Hantavirus pulmonary syndrome
Hantavirus pulmonary syndrome, also called hantavirus cardiopulmonary syndrome, is a severe respiratory disease caused by hantaviruses. The main features of illness are microvascular leakage and acute respiratory distress syndrome. Symptoms occur anywhere from one to eight weeks after exposure to the virus and come in three distinct phases. First, there is an early phase with flu-like symptoms such as fever, muscle aches, headache, and shortness of breath, as well as low platelet count. Second, there is cardiopulmonary phase during which people experience elevated or irregular heart rate, cardiogenic shock, and pulmonary capillary leakage, which can lead to respiratory failure, low blood pressure, and buildup of fluid in the lungs and chest cavity. The final phase is recovery, which typically takes months, but difficulties with breathing can persist for up to two years. The disease has a case fatality rate of 30 to 60 percent. Death usually occurs suddenly during the cardiopulmonary phase.
HPS is caused mainly by infection with New World hantaviruses in the Americas. In North America, Sin Nombre virus is the most common cause of HPS and is transmitted by the western deer mouse. In South America, Andes virus is the most common cause of HPS and is transmitted mainly by the long-tailed pygmy rice rat. In their rodent hosts, these hantaviruses cause a persistent, asymptomatic infection. Transmission occurs mainly through inhalation of aerosols that contain rodent saliva, urine, or feces, but can also occur through contaminated food, bites, and scratches. Vascular endothelial cells and macrophages are the primary cells infected by hantaviruses, and infection causes abnormalities with blood clotting, all of which results in fluid leakage responsible for the more severe symptoms. Recovery from infection likely confers life-long protection.
The main way to prevent infection is to avoid or minimize contact with rodents that carry hantaviruses. Removing sources of food for rodents, safely cleaning up after them, and preventing them from entering one's house are all important means of protection. People who are at a risk of interacting with infected rodents can wear masks to protect themselves. No vaccines exist that protect against HPS. Initial diagnosis of infection can be made based on epidemiological information and symptoms. Confirmation of infection can be done by testing for hantavirus nucleic acid, proteins, or hantavirus-specific antibodies. Supportive treatment is always performed for HPS and entails continual cardiac monitoring and respiratory support, including mechanical ventilation, extracorporeal membrane oxygenation, and hemofiltration. No specific antiviral drugs exist for hantavirus infection.
In North America, dozens of HPS cases occur each year, while in South America more than 100 cases occur every year. Isolated cases and small outbreaks have occurred in Europe and Turkey. The distribution of viruses that cause HPS is directly tied to the distribution of their natural reservoir. Transmission is also greatly influenced by environmental factors such as rainfall, temperature, and humidity, which affect the rodent population and virus transmissibility. The discovery of HPS came in 1993 during an outbreak in the Four Corners region of the United States, which was indirectly caused by the El Niño climate pattern. Sin Nombre virus was found to be responsible for the outbreak, and since then numerous other hantaviruses that cause HPS have been identified throughout the Americas.
Signs and symptoms
HPS symptoms occur about 1–8 weeks after exposure to the virus. The main features of the illness are microvascular leakage and acute respiratory distress syndrome. The disease has three phases: early, cardiopulmonary, and recovery. Prodromal symptoms last for 1–5 days and include flu-like symptoms such as fever, headache, muscle pain, nausea, vomiting, dizziness, chills, coughing, and shortness of breath, as well as low platelet count in the blood. Within 10 days, the cardiopulmonary phase begins and lasts for several days. It is marked by elevated heart rate, irregular heartbeats, and cardiogenic shock, a condition in which the heart is unable to pump enough blood for the body. Pulmonary capillary leakage can lead to respiratory failure, buildup of fluids in the lungs, low blood pressure, and buildup of fluid in the chest cavity between the lungs and chest wall.While HPS is typically associated with cardiopulmonary symptoms, it may include renal symptoms typically associated with hemorrhagic fever with renal syndrome, namely acute kidney injury and excess protein in urine, which sometimes occur during the cardiopulmonary phase. During the recovery phase, increased urination occurs as renal function returns. Repeated infections of hantaviruses have not been observed, so recovering from infection likely grants life-long immunity.
Virology
Genome and structure
The genome of hantaviruses is segmented into three parts: the large, medium, and small segments. Each part is a single-stranded negative-sense RNA strand, consisting of 10,000–15,000 nucleotides in total. The segments form into circles via non-covalent bonding of the ends of the genome. The L segment is about 6.6 kilobases in length and encodes RNA-dependent RNA polymerase, which mediates transcription and replication of viral RNA. The M segment, about 3.7 kb in length, encodes a glycoprotein precursor that is co-translated and cleaved into Gn and Gc. Gn and Gc bind to cell receptors, regulate immune responses, and induce protective antibodies. The S segment is around 2.1 kb in length and encodes the N protein, which binds to and protects viral RNA. An open reading frame in the N gene on the S segment of some hantaviruses also encodes the non-structural protein NS that inhibits interferon production in host cells. The untranslated regions at the ends of the genome are highly conserved and participate in the replication and transcription of the genome.Individual hantavirus particles are usually spherical, but may be oval, pleomorphic, or tubular. The diameter of the virion is 70–350 nanometers. The lipid envelope is about 5 nm thick. Embedded in the envelope are the surface spike glycoproteins Gn and Gc, which are arranged in a lattice pattern. Each surface spike is composed of a tetramer of Gn and Gc that has four-fold rotational symmetry and extends about 10 nm out from the envelope. Gn forms the stalk of the spike and Gc the head. Inside the envelope are helical nucleocapsids made of many copies of the nucleocapsid protein N, which interact with the virus's genome and RdRp. Hantaviruses do not encode matrix proteins to assist with structuring the virion, so how surface proteins organize into a sphere with a symmetrical lattice is not yet known.
Life cycle
Vascular endothelial cells and macrophages are the primary cells infected by hantaviruses. Podocytes, tubular cells, dendritic cells, and lymphocytes can also be infected. Attachment and entry into the host cell is mediated by the binding of the viral glycoprotein spikes to host cell receptors, particularly β1 and β3 integrins. Decay acceleration factors, complement receptors, and, for New World hantaviruses, protocadherin-1 have also been proposed to be involved in attachment. After attachment, hantaviruses rely on several ways to enter a cell, including micropinocytosis, clathrin-independent receptor-mediated endocytosis and cholesterol- or caveolae-dependent endocytosis. Old World hantaviruses use clathrin-dependent endocytosis while New World hantaviruses use clathrin-independent endocytosis.After entering a cell, virions form vesicles that are transported to early endosomes, then late endosomes and lysosomal compartments. A decrease in pH then causes the viral envelope to fuse with the endosome or lysosome. This fusion releases viral ribonucleoprotein complexes into the cell cytoplasm, initiating transcription and replication by RdRp. RdRp transcribes viral -ssRNA into complementary positive-sense strands, then snatches 5′ ends of host messenger RNA to prepare mRNA for translation by host ribosomes to produce viral proteins. Complementary RNA strands are also used to produce copies of the genome, which are encapsulated by N proteins to form RNPs.
During virion assembly, the glycoprotein precursor is cleaved in the endoplasmic reticulum into the Gn and Gc glycoproteins by host cell signal peptidases. Gn and Gc are modified by N-glycan chains, which stabilize the spike structure and assist in assembly in the Golgi apparatus for Old World hantaviruses or at the cell membrane for New World hantaviruses. Old World hantaviruses obtain their viral envelope from the Golgi apparatus and are then transported to the cell membrane in vesicles to leave the cell via exocytosis. On the other hand, New World hantavirus RNPs are transported to the cell membrane, where they bud from the surface of the cell to obtain their envelope and leave the cell.