Kinin Dysregulation in Hantavirus Cardiopulmonary Syndrome and Possible Treatment Targets

Frank L. van de Veerdonk; Job J. Engel; Roger J. Brüggemann; Loek P. Smits; Chantal P. Rovers; Mihai G. Netea; Quirijn de Mast

doi:10.20944/preprints202605.2073.v1

Submitted:

28 May 2026

Posted:

29 May 2026

You are already at the latest version

Abstract

Hantavirus cardiopulmonary syndrome (HCPS) is characterized by endothelial dysfunction and sudden vascular collapse, with a stereotyped biphasic course: a prodromal febrile phase with thrombocytopenia, followed in severe cases by explosive non-cardiogenic pulmonary oedema, shock and death (case-fatality 30–45% for HCPS causing species). We propose that HCPS is fundamentally a disease of kinin dysregulation, in which an endothelial IL-18/IFN-γ autoinflammatory loop predisposes to uncontrolled contact-system activation and bradykinin-driven capillary leak.Pathogenic hantaviruses can inhibit endothelial cell death pathways, maintaining long-lived endothelial “viral factories” that continue to trigger type I interferon and non-canonical caspase-4 activation. This pathway could drive selective IL-18 release (without IL-1β surge), which in concert with IL-12 licenses an NK/CD8 IFN-γ response. IFN-γ signals back on the endothelium in a self-sustaining loop that has no intrinsic off-switch because the virus maintains endothelial persistence without triggering cell death pathways. This loop's primary effect is not acute lethality but dysregulation of the kinin system resulting in chronic IFN-γ signalling that remodels the kinin-receptor repertoire in the inflammatory environment, with upregulation of the inducible B1 receptor (BKB1R) that can act as a synergistic receptor for B2 receptor (BKB2R). The clinical fingerprint is rising ferritin with disproportionately low CRP.Around day 7–10, antibody-mediated changes in viral-endothelial-platelet interactions may unmask a procoagulant endothelial surface, triggering FXII autoactivation and a bradykinin burst. On an endothelium already dysregulated by chronic IFN-γ, the newly induced BKB1R amplifies the BKB2R-mediated permeability response, precipitating explosive capillary leak. These inflammatory events inevitably produce TNF/IL-1/IL-6, that will happen in any antimicrobial response that normally aid immune recruitment and tissue repair. However, when standing IFN-γ remains elevated and compensatory mechanisms (IL-1Ra, IL-10) fail to contain these innate signals, TNF/IL-1/IL-6 potentiate endothelial dysfunction and risk amplification toward systemic shock. Critically, icatibant (a selective B2R antagonist) is sufficient to arrest progression, a clinical observation that unifies hantavirus pathogenesis with the bradykinin-dysregulation framework previously established for severe COVID-19.This model identifies kinin-system antagonism (icatibant) as the rational primary intervention, with short-acting JAK inhibition as supportive but balanced modulators of the inflammatory dysregulation driver. Here, the balance is critical, while JAK/IFN-γ blockade reduces the dysregulation substrate, excessive suppression of type I/II IFN impairs antiviral immunity and risks enabling viral persistence. The predictions are testable with existing assays and drugs, the time to test them is now.

Keywords:

hantavirus

;

ANDV

;

Andes

;

Bradykinin

;

platelets

;

endothial cell

;

cytokines

;

ferritin

;

IL‐18

;

BKB2R

;

icatibant

;

JAKinh

;

IFNg

;

caspase‐4

;

HCPS

Subject:

Biology and Life Sciences - Immunology and Microbiology

Introduction

Hantaviruses are rodent-borne RNA viruses causing two syndromes: haemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus cardiopulmonary syndrome (HCPS) in the Americas [1]. Both share a central feature, non-cytopathic infection of microvascular endothelial cells coupled with increased vascular permeability, but not through cell lysis [2,3]. Instead, permeability arises from functional disruption of the endothelial barrier rather than cell death, placing hantaviruses within the non-cytopathic, endothelial-tropic hemorrhagic fevers, alongside dengue and arenaviruses such as Lassa, in contrast to the directly cytopathic filoviruses (Ebola, Marburg) [4,5,6].

The clinical course of HCPS is strikingly biphasic. After 1–6 weeks incubation, symptomatic disease begins with a 2–7-day febrile prodrome of fever, myalgias, abdominal pain and headache, but notably sparse in respiratory symptoms [1]. A subset of patients then deteriorates within hours into non-cardiogenic pulmonary edema, respiratory failure and refractory shock, with most deaths occurring in the first 24 hours of admission [1,7]. Survivors can recover quickly once supported through the cardiopulmonary phase, suggesting that the underlying endothelial dysfunction is reversible [8,9].

The laboratory signature is distinctive and mechanistically informative: early and progressive thrombocytopenia, a platelet count <40,000/µL predicts mortality, relative leukocytosis with lymphopenia, immunoblastosis, hemoconcentration, and markedly elevated D-dimers without overt thromboembolism [1,10]. Critically, IL-6 and CRP remain modest while IL-18, IFN-γ and IFN-γ-induced chemokines (CXCL9, CXCL10) are conspicuously elevated, a signature of IL-18/IFN-γ-driven pathology rather than classical cytokine storm or HLH/MAS [7].

No specific antiviral or immunomodulatory therapy is licensed for HCPS. Randomized trials of ribavirin and, high-dose corticosteroids were negative, and supportive care usually avoids aggressive fluid resuscitation because of the vascular leakage [11,12,13]. Yet two individual cases of severe Puumala HFRS were given icatibant, a selective B2-receptor bradykinin antagonist, with stabilization of disease progression and recovery, a hint that has been overlooked [14,15]. Although the kallikrein-kinin system (KKS) has been sporadically investigated in select viral infections, including one early study in dengue hemorrhagic fever in 1975 [16] and a few reports on viral hepatitis, Influenza, and viral hemorrhagic fevers (VHF) through the 1990s, mostly reported in Russian language literature [16,17,18,19], systematic exploration of KKS dysregulation as a driver of viral pathogenesis has been limited. While Joseph and Kaplan established the theoretical foundation for understanding bradykinin-forming pathways in innate inflammation [20,21,22], their work focused primarily on hereditary angioedema (HAE) and chronic inflammatory conditions, leaving acute viral pathogenesis largely unexplored through a KKS lens. A significant but notable exception was a 2013 study demonstrating that hantavirus directly activates the plasma kallikrein-kinin system to induce endothelial hyperpermeability [23], yet this mechanistic insight did not catalyze broader investigation into KKS dysfunction across the spectrum of hemorrhagic viral infections.

Among early investigations of dysregulated bradykinin signaling in severe COVID-19, our mechanistic hypothesis [24] contributed to broader attention to the KKS as a pathophysiological axis in viral disease. The hypothesis proposed that ACE2 downregulation impairs bradykinin inactivation, thereby driving unopposed B1/B2 receptor activation and vascular leak [24]. This hypothesis has been independently substantiated by different mechanistic studies documenting elevated plasma and tissue kallikrein activity, accumulation of kinin peptides, and mast cell-mediated endothelial dysfunction [25,26,27,28,29,30,31,32]. Moreover, clinical proof-of-concept has emerged from one randomized trials and one exploratory studies demonstrating beneficial clinical outcomes of bradykinin B2 receptor antagonism (icatibant) in COVID-19, while one randomized trial did not show efficacy [33,34,35,36]. Plasma kallikrein inhibition (with lanadelumab) demonstrated no effect in mild COVID-19 [37]. Lanadelumab was also enrolled in the COMMUNITY platform trial (NCT04590586), an ambitious multi-sponsor, adaptive design study launched in late 2020 through the COVID R&D Alliance involving Amgen, UCB, and other major pharmaceutical companies across global sites. Despite this enormous coordinated effort, peer-reviewed efficacy outcomes for the lanadelumab arm have not yet been published. After promising data from a pilot study, a subsequent larger trial with C1 esterase inhibitor replacement demontrated no effect in severe COVID-19 pneumonia [38,39]. Several mechanistic reviews further support KKS involvement in viral infection [40,41,42].

Recognizing that both hantavirus cardiopulmonary syndrome and severe COVID-19 manifest as non-cytopathic, endothelial-tropic diseases with dysregulated vascular permeability as a final common pathway [30], we propose that the detailed mechanistic KKS framework that is now established in COVID-19 provides a robust template for systematically reinvestigating kallikrein-kinin system dysfunction in hantavirus disease. The 2013 hantavirus KKS observation, viewed through the lens of modern mechanistic understanding and clinical therapeutic validation from COVID-19, warrants comprehensive translational investigation in this parallel viral setting.

Hantavirus Disease as Kinin Dysregulation, a Testable Mechanistic Framework

Non-Lytic Infection Sustains a Productively Infected Endothelium

Hantaviruses replicate to high titres in endothelial cells without inducing cell death [2,43] (Figure 1). Hantaviruses, including Andes virus, actively blocks endothelial cell death pathways through caspase-3 inhibition and BCL2 upregulation [44,45]. The consequence is a long-lived, productively infected endothelial cell that continuously exposes viral RNA and other pathogen-associated molecular patterns (PAMPs) to its cytosol while remaining morphologically intact. This enforced survival is the pivot-point of the disease, it removes the natural off-switch that would terminate inflammation in normal infections, enabling instead a self-sustaining deregulatory loop.

Type I Interferon, GBPs and Caspase-4 Drive Selective IL-18 Release

Cytosolic viral RNA engages RIG-I and cGAS–STING sensors, triggering type I interferon (IFN-α/β) production [46,47]. Type I IFN upregulates guanylate-binding proteins (GBPs), which activate caspase-4 (the non-canonical inflammasome caspase) [48]. Caspase-4 can cleave gasdermin D (GSDMD) and IL-18, generating sublytic pores that permit selective release of mature IL-18 [49,50,51], and the apoptotic and necroptotic executioners that have been suppressed by viral anti-death proteins keep this process ongoing. The result is high IL-18 release without the IL-1β/IL-6 surge of classical inflammasome activation, precisely the laboratory pattern observed in hantavirus infection (Figure 1).

Platelet Recruitment and a Platelet-Adherent Endothelial Layer

Infected endothelial cells recruit circulating platelets to their luminal surface [52]. Hantavirus has also been shown to attach to b3-integrins on platelets and therefore might lead and drive an interaction between virus, platelets and endothelium that will lead to an aggregate layering the pulmonary endothelium [52] (Figure 1). Adherent platelets become activated, and degranulate, releasing inorganic polyphosphate (polyP), zinc and phosphatidylserine-bearing microparticles [53] (Figure 1). This adhesive interaction could contribute to the progressive prodromal thrombocytopenia that is one of the earliest and most reliable laboratory findings associated with HCPS, often preceding overt vascular leak by days [8,52,54].

A central hypothesis is that, in this prodromal configuration, a "platelet carpet", may partially shield the endothelial membrane from contact-system activation (Figure 1). While polyP is inherently procoagulant, the endothelial surface might remain covered and relatively inaccessible to FXII to trigger fulminant activation in the prodromal stage. This is the key reason why FXII activation and bradykinin generation are restrained during the prodrome, even as the circulating platelet count falls. The virus attached to the platelets in the aggregate and the infected endothelium are thus protected by a dynamic equilibrium. Platelets are continuously recruited and consumed, resulting in the falling platelet count, but the supply is sufficient to maintain endothelial surface coverage. The platelets serve a dual purpose, they deposit the raw material (polyP, zinc, PS) that will later fuel contact-system activation, but for now they shield it from access. This is a remarkable example of viral exploitation of host hemostasis, as the virus maintains a "Trojan carpet" of platelets that simultaneously sustains infection by preventing the immune counterattack that exposition of the infected endothelial cells would trigger (Figure 1).

The IL-18/IFN-γ Loop Is Self-Amplifying and Dysregulates the Kinin System

Mature IL-18, synergizing with IL-12, drives NK cells and Th1 effector cells to produce IFN-γ [55]. IFN-γ then signals back on the surviving endothelium through JAK1/JAK2 and STAT1, upregulating interferon-stimulated genes including GBPs, caspase-4, and chemokines (CXCL9, CXCL10, CXCL11) [49,56,57,58,59]. This recruits more CD8-T cells and NK cells, perpetuating the loop, IFN-γ → caspase-4 → IL-18 → more IFN-γ [49,60,61]. Because the infected endothelial cell does not enter a cell death program [44], this loop escalates as a self-sustaining autoinflammatory state, even despite IL-18BP (which is the natural inhibitor of IL-18 [62]). Critically, prolonged high-level IFN-γ signaling does more than sustain inflammation, it dysregulates the kinin system. IFN-γ upregulates the inducible BKB1R on endothelial cells [63]. The endothelium is thus remodeled toward kinin sensitivity, over days 1–7, IFN-γ signaling creates a surface primed for increased bradykinin signaling due to upregulation of BKB1R that works synergistically with BKB2R, should the contact system ever be activated [64,65].

Day 7-10, Contact-System Activation and the Bradykinin Burst

Around day 7–10, neutralizing IgG antibodies appear and the virus is significantly neutralized halting virus-induced pathological host dysregulation [1,66]. In vitro data has shwn that platelet adherence to infected endothelial cells is β3-integrins dependent and can be neutralized by ANDV-specific neutralizing antibodies [52]. We hypothesize that these neutralizing antibodies reduces the protective coating on platelets that shields the endothelial surface exposing an anionic endothelial surface. These dynamics result in a biphasic platelet behavior characterized by inhibition of adhesion with progressive thrombocytopenia and subsequent restoration of platelet-endothelial interactions with circulating platelet counts stabalizing and eventually rising again. This exposed surface may be decorated with residual polyphosphate (polyP), zinc and phosphatidylserine from activated and possible now dying endothelial cells. This is an ideal scaffold for FXII autoactivation, polyP aligns and stabilizes FXII, and zinc bridges histidine residues to the negatively charged surface and FXII then autoactivates (with zinc as cofactor, the dominant source are platelets) into FXIIa, cleaving prekallikrein to generate plasma kallikrein, which reciprocally amplifies FXII activation and cleaves high-molecular-weight kininogen to release bradykinin [22,67,68]. Bradykinin encounters endothelial B2 receptors that are constitutive, and can initiate an acute permeability response, and the newly induced B1 receptors, which are inducible, pro-inflammatory, and amplify the permeability response [22,69]. The consequence is explosive non-cardiogenic pulmonary oedema, the signature of HCPS.

The same day 7-10 events that unmasks the contact surface might also deliver a more significant TNF/IL-1/IL-6 signal, from virus-specific T cells, from recruited monocytes/macrophages, or from lytic death of infected endothelium. This combination of TNF/IL-1/IL-6, when not kept in control by natural counterregulatory mechanisms, might synergizes with the standing high IFN-γ a combination of cytokines known to induce cytokine-driven shock [70]. Once initiated, the bradykinin burst is self-amplifying through TMEM16F-dependent phosphatidylserine externalization on the endothelial surface [71,72], creating more FXII-binding sites [73]. Without intervention, the cascade does not self-terminate until the supply of prekallikrein and HMWK is exhausted or the patient dies. With intervention, such as icatibant to block B2R, the loop is broken, and because most endothelial cells are not lytically destroyed, recovery can be remarkably rapid (Figure 3).

Parallel to COVID-19 Bradykinin Dysregulation and Other Coronavirus Infections

The bradykinin-dysregulation framework advanced here for hantavirus closely parallels the hypothesis developed for severe COVID-19 [24]. In both diseases: (1) an endothelial-interacting virus triggers inflammatory responses that dysregulates the kinin system (2) contact-system activation is a downstream consequence, not the primary driver (3) the result is bradykinin-mediated permeability and vascular collapse in the context of inflammation (4) icatibant (B2R antagonist) alone might halt progression, a clinical observation from both severe COVID-19 and the Puumala HFRS cases [14,15,33,35]. This convergence suggests that kinin dysregulation may be a shared pathophysiological motif across endothelial-interacting infections, including coronavirus and virus that causes viral hemorrhagic fevers [4,5,6].

In COVID-19, dysregulation runs partly through direct dysregulation of ACE2 because it is the receptor for SARS-CoV2, permitting produced des-Arg bradykinin, which acts on B1R to accumulate. In hantavirus, the mechanism appears to be more direct, IFN-γ primes the B1R itself, while the virus non-lytically sustains endothelial infection. The endpoint is identical: bradykinin-amplified permeability on a dysregulated endothelium, treatable with B2R antagonism. Strikingly to note, is that entry receptors for coronaviruses are angiotensin converting enzyme 2 (ACE2; SARS and SARS-CoV2), dipeptidyl peptidase 4 (DPP4; MERS), and APN (CD13, several alpha coronaviruses, including HCoV-229E, canine coronavirus, and porcine coronaviruses (TGEV and PEDV)) all serve as enzymes involved in regulating kinin profiles and concentrations [74]. Although coronavirus acting on these receptors have been separately linked to RAS and KKS, the overall connection to the kinin system, since they are all peptidases that regulate kinin levels is striking. Widely used medication including ACE inhibitors, NEP inhibitors [hypertension] and DPP4 inhibitors (diabetes) should also be taken into account when patients have severe coronavirus infection or Hantavirus infection, especially due to their capacity to modulate bradykinin levels. These data together suggest that kinin antagonism is a rational primary intervention to explore across this family of diseases when the final common pathway would be a bradykinin storm at the site of infection that is amendable by B2R blocking. Finally, in COVID-19 kallidin (bradykinin produced from the tissue via tissue kallikreins) probably plays a major role. In hantavirus there might also be a contribution from tissue kallikrein-kallidin for the lung (or the kidney in HFRS), although this is not clear now and needs further investigation.

Biomarkers of Dysregulation and Collapse

The biphasic model predicts a distinct biomarker hierarchy.

Days 1–7 (prodromal phase and dysregulation phase). Ferritin rises and tracks the IL-18/IFN-γ loop, regardless of clinical disease severity. IL-18 and CXCL9/CXCL10 are elevated. CRP and IL-6 remain disproportionately low (in Supplement Table 4 of [7]. Thrombocytopenia progresses as platelets adhere to infected endothelium. This phase is present in all symptomatic patients; mild or severe [7] (Figure 1).

Days 7–10 (transition and collapse). Platelet count trajectory accalerating downward is halted and might even rise already as the protective aggregate (the 'Trojan carpet') is consumed and cleared, with progressively increasing exposure of the affected endothelial layer to the contact system. D-dimers rise markedly, reflecting fibrin generation from contact-system activation in the subendothelial space and its subsequent turnover by kallikrein-driven fibrinolysis. Functional C1-inhibitor activity begins to decline as the contact cascade engages. Free bradykinin rises and acts on B2R, more potently due to additional B1R expression that has been build up in the inflammatory phase. IL-1/TNF/IL-6 will emerge as a secondary response, and has to be kept in control by host anti-inflammatory responses such as IL-1Ra and IL-10. This is the window of vulnerability to catastrophic progression (Figure 2). These predictions are testable with existing assays. Clinical trajectory, cytokine dynamics, D-dimer kinetics, combined with platelet trajectory, should prospectively identify patients at imminent risk of collapse, enabling early intervention with icatibant.

Mechanism-Matched Therapeutic Targets

B2R Antagonism (Icatibant)

Icatibant, a selective B2-receptor antagonist (with a very short half life 1-2h), demonstrated efficacy in hereditary angioedema (HAE) and received FDA approval for this indication [75], Based on this rationale, icatibant was evaluated in two exploratory COVID-19 trials, where it was administered as a 30 mg subcutaneous injection, with doses repeated at 6-or 8-hour intervals [33,35,36]. Its efficacy in two cases of severe Puumala HFRS demonstrates proof-of-concept, blocking B2R may be sufficient to interrupt the bradykinin-driven cascade in severe hantavirus infection and arrest progression [14,15]. The short half-life allows rapid titration and discontinuation once the patient stabilizes, minimizing prolonged immunosuppression. Alternative oral B2R antagonists in development (deucrictibant) might reach therapeutic exposure faster and have a longer half-life, potentially enabling deployment in remote endemic regions with limited ICU infrastructure [76].

Contact-System Upstream Inhibition

If icatibant is insufficient, or as an adjunct, contact-system inhibitors may be appropriate. C1-esterase inhibitor (C1-INH, plasma-derived or recombinant) simultaneously inhibits FXIIa and kallikrein and has a long clinical track record in hereditary angio-oedema [77]. Specific FXIIa inhibitors are in development [78]. Ecallantide (kallikrein inhibitor) is another licensed option [79]. These agents work upstream of bradykinin generation and may be more comprehensive in blocking the cascade, though they have longer half-lives.

JAK Inhibition and IFN-γ Modulation

Short-acting JAK inhibitors (JAKinh; baricitinib, ruxolitinib) can be layered in as supportive therapy, targeting the dysregulation driver. However, the balance is critical. First, the endothelium is not lytically destroyed. Normal barrier function returns within days once the bradykinin burst is interrupted and viral driven host pathology wanes. “Over suppression” of IFN-γ, and with JAKinh also type I IFN, is unnecessary and risks impairing the adaptive immune response needed to counteract viral replication and clear the infection. Second, hantaviruses persist in vivo longer than once appreciated, with viral RNA detectable in blood for weeks after clinical resolution. Prolonged or intense IFN-γ/type I IFN blockade could enable viral persistence and late relapse, a risk particularly acute in a patient already immunocompromised by ECMO and ICU stay.

Therefore, IFN-γ/JAK modulation is best deployed selectively. JAK inhibition or anti-IFN-γ titrated against ferritin trajectory in high-amplitude loops, discontinued once the patient stabilizes or the ferritin begins to fall. The therapeutic portfolio should be serial and biomarker-guided, not prolonged or prophylactic, and needs further investigation.

Brief TNF/IL-1/IL-6 Blockade for the Second Hit Leading to Shock

Short-acting recombinant IL-1 receptor antagonist (anakinra), TNF-neutralizing agents, or anti-IL-6 (tocilizumab) may blunt the potential TNF/IL-1/IL-6 second hit if given at the right time. A very short half-live would make them ideal for an acute, biomarker-triggered strategy (rising CRP). The primary mechanism of systemic collapse and shock is the combination of high IFN-γ that synergizes with IL-1/TNF/IL-6 and the bradykinin-driven vascular leakage, not TNF/IL-1/IL-6 per se, these blocking agents are supportive, not primary.

Why short-acting drugs are essential

The pharmacology must match the biology. Hantavirus infection in recovering patients is reversible, viral replication is self-limited, and then suppressed by adaptive immunity, and prolonged immunosuppression risks opportunistic infection in a patient emerging from ICU. A panel of biomarker-titrated, short-acting interventions, (eg icatibant, anakinra, short-acting JAK inhibition), allows for rapid escalation on deterioration and rapid de-escalation once stabilization begins. Long-half-life immunosuppression therefore must be considered carefully. However, this has to be explored in a well designed clinical trial.

Conclusions: Kinin Dysregulation as a Unifying Framework

Hantavirus cardiopulmonary syndrome is not a cytokine storm in the conventional sense. We proposse that it is a disease of kinin dysregulation, in which a non-lytic, endothelial-tropic virus sustains a self-amplifying IL-18/IFN-γ loop that dysregulates the bradykinin system, priming the endothelium for explosive bradykinin-mediated capillary leak. The clinical observation that icatibant (a selective BKB2R antagonist) might stop a progressing cascade in the severe early stage of HCPS (two case reports published), coupled with the parallel clinical experiences of icatibant in COVID-19 and the described distinctive clincial picture in Hantavirus, cytokine profile and laboratory phenotype (high CXCL9, CXCL10, reltaively low IL-6, and elevated D-dimer), supports the IFN-axis and kinin system as the central pathogenic pathway.

Figure 3 synthesizes these observations into a dual-pathway mechanistic model, illustrating how the same endothelial infection simultaneously drives a self-amplifying IL-18/IFN-γ loop (left) and a contact-system-bradykinin cascade (Bradykinin storm, right), with each arm feeding back on the other to produce the distinctive HCPS phenotype.

This model rationalizes the failure of broad anti-inflammatory, antiviral, and volume-resuscitation strategies. It also identifies mechanism-matched, short-acting, biomarker-guided interventions, and icatibant as the primary bradykinin-blocking layer, short-acting JAK/IFN-γ modulation to reduce dysregulation amplitude, and minimal, reversible immunosuppression tailored to the patient's trajectory. The model unifies hantavirus pathogenesis with the bradykinin hypothesis of severe COVID-19 and opens a framework applicable across endothelial-tropic viral hemorrhagic fevers. The predictions are testable, the biomarkers are measurable with existing assays, the drugs are licensed or in trials, and the time to test them, in a disease that has no current specific therapy and carries a 30–45% case-fatality rate, is now.

Abbreviations

ACE	Angiotensin-Converting Enzyme
BCL2	B-cell lymphoma 2 (anti-apoptotic protein)
BK	Bradykinin
BKB1R	Bradykinin B1 receptor
BKB2R	Bradykinin B2 receptor
CK1	Cytokeratin 1
CXCL9/10	C-X-C Motif Chemokine Ligand 9 and 10
DAMPs	Damage-Associated Molecular Patterns
EC	Endothelial Cell
FXII / FXIIa	Coagulation Factor XII / activated Factor XII
gC1qR	Globular C1q Receptor
GBP	Guanylate-Binding Proteins
GSDMD	Gasdermin D
HCPS	Hantavirus Cardiopulmonary Syndrome
HK	High Molecular Weight Kininogen
IFN / IFN-γ	Interferon / Interferon-gamma
IL-12 / IL-18	Interleukin-12 / Interleukin-18
ISG	Interferon-Stimulated Genes
JAK	Janus Kinase
JAKinh	JAK inhibitor (therapeutic agent)
KAL	Kallikrein
NK	Natural Killer cell
PAMPs	Pathogen-Associated Molecular Patterns
PK	Prekallikrein
polyP	Polyphosphate
PS	Phosphatidylserine
STAT1	Signal Transducer and Activator of Transcription 1
TMEM16F	Transmembrane protein 16F (phospholipid scramblase)
uPAR	Urokinase Plasminogen Activator Receptor
Zn²⁺	Zinc ions
Icatibant	Synthetic BKB2R antagonist (therapeutic agent)

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Figure 1. Early-phase HCPS pathophysiology: Non-lytic hantavirus infection, innate immune activation, and formation of the protective platelet aggregate "Trojan carpet". Andes virus (ANDV) infects pulmonary microvascular endothelial cells non-lytically, evading cell death through upregulation of anti-apoptotic BCL-2 and caspase-3 inhibition mediated by the viral nucleocapsid protein. Infected endothelial cells activate both Type I interferon (IFN-α/β) signaling, which (reflected by elevated IP10) and recruits innate immune cells, and a distinctive endothelial-driven caspase-4 dependent IL-18 response (reflected by elevated serum ferritin). IL-18, in concert with Type II interferon (IFN-γ) produced by activated NK and CD8+ T cells, amplifies a feed-forward immune response (reflected by CXCL9) and recruitment of additional lymphocytes. Despite vigorous cytotoxic immune activation, infected endothelial cells resist killing due to hantavirus-mediated cell detah signalling suppression. Platelets adhere to the infected endothelial surface and form a protective aggregate scaffold, the "Trojan carpet", composed of platelets, fibrin, and polyphosphate (PolyP) enriched with zinc ions (Zn²⁺) and upregulated bradykinin B1 receptor (BKB1R). This aggregate physically shields the underlying endothelial surface from Factor XII (FXII) and the contact system, preventing autoactivation of FXII. Endothelial caspase-4 activation is maintained, reflecting innate immune stress. This phase represents a precarious equilibrium where protective mechanisms temporarily contain vascular leakage despite massive immune activation.

Figure 2. Pathophysiology of HCPS during the transition-collapse phase (Days 7–10): Clearance of the protective platelet aggregate and contact system activation. During the prodromal phase, a protective aggregate of platelets, fibrin, and immune cells (the "Trojan carpet") accumulates on the surface of hantavirus-infected endothelial cells, preventing exposure to the contact system (Figure 1). By Days 7–10, as this aggregate is progressively cleared by immune surveillance, the underlying endothelial surface becomes exposed to Factor XII (FXII) and the contact system machinery. FXII activation initiates a cascade leading to bradykinin generation. Bradykinin acts through BKB2 receptors (BKB2R) on endothelial cells, combined with direct endothelial effects of hantavirus infection (RhoA activation, VE-cadherin internalization, and resistance to induction of cell death pathways), resulting in massive vascular leakage and non-cardiogenic pulmonary edema. Elevated D-dimer reflects ongoing coagulation and fibrinolysis. This contact system activation, occurring precisely when cellular immunity (NK cells, CD8+ T cells) and humoral immunity (Neutralizing Ab) is most vigorous, creating a self-perpetuating loop of inflammation and vascular dysfunction with no intrinsic resolution mechanism, as infected endothelial cells persist without undergoing apoptosis. PolyP, polyphosphate; Zn²⁺, zinc ions. Probably teh combination of neutralizing the virus-induced pathological conditions and the depletion of components from these zymogen systems leads to a halt of teh bradykinin storm and can therefore be self-limiting.

Figure 3. Dual immunopathological pathways in Hantavirus infection: Endothelial IL-18/IFN-γ signalling and the bradykinin storm. The figure illustrates two parallel, interconnected pathogenic cascades initiated upon Hantavirus infection of endothelial cells. Both pathways are characterised by the absence of direct cytopathic cell death, facilitated by viral caspase-3 inhibition and BCL2 upregulation. Left panel; Endothelial IL-18/IFNγ pathway (present in all symptomatic patients; amplitude reflected by serum ferritin). Accumulation of cytosolic viral PAMPs and DAMPs triggers type I IFN priming and GBP induction. Subsequent caspase-4 activation in the endothelium leads to IL-18 and GSDMD cleavage and sublytic pore formation, enabling non-lytic release of mature IL-18. IL-18, in concert with IL-12, drives IFN-γ production by NK cells and CD8⁺ T cells. IFN-γ signals via JAK/STAT1, inducing ISGs and chemokines including CXCL9/CXCL10, which results in an endotheliopathy. A STAT1-driven feed-forward loop is established whereby GBPs prime further caspase-4 activation, and BKB1R becomes upregulated on the endothelial surface. Therapeutic target: JAK inhibition (JAKinh). Right panel; Bradykinin storm (predominant in patients progressing to HCPS; reflected by elevated D-dimers). Platelet adhesion to infected endothelium leads to their consumption (thrombocytopenia) and release of polyP, Zn²⁺, and PS-exposing microparticles, rendering the EC surface anionic and zinc-rich. This environment promotes FXII binding to surface receptors gC1qR, uPAR, and CK1, triggering autoactivation to FXIIa. FXIIa cleaves PK to KAL, which in turn cleaves HK to release BK, normally degraded by ACE. Excess BK signals through BKB2R on the endothelium, causing Ca²⁺ influx, vasodilation, and increased permeability, and through BKB1R (upregulated via the left pathway), further amplifying the response. Additionally, BK activates TMEM16F, inducing PS flip on EC membranes, generating new FXII binding sites and closing a self-amplifying feedback loop. The net result is capillary leak and eventually shock. Therapeutic target: icatibant (BKB2R antagonist). Dashed arrows indicate cross-pathway feedback amplification loops.

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