardiopulmonary stage begins around day 7 of illness and is marked by the rapid onset of respiratory distress and hypotension. The patient develops pulmonary edema, which is the accumulation of fluid in the lungs, resulting in shortness of breath, coughing and gasping for air. The patient may also experience chest pain, palpitations and tachycardia.

The mortality rate of HPS is about 38%, and most deaths occur within the first 48 hours of the cardiopulmonary stage. The survivors usually recover completely within a few weeks.

Hemorrhagic Fever with Renal Syndrome (HFRS)

HFRS is a systemic disease that occurs mainly in Eurasia. It is caused by several hantavirus species that are transmitted by rodents, such as striped field mice, yellow-necked mice, bank voles and Norway rats.

The incubation period of HFRS is estimated to range from 1 to 6 weeks after exposure to rodent excreta or saliva. The disease progresses through four phases: febrile phase, hypotensive phase, oliguric phase and diuretic phase.

The febrile phase lasts for 3 to 7 days and is characterized by sudden onset of symptoms, such as:

• Fever
• Chills
• Headache
• Back pain
• Abdominal pain
• Nausea
• Vomiting
• Diarrhea
• Blurred vision
• Flushing of the face
• Redness or inflammation of the eyes
• Rash

The patient may also develop hemorrhagic manifestations, such as petechiae, ecchymoses, epistaxis, hematemesis or hematuria.

The hypotensive phase lasts for 2 to 4 days and is marked by a drop in blood pressure and shock. The patient may experience tachycardia, dyspnea, chest pain and confusion. This phase is associated with increased vascular permeability and plasma leakage into the interstitial spaces.

The oliguric phase lasts for 3 to 7 days and is characterized by acute kidney injury and reduced urine output. The patient may develop edema, electrolyte imbalance, metabolic acidosis and uremia. This phase is associated with damage to the renal tubules and glomeruli caused by hantavirus infection or immune-mediated mechanisms.

The diuretic phase lasts for 3 to 6 days and is characterized by recovery of renal function and increased urine output. The patient may experience polyuria, dehydration, hypokalemia and hypotension. This phase is associated with restoration of glomerular filtration and tubular reabsorption.

The mortality rate of HFRS ranges from 1% to 15%, depending on the virus strain and the severity of the disease. The survivors usually recover completely within a few months.

The laboratory diagnosis of hantavirus infection can be done by various methods, such as serological tests, molecular tests, immunohistochemistry and virus isolation. However, not all of these methods are widely available or routinely used in clinical settings. The most common and practical approach for diagnosing hantavirus pulmonary syndrome (HPS) and hemorrhagic fever with renal syndrome (HFRS) is the detection of antihantavirus IgM and/or IgG antibodies in serum samples.

Serological tests

Serological tests are based on the detection of specific antibodies that the human immune system produces in response to hantavirus infection. These antibodies can be detected by different techniques, such as enzyme-linked immunosorbent assay (ELISA), indirect immunofluorescence assay (IFA), immunoblot assay and neutralization test .

ELISA is a simple and sensitive method that uses hantavirus antigens (usually recombinant nucleocapsid proteins) coated on a solid phase to capture antibodies from serum samples. The bound antibodies are then detected by enzyme-labeled secondary antibodies and a colorimetric substrate. ELISA can be used to measure IgM or IgG antibodies separately or together. IgM antibodies usually appear early in the course of infection and indicate acute infection, while IgG antibodies appear later and persist for a long time. A four-fold rise in IgG antibody titer or the presence of IgM in acute-phase serum samples is considered diagnostic for hantavirus infection .

IFA is another widely used method that uses hantavirus-infected cells fixed on glass slides as antigens. The serum samples are incubated with the slides and then stained with fluorescent-labeled secondary antibodies. The presence of specific antibodies is visualized by fluorescence microscopy. IFA can also differentiate IgM and IgG antibodies and detect cross-reactivity with other hantaviruses.

Immunoblot assay is a more specific method that uses recombinant or synthetic hantavirus proteins or peptides separated by electrophoresis on a membrane as antigens. The serum samples are incubated with the membrane and then detected by enzyme-labeled secondary antibodies and a chemiluminescent substrate. The presence of specific antibodies is revealed by the appearance of bands corresponding to the antigens on the membrane. Immunoblot assay can also distinguish IgM and IgG antibodies and identify different hantavirus strains.

Neutralization test is the most definitive method to confirm hantavirus infection and serotype. It involves incubating serum samples with live hantavirus in cell culture and measuring the reduction of viral infectivity by plaque assay or immunofocus assay. Neutralization test requires biosafety level 3 facilities and trained personnel, and it is not commercially available.

Molecular tests

Molecular tests are based on the detection of hantavirus genome by reverse transcription polymerase chain reaction (RT-PCR) or other nucleic acid amplification techniques. These tests can identify hantavirus RNA in clinical samples, such as blood, serum, urine or tissue specimens, usually from the first day after the onset of symptoms until 10 days later .

RT-PCR is a rapid and sensitive method that uses specific primers to amplify hantavirus RNA segments by reverse transcription and polymerase chain reaction. The amplified products are then detected by gel electrophoresis, hybridization probes, fluorescence probes or sequencing. RT-PCR can also differentiate various hantavirus species and genotypes .

Real-time RT-PCR is a more advanced method that allows simultaneous amplification and detection of hantavirus RNA by using fluorescent probes that emit signals when hybridized to the target sequences. Real-time RT-PCR can also quantify the viral load in clinical samples, which can be correlated with disease severity and prognosis.

Immunohistochemistry

Immunohistochemistry (IHC) is a method that uses specific monoclonal or polyclonal antibodies to detect hantavirus antigens in formalin-fixed tissues, such as lung, kidney, liver or spleen. The bound antibodies are then visualized by enzyme-labeled secondary antibodies and a chromogenic substrate. IHC can be used to confirm hantavirus infection in patients from whom serum samples or frozen tissues are unavailable or inconclusive .

Virus isolation

Virus isolation is the most direct method to demonstrate hantavirus infection, but it is also the most difficult and hazardous one. It involves inoculating clinical samples into cell culture, mostly Vero E6 cells (green monkey kidney cells), and observing cytopathic effects or viral antigens by immunofluorescence assay or immunoperoxidase assay. Virus isolation requires biosafety level 3 facilities and trained personnel, and it is not routinely performed for diagnostic purposes .

There is no specific treatment, cure, or vaccine for hantavirus infections. However, early recognition and supportive care in an intensive care unit (ICU) may improve the chances of survival. Supportive care includes:

• Managing fluid and electrolyte balance
• Maintaining oxygen and blood pressure levels
• Treating any secondary infections
• Dialysis for severe fluid overload
• Intravenous ribavirin, an antiviral drug, for some cases of hemorrhagic fever with renal syndrome (HFRS)

Supportive Care

Supportive care is the mainstay of treatment for patients with hantavirus infections. It involves monitoring and correcting the patient`s vital signs and organ functions, such as heart rate, blood pressure, oxygen saturation, kidney function, and fluid balance. Supportive care may also include:

• Antipyretics and analgesics for fever and pain relief
• Fluid replacement therapy for dehydration or shock
• Oxygen therapy or mechanical ventilation for respiratory distress
• Vasopressors or inotropes for low blood pressure or cardiac dysfunction
• Antibiotics for secondary bacterial infections

Supportive care should be initiated as soon as possible after the onset of symptoms and continued until the patient recovers. The duration and intensity of supportive care may vary depending on the severity of the disease and the patient`s response.

Dialysis

Dialysis is a procedure that removes excess fluid and waste products from the blood when the kidneys are not functioning properly. Dialysis may be required for patients with hantavirus infections who develop severe fluid overload, acute kidney failure, or electrolyte imbalances. Dialysis can help reduce the risk of complications such as pulmonary edema, cardiac arrhythmias, or metabolic acidosis.

Dialysis can be performed either by hemodialysis or peritoneal dialysis. Hemodialysis uses a machine that filters the blood through an artificial membrane. Peritoneal dialysis uses a catheter that infuses a fluid into the abdominal cavity and then drains it out along with the waste products. The choice of dialysis modality depends on the availability of resources, the patient`s condition, and the preference of the medical team.

Ribavirin

Ribavirin is an antiviral drug that inhibits the replication of some RNA viruses, including some hantaviruses. Ribavirin has been shown to decrease the mortality and morbidity associated with HFRS if given early in the course of the disease. However, ribavirin has not been proven to be effective for hantavirus pulmonary syndrome (HPS) and may have serious side effects such as hemolytic anemia, teratogenicity, and mutagenicity.

Ribavirin is given intravenously at a dose of 33 mg/kg as a loading dose, followed by 16 mg/kg every 6 hours for 4 days, and then 8 mg/kg every 8 hours for 3 days. Ribavirin should be administered only under strict medical supervision and with informed consent from the patient or their legal representative. Ribavirin should not be given to pregnant women or women who may become pregnant during or within 6 months after treatment.

The best way to prevent hantavirus infection is to avoid or minimize contact with rodents and their droppings. There is no vaccine or specific treatment for hantavirus infection, so early recognition and medical care are crucial for improving the chances of survival. Here are some prevention and control measures that can help reduce the risk of hantavirus infection:

• Seal up holes and gaps in your home, workplace, cottage or campsite that may allow rodents to enter. Use wire mesh, steel wool, caulk or other materials to block rodent access points.
• Trap rodents around your home, workplace, cottage or campsite using snap traps or live traps. Dispose of dead rodents safely by wearing gloves and placing them in a plastic bag. Wash your hands with soap and water after handling rodents or traps.
• Clean up any easy-to-get food that may attract rodents. Store food in rodent-proof containers and dispose of garbage regularly. Keep pet food in sealed containers and do not leave it out overnight.
• Avoid disturbing rodent nests or burrows in your yard, garden or woodpile. If you need to remove them, use gloves and a shovel and place them in a plastic bag. Do not use a vacuum cleaner or a broom to clean up rodent droppings or nesting materials as this can create aerosols that may contain the virus.
• Air out rodent-infested areas before entering them. If you find signs of rodent activity in an abandoned or unused cabin, shed or barn, open the doors and windows and wait at least 30 minutes before entering. Use cross-ventilation to ensure adequate air flow.
• Clean and disinfect rodent-contaminated areas using a bleach solution or a commercial disinfectant. Wear rubber gloves, goggles and a mask that covers your nose and mouth. Spray the rodent droppings, urine, nesting materials and surrounding areas with the disinfectant and let it soak for 10 minutes. Then wipe up the materials with a paper towel or a mop and place them in a plastic bag. Wash your gloves before removing them and wash your hands with soap and water afterwards.
• Avoid touching live or dead rodents with bare hands. If you encounter a live rodent, do not try to catch or handle it. If you find a dead rodent, use gloves and a shovel to place it in a plastic bag. Wash your hands with soap and water after handling rodents or gloves.
• Do not camp or sleep near rodent burrows or nests. If you are camping or hiking in an area where hantavirus may be present, choose a site that is away from signs of rodent activity. Use a tent with a floor and keep the door closed. Store food in rodent-proof containers and do not leave it out overnight. Do not use cabins that have signs of rodent infestation such as droppings or nests.
• Be aware of the symptoms of hantavirus infection and seek medical attention immediately if you develop them. The symptoms of hantavirus pulmonary syndrome (HPS) include fever, chills, muscle aches, headache, coughing, shortness of breath, nausea, vomiting and abdominal pain. The symptoms of hemorrhagic fever with renal syndrome (HFRS) include fever, headache, back and abdominal pain, rash, low blood pressure, blurred vision, red eyes and kidney failure.

By following these prevention and control measures, you can reduce your risk of exposure to hantavirus and protect yourself from its potentially fatal consequences. Remember to always practice good hygiene and sanitation when dealing with rodents or their droppings.

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