8. Pathogenesis of hantaviruses
Human infections with hantaviruses can cause acute diseases, and the severity varies by viral species and strains.3,19,20HFRS mainly affects the kidney and blood vessels, and HCPS/HPS mainly affect the heart and lung.67 Other organs and systems, such as the nervous system, spleen, and liver, can also be affected.85
In both animals and humans, hantavirus infection mainly occurs in renal or pulmonary endothelial cells (ECs) and macrophages.65 The main pathogenesis of HFRS and HCPS/HPS covers increased vascular permeability and acute thrombocytopenia.5 Infection begins with the interaction between hantavirus glycoproteins (Gn and Gc) and β-integrin receptors (e.g., αvβ1 and αvβ3) on target cell membranes.86 Immature dendritic cells located near epithelial cells transport virions from lymphatic vessels to local lymph nodes, to infect more ECs. These cells act as antigen-presenting cells and induce immune activation, especially those associated with macrophages and CD8+ T lymphocytes.5Delayed type I interferon response leads to higher virus titers.87 After immune activation, cytotoxic T lymphocytes produce pro-inflammatory cytokines that can damage the infected endothelial cells, leading to increased vascular permeability and inflammatory reactions.88Activation of complements and release of pro-inflammatory cytokines, such as interferon (IFN), interleukins (IL-1, IL-6, and IL-10), and tumor necrosis factor-α (TNF-α), play a crucial role in changing endothelial cell permeability.86 Different hantaviruses elicit different immune responses. High levels of cytotoxic CD8+ T lymphocytes can be detected in HFRS patients. Elevated IL-6 levels are associated with thrombocytopenia and renal failure.86
Human leukocyte antigen (HLA) is responsible for presenting viral antigens to T lymphocytes. Genetic susceptibility to severe HFRS disease is related to the HLA type, and different hantaviruses are associated with different HLA haplotypes.65
Natural reservoir hosts of hantaviruses often exhibit asymptomatic persistent infection with hantaviruses, which may result from the innate immunity of the reservoir hosts.85 In rodents, it is possible that T lymphocytes can be regulated with the immune receptor NLRC3, leading to persistent viral infection without symptoms, and the lack of such an immune regulation in humans leads to disease.89
The lack of obvious symptoms in natural hosts and the lack of suitable animal models restricted research on the pathogenesis of HTNV and SEOV to humans.90 HTNV infectedNlrc3 -/- mice can develop clinical symptoms and pathological changes resembling those seen in patients with HFRS, suggesting a new model for studying the pathogenesis of HTNV. Monkeys can be infected with PUUV through laboratory infection with similar symptoms to NE and can be used as an animal model of NE.85 Research into the pathogenesis of HCPS/HPS has been aided with the hamster model, which mimics the pulmonary capillary leak and the hypotension characteristic of human HCPS/HPS.5