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