Hantavirus infection pathophysiology
|
Hantavirus infection Microchapters |
|
Patient Information |
|---|
|
Diagnosis |
|
Treatment |
|
Case Studies |
|
Hantavirus infection pathophysiology On the Web |
|
American Roentgen Ray Society Images of Hantavirus infection pathophysiology |
|
Directions to Hospitals Treating Hantavirus pulmonary syndrome |
|
Risk calculators and risk factors for Hantavirus infection pathophysiology |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2] Basir Gill, M.B.B.S, M.D.[3]
Overview
Hantavirus is usually transmitted via the inhalation of aerosolized viral antigens from rodent excreta (urine, feces, saliva) or, rarely, via rodent bites. The incubation period of hantavirus infection is 2 to 6 weeks.[1] Following inhalation, the virus replicates in pulmonary macrophages and dendritic cells. The primary target cells of hantavirus infection are endothelial cells of capillaries and small vessels. Increased vascular permeability is central to pathogenesis and does not appear to be caused by a lytic effect of the virus, but rather by functional changes of the endothelial barrier.[1] According to histopathological studies, HFRS-causing hantaviruses primarily affect renal medulla capillaries, whereas HCPS-causing hantaviruses mainly affect pulmonary capillaries.[1] The central phenomena behind the pathogenesis of both hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS) are increased vascular permeability and acute thrombocytopenia.[2] The pathogenesis is a complex multifactorial process that includes contributions from immune responses, platelet dysfunction, deregulation of endothelial cell barrier functions, activation of the complement system, the kallikrein-kinin system, and coagulation pathways.[2][3]
Pathophysiology
Reservoir and Transmission
Each hantavirus species is associated with a specific rodent host in a given geographic region. Rodent subfamilies associated with hantaviruses include:
Arvicolinae (Europe): hosts for Puumala virus, Tula virus
Murinae (Europe and Asia): hosts for Hantaan virus, Seoul virus, Dobrava-Belgrade virus
Sigmodontinae/Neotominae (Americas): hosts for Sin Nombre virus, Andes virus, and other New World hantaviruses
Hantavirus is usually transmitted via the inhalation of aerosolized viral antigens from rodent excreta. Human-to-human transmission has been documented only for Andes virus.[1]
Incubation Period
The incubation period of hantavirus infection ranges from 2 to 6 weeks.[1] Earlier estimates based on HCPS cases in the United States reported a median incubation period of 9 to 33 days.[4]
Initial Viral Replication
Following inhalation, the virus replicates in pulmonary macrophages and dendritic cells.[1] Endothelial cells in the lungs, kidneys, heart, liver, and spleen are subsequently infected. Macrophages, mononuclear blood cells, dendritic cells, and respiratory and tubular epithelium can also be infected.[1]
Viral Entry via β3 Integrins
Pathogenic hantaviruses (both HFRS- and HCPS-causing) enter endothelial cells via αvβ3 integrins, which are highly expressed on endothelial cells, platelets, and macrophages.[5] Non-pathogenic hantaviruses (e.g., Prospect Hill virus) use α5β1 integrins instead. Since β3 integrins regulate vascular permeability and platelet function, this receptor usage correlates with common elements of hantavirus pathogenesis.[5]
Hantaviruses attach to β3 integrin receptors of endothelial cells and stimulate T cells. Neutralizing antibodies (NAbs) are produced as a result of stimulation and β3 integrins are inactivated. Inactivation of virus-bound β3 integrins contributes to deregulation of vascular endothelial growth factor receptor 2 (VEGFR2) and diminished antagonism of vascular endothelial growth factor (VEGF).[6] Pathogenic hantaviruses also selectively inhibit β3 integrin-directed endothelial cell migration.[7]
Impairment of Endothelial Barrier Function
VEGF-VEGFR2-β3 Integrin Axis
The β3 integrin and VEGFR2 form a functional complex on endothelial cells. Hantavirus infection upregulates expression of both β3 and VEGFR2 but blocks the function of the VEGFR2-β3 integrin complex, contributing to cytoskeletal reorganization and hyperpermeability in response to VEGF.[6] Overexpressed VEGF promotes degradation of VE-cadherin, an adhesion molecule critical for endothelial barrier integrity, leading to loss of endothelial barrier function and increased vascular permeability.[8]
Nucleocapsid Protein–RhoA–RhoGDI Pathway
The Andes virus nucleocapsid (N) protein activates the GTPase RhoA in pulmonary microvascular endothelial cells, causing VE-cadherin internalization from adherens junctions and endothelial permeability.[9] ANDV N protein binds RhoGDI (Rho GDP dissociation inhibitor), the primary RhoA repressor that normally sequesters RhoA in an inactive state. By sequestering RhoGDI, the N protein reduces the amount available to suppress RhoA. In response to hypoxia and VEGF-activated protein kinase Cα (PKCα), ANDV N protein additionally directs the release of RhoA from S34-phosphorylated RhoGDI, synergistically activating RhoA and endothelial permeability.[9] This provides a fundamental edemagenic mechanism that permits ANDV to amplify permeability in hypoxic HCPS patients. RhoA/Rho kinase inhibitors (fasudil and Y27632) dramatically reduced the permeability of ANDV-infected endothelial cells by 80% to 90%.[10]
Pericyte Infection
ANDV also persistently infects primary human vascular pericytes, which play critical roles in regulating endothelial cell permeability and immune cell recruitment. ANDV-infected pericytes secrete high levels of VEGF, and supernatants from infected pericytes increase endothelial monolayer permeability. This reveals a novel mechanism of pericyte-directed vascular barrier dysfunction contributing to HCPS.[11]
Kallikrein-Kinin System and Bradykinin
Hantavirus-infected endothelial cells show increased Factor XII (FXII) binding and autoactivation on their surface. Incubation of FXII, prekallikrein, and high molecular weight kininogen (HK) with infected endothelial cells results in increased cleavage of HK, higher enzymatic activities of FXIIa/kallikrein, and increased liberation of bradykinin (BK).[12] Bradykinin is an extremely potent inflammatory molecule that induces vasodilation and vascular permeability. Permeability changes could be prevented using inhibitors that block BK binding, FXIIa activity, or kallikrein activity.[12] Successful treatment of Puumala virus-infected patients using BK antagonists (icatibant) supports the clinical relevance of this pathway.[8]
MicroRNA Dysregulation
ANDV infection alters the expression of endothelial cell-specific microRNAs (miRNAs) that regulate vascular integrity. Fourteen miRNAs were upregulated >4-fold following ANDV infection, including six associated with regulating vascular integrity. Increased expression of SPRED1 and PIK3R2 mRNAs (targets of miR-126) contributes to enhanced paracellular permeability of ANDV-infected endothelial cells.[13]
Fluid Extravasation and Platelet Consumption
Loss of endothelial barrier function leads to fluid extravasation into the interstitial space, resulting in pulmonary edema (in HCPS) or renal interstitial edema (in HFRS). Platelets are consumed in high numbers in response to endothelial damage, resulting in thrombocytopenia.[2] Increased thrombopoiesis occurs during HFRS as evidenced by elevated thrombopoietin, immature platelet fraction, and mean platelet volume, but circulating platelets have reduced ex vivo function. In vivo platelet activation (elevated soluble P-selectin and soluble glycoprotein VI) is significantly increased in HFRS patients with intravascular coagulation.[14]
Cytokine Storm and Immunopathogenesis
Hantavirus infection induces a cytokine storm with upregulation of proinflammatory cytokines including IL-1β, IL-2, IL-6, IL-8, IL-18, TNF-α, IFN-γ, and chemokines CXCL9, CXCL10, and MIF.[15] HCPS is characterized by a more massive upregulation of proinflammatory cytokines compared to HFRS/NE. High IL-6 levels have been associated with more severe forms of both HFRS and HCPS and with fatal outcomes of HCPS.[15]
IL-6 Trans-Signaling
A 2025 study demonstrated that IL-6 trans-signaling (via soluble IL-6 receptor, sIL-6R) enhances IL-6 and CCL2 secretion, upregulates ICAM-1, and disrupts VE-cadherin-mediated cell barrier integrity in hantavirus-infected endothelial cells. HFRS patients showed altered plasma levels of sIL-6R and soluble gp130 (sgp130) resulting in an increased sIL-6R/sgp130 ratio, suggesting enhanced IL-6 trans-signaling potential. Plasma sgp130 levels negatively correlated with number of interventions and positively with albumin levels. Patients requiring oxygen treatment displayed a higher sIL-6R/sgp130 ratio compared to patients who did not.[16]
Cellular Immune Response
Sensitized mononuclear cells infiltrate the lung, myocardial interstitium, and spleen to produce cytokines, particularly TNF-α and IFN-γ, resulting in pulmonary edema and myocarditis.[17]
CD8+ T cells: Elevated CD8+ T cell responses correlate with disease severity and systemic organ dysfunction. Individuals with HLA-B3501 have an increased risk of developing severe HCPS, and significantly higher frequencies of Sin Nombre virus-specific CD8+ T cells (up to 44.2% of CD8+ T cells) were found in patients with severe HCPS requiring mechanical ventilation compared to moderately ill patients (up to 9.8%).[18]
NK cells: Excessive NK cell activation with persistence of elevated numbers in peripheral blood following infection. NK cells localize to the lung during acute infection.[15]
T regulatory cells (Treg): Treg response is downregulated in humans during hantavirus infection (in contrast to rodent reservoirs where upregulated Treg promotes viral persistence). This suppression of Treg may contribute to HCPS pathogenesis.[8]
Neutrophils: Attachment of hantavirus to β2 integrin receptors on neutrophils induces the release of neutrophil extracellular traps (NETs). Neutrophil activation products (myeloperoxidase and neutrophil elastase), together with IL-8, are strongly elevated in acute PUUV-HFRS and positively correlate with kidney dysfunction. These markers localize mainly in the tubulointerstitial space of the kidneys.[19]
Plasmablasts: Significant early increase with early IgM/IgG production. Early neutralizing antibody production is broadly associated with positive prognosis in both HCPS and HFRS.[15]
Innate Immune Evasion
Hantaviruses have evolved multiple strategies to evade the type I interferon (IFN) response:
Glycoprotein precursor (GPC/Gn): The cytoplasmic tail of the Gn protein (GnT) from pathogenic hantaviruses binds TRAF3 and inhibits RIG-I/TBK1-directed IRF3 phosphorylation and IFN-β induction. A single residue (Y627) in the NY-1V GnT is required for this inhibition.[20]
Nucleocapsid protein (N): ANDV NP interferes with IRF3 phosphorylation and TBK1 autophosphorylation. SNV GPC alone is sufficient for IFN antagonism, whereas ANDV requires both NP and GPC.[21]
Non-structural protein (NSs): ANDV NSs antagonizes type I IFN induction by binding MAVS and reducing its ubiquitination, thereby suppressing downstream signaling from RIG-I and MDA5.[15] NSs proteins from PUUV, TULV, and PHV also inhibit the RIG-I-activated IFNβ promoter.[22]
Autophagy manipulation: Hantaan virus (HTNV) restrains innate immune responses by manipulating host autophagy flux. The Gn protein translocates to mitochondria and interacts with TUFM, recruiting LC3B and promoting mitophagy, which inhibits type I IFN responses by degrading MAVS. The NP competes with Gn for binding to LC3B and interacts with SNAP29, preventing autophagosome-lysosome fusion.[23]
Neutralizing antibodies (NAbs) also inhibit innate type I interferon (IFN) responses of endothelial cells. This results in inhibition of upregulation of CD73 by IFN-β on endothelial cells and promotes vascular leakage.[24]
Coagulation, Complement, and DIC
Coagulopathy
PUUV-infected patients show altered coagulation with increased thrombin formation (prothrombin fragments F1+2), consumption of fibrinogen, and decreased natural anticoagulants (antithrombin, protein C, protein S). Cross-talk between inflammation and coagulation systems is a hallmark of acute hantavirus infection.[3] Patients with HFRS have an increased risk for disseminated intravascular coagulation (DIC) and venous thromboembolism. Circulating extracellular vesicle tissue factor activity is transiently increased during HFRS and is significantly associated with intravascular coagulation.[25]
In a prospective study of 106 HFRS patients, DIC was found in approximately 18.9% to 28.3% of patients (depending on scoring template used) and correlated with more severe disease.[26] In a cohort of 395 HFRS patients, 27.30% (107/392) presented with DIC on admission, and DIC was more common in the death group. Prolonged prothrombin time (PT), low fibrinogen, and elevated total bilirubin on admission were independent risk factors for mortality.[27]
Complement Activation
The complement system becomes activated via the alternative pathway in the acute stage of PUUV infection. Levels of the terminal complement complex SC5b-9 are significantly increased and C3 decreased in the acute stage compared to recovery. SC5b-9 levels correlate with several clinical and laboratory parameters reflecting disease severity, including chest X-ray abnormalities.[28]
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Vial PA, Ferrés M, Vial C, Klingström J, Ahlm C, López R, Le Corre N, Mertz GJ (2023). "Hantavirus in Humans: A Review of Clinical Aspects and Management". Lancet Infect Dis. 23 (9): e371–e382. doi:10.1016/S1473-3099(23)00128-7. PMID 37105214 Check
|pmid=value (help). - ↑ 2.0 2.1 2.2 Avšič-Županc T, Saksida A, Korva M (2019). "Hantavirus Infections". Clin Microbiol Infect. 21S: e6–e16. doi:10.1111/1469-0691.12291. PMID 24750436.
- ↑ 3.0 3.1 Koskela S, Mäkelä S, Strandin T, Vaheri A, Outinen T, Joutsi-Korhonen L, Pörsti I, Mustonen J, Laine O (2021). "Coagulopathy in Acute Puumala Hantavirus Infection". Viruses. 13 (8): 1553. doi:10.3390/v13081553. PMID 34452419 Check
|pmid=value (help). - ↑ "Incubation Period of Hantavirus Cardiopulmonary Syndrome". Emerging Infectious Diseases, CDC. 2006.
- ↑ 5.0 5.1 Gavrilovskaya IN, Shepley M, Shaw R, Ginsberg MH, Mackow ER (1998). "beta3 Integrins mediate the cellular entry of hantaviruses that cause respiratory failure". Proc Natl Acad Sci USA. 95 (12): 7074–9. PMC 22743. PMID 9618541.
- ↑ 6.0 6.1 Geimonen E, Neff S, Raymond T, Kocer SS, Gavrilovskaya IN, Mackow ER (2002). "Pathogenic and nonpathogenic hantaviruses differentially regulate endothelial cell responses". Proc Natl Acad Sci USA. 99 (21): 13837–42. doi:10.1073/pnas.192298899. PMC 129784. PMID 12368479.
- ↑ Gavrilovskaya IN, Peresleni T, Geimonen E, Mackow ER (2002). "Pathogenic hantaviruses selectively inhibit beta3 integrin directed endothelial cell migration". Arch Virol. 147 (10): 1913–31. doi:10.1007/s00705-002-0852-0. PMID 12376753.
- ↑ 8.0 8.1 8.2 Llah ST, Mir S, Sharif S, Khan S, Mir MA (2018). "Hantavirus induced cardiopulmonary syndrome: A public health concern". J Med Virol. 90 (6): 1003–1009. doi:10.1002/jmv.25054.
- ↑ 9.0 9.1 Gorbunova EE, Mackow ER (2021). "Binding of the Andes Virus Nucleocapsid Protein to RhoGDI Induces the Release and Activation of the Permeability Factor RhoA". J Virol. 95 (17): e0039621. doi:10.1128/JVI.00396-21. PMID 34133221 Check
|pmid=value (help). - ↑ Gorbunova EE, Simons MJ, Gavrilovskaya IN, Mackow ER (2016). "The Andes Virus Nucleocapsid Protein Directs Basal Endothelial Cell Permeability by Activating RhoA". mBio. 7 (5): e01747–16. doi:10.1128/mBio.01747-16. PMID 27795403.
- ↑ Perez RD, Gorbunova EE, Mackow ER (2021). "Novel Infection of Pericytes by Andes Virus Enhances Endothelial Cell Permeability". Virus Res. 306: 198584. doi:10.1016/j.virusres.2021.198584. PMID 34624404 Check
|pmid=value (help). - ↑ 12.0 12.1 Taylor SL, Wahl-Jensen V, Copeland AM, Jahrling PB, Schmaljohn CS (2013). "Endothelial Cell Permeability During Hantavirus Infection Involves Factor XII-dependent Increased Activation of the Kallikrein-Kinin System". PLoS Pathog. 9 (7): e1003470. doi:10.1371/journal.ppat.1003470. PMID 23874198.
- ↑ Pepini T, Gorbunova EE, Gavrilovskaya IN, Mackow JE, Mackow ER (2010). "Andes Virus Regulation of Cellular microRNAs Contributes to Hantavirus-Induced Endothelial Cell Permeability". J Virol. 84 (22): 11929–36. doi:10.1128/JVI.01658-10. PMID 20844033.
- ↑ Connolly-Andersen AM, Sundberg E, Ahlm C, Hultdin J, Baudin M, Larsson J, Dunne E, Kenny D, Lindahl TL, Ramström S (2015). "Increased Thrombopoiesis and Platelet Activation in Hantavirus-Infected Patients". J Infect Dis. 212 (7): 1061–9. doi:10.1093/infdis/jiv161. PMID 25762786.
- ↑ 15.0 15.1 15.2 15.3 15.4 Saavedra F, Díaz FE, Retamal-Díaz A, Bueno SM, Kalergis AM, Riedel CA (2021). "Immune Response During Hantavirus Diseases: Implications for Immunotherapies and Vaccine Design". Immunology. 163 (3): 262–277. doi:10.1111/imm.13322.
- ↑ Maleki KT, Niemetz L, Christ W, Gille C, Hober S, Klingström J (2025). "IL-6 Trans-Signaling Mediates Cytokine Secretion and Barrier Dysfunction in Hantavirus-Infected Cells and Correlates to Severity in HFRS". PLoS Pathog. 21 (4): e1013042. doi:10.1371/journal.ppat.1013042. PMID 40203030 Check
|pmid=value (help). - ↑ Mori M, Rothman AL, Kurane I, Montoya JM, Nolte KB, Norman JE, Waite DC, Koster FT, Ennis FA (1999). "High levels of cytokine-producing cells in the lung tissues of patients with fatal hantavirus pulmonary syndrome". J Infect Dis. 179 (2): 295–302. doi:10.1086/314597. PMID 9878011.
- ↑ Kilpatrick ED, Terajima M, Koster FT, Catalina MD, Cruz J, Ennis FA (2004). "Role of Specific CD8+ T Cells in the Severity of a Fulminant Zoonotic Viral Hemorrhagic Fever, Hantavirus Pulmonary Syndrome". J Immunol. 172 (5): 3297–304. doi:10.4049/jimmunol.172.5.3297. PMID 14978138.
- ↑ Strandin T, Mäkelä S, Mustonen J, Vaheri A (2018). "Neutrophil Activation in Acute Hemorrhagic Fever With Renal Syndrome Is Mediated by Hantavirus-Infected Microvascular Endothelial Cells". Front Immunol. 9: 2098. doi:10.3389/fimmu.2018.02098. PMID 30283445.
- ↑ Matthys VS, Cimica V, Dalrymple NA, "; Mackow ER (2014). "Hantavirus GnT Elements Mediate TRAF3 Binding and Inhibit RIG-I/TBK1-directed Beta Interferon Transcription by Blocking IRF3 Phosphorylation". J Virol. 88 (4): 2246–59. doi:10.1128/JVI.02647-13. PMID 24390324. Vancouver style error: punctuation (help)
- ↑ Levine JR, Prescott J, Brown KS, Best SM, Ebihara H, Feldmann H (2010). "Antagonism of Type I Interferon Responses by New World Hantaviruses". J Virol. 84 (22): 11790–801. doi:10.1128/JVI.00916-10. PMID 20844031.
- ↑ Gallo G, Caignard G, Badonnel K, Cheber S, Bouloy M, Panthier JJ, Passuni F, Bhella D, Schwemmle M, Bhatt P (2021). "Interactions of Viral Proteins From Pathogenic and Low or Non-Pathogenic Orthohantaviruses With Human Type I Interferon Signaling". Viruses. 13 (1): 140. doi:10.3390/v13010140. PMID 33478127 Check
|pmid=value (help). - ↑ Wang K, Ma H, Liu H, Ye W, Li Z, Cheng L, Zhang L, Lei Y, Shen L, Zhang F (2019). "The Glycoprotein and Nucleocapsid Protein of Hantaviruses Manipulate Autophagy Flux to Restrain Host Innate Immune Responses". Cell Rep. 27 (7): 2075–2091.e5. doi:10.1016/j.celrep.2019.04.061. PMID 31091447.
- ↑ Spiropoulou CF, Srikiatkhachorn A (2013). "The role of endothelial activation in dengue hemorrhagic fever and hantavirus pulmonary syndrome". Virulence. 4 (6): 525–36. doi:10.4161/viru.25569. PMC 5359750. PMID 23841977.
- ↑ Schmedes CM, Grover SP, Hisada YM, Goeijenbier M, Cosper PF, "; Mackman N, Ahlm C (2020). "Circulating Extracellular Vesicle Tissue Factor Activity During Orthohantavirus Infection Is Associated With Intravascular Coagulation". J Infect Dis. 222 (8): 1392–1399. doi:10.1093/infdis/jiz597. PMID 31722433. Vancouver style error: punctuation (help)
- ↑ Sundberg E, Hultdin J, Nilsson S, Ahlm C (2011). "Evidence of Disseminated Intravascular Coagulation in a Hemorrhagic Fever With Renal Syndrome-Scoring Models and Severe Illness". PLoS One. 6 (6): e21134. doi:10.1371/journal.pone.0021134. PMID 21731657.
- ↑ Chen WJ, Du H, Hu HF, Li J, Bai L, Wang PZ (2024). "Levels of peripheral Blood routine, Biochemical and Coagulation Parameters in Patients With Hemorrhagic Fever With Renal Syndrome and Their Relationship With Prognosis: An Observational Cohort Study". BMC Infect Dis. 24 (1): 75. doi:10.1186/s12879-023-08777-w. PMID 38212688 Check
|pmid=value (help). - ↑ {{cite journal |vauthors=Sane J, Laine O, Mäkelä S, Paakkala A, Jarva H, Mustonen J, Vapalahti O, Meri S, Vaheri A |title=Complement Activation in Puumala Hantavirus Infection Correlates With Disease Severity |journal=Ann Med |volume=44 |issue=5 |pages=468-75