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Project Title
Understanding host response to ANDV infection, immunological and transcriptomics approach
Partner Organisations
Internal ID
1161447
Principal Investigator
Status
TERMINADO
Start Date
2016
Investigators
Pablo Vial, Luis Leon

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Hemodynamic and Pulmonary Permeability Characterization of Hantavirus Cardiopulmonary Syndrome by Transpulmonary Thermodilution

2019 , LOPEZ HERNANDEZ, RENE RAMON , Rodrigo Pérez-Araos , Álvaro Salazar , Ana L. Ulloa , VIAL COX, MARIA CECILIA , VIAL CLARO, PABLO AGUSTIN , GRAF SANTOS, JERÓNIMO

Hantavirus cardiopulmonary syndrome (HCPS) is characterized by capillary leak, pulmonary edema (PE), and shock, which leads to death in up to 40% of patients. Treatment is supportive, including mechanical ventilation (MV) and extracorporeal membrane oxygenation (ECMO). Hemodynamic monitoring is critical to titrate therapy and to decide ECMO support. Transpulmonary thermodilution (TPTD) provides hemodynamic and PE data that have not been systematically used to understand HCPS pathophysiology. We identified 11 HCPS patients monitored with TPTD: eight on MV, three required ECMO. We analyzed 133 measurements to describe the hemodynamic pattern and its association with PE. The main findings were reduced stroke volume, global ejection fraction (GEF), and preload parameters associated with increased extravascular lung water and pulmonary vascular permeability compatible with hypovolemia, myocardial dysfunction, and increased permeability PE. Lung water correlated positively with heart rate (HR, r = 0.20) and negatively with mean arterial pressure (r = −0.27) and GEF (r = −0.36), suggesting that PE is linked to hemodynamic impairment. Pulmonary vascular permeability correlated positively with HR (r = 0.31) and negatively with cardiac index (r = −0.49), end-diastolic volume (r = −0.48), and GEF (r = −0.40), suggesting that capillary leak contributes to hypovolemia and systolic dysfunction. In conclusion, TPTD data suggest that in HCPS patients, increased permeability leads to PE, hypovolemia, and circulatory impairment.

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Assessing Pulmonary Epithelial Damage in Hantavirus Cardiopulmonary Syndrome: Challenging the Predominant Role of Vascular Endothelium through sRAGE as a Potential Biomarker

2023 , Gabriela Meza-Fuentes , LOPEZ HERNANDEZ, RENE RAMON , RETAMAL LUCERO, MAURICIO ANTONIO , CORTES SALINAS, LINA JIMENA , VIAL COX, MARIA CECILIA , DELGADO BECERRA, OROZIMBA IRIS , VIAL CLARO, PABLO AGUSTIN

Hantavirus cardiopulmonary syndrome (HCPS) is a severe respiratory illness primarily associated with microvascular endothelial changes, particularly in the lungs. However, the role of the pulmonary epithelium in HCPS pathogenesis remains unclear. This study explores the potential of soluble Receptors for Advanced Glycation End-products (sRAGE) as a biomarker for assessing pulmonary epithelial damage in severe HCPS, challenging the prevailing view that endothelial dysfunction is the sole driver of this syndrome. We conducted a cross-sectional study on critically ill HCPS patients, categorizing them into mild HCPS, severe HCPS, and negative control groups. Plasma sRAGE levels were measured, revealing significant differences between the severe HCPS group and controls. Our findings suggest that sRAGE holds promise as an indicator of pulmonary epithelial injury in HCPS and may aid in tracking disease progression and guiding therapeutic strategies. This study brings clarity on the importance of investigating the pulmonary epithelium’s role in HCPS pathogenesis, offering potential avenues for enhanced diagnostic precision and support in this critical public health concern.

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NPC1 as a Modulator of Disease Severity and Viral Entry of SARSCoV- 2

2021 , VIAL COX, MARIA CECILIA , CALDERON GIADROSIC, JUAN FRANCISCO , KLEIN POSTERNACK, ANDRES DAVID

The COVID-19 plague is hitting mankind. Several viruses, including SARS-CoV-1, MERS-CoV, EBOV, and SARS-CoV-2, use the endocytic machinery to enter the cell. Genomic variants in NPC1, which encodes for the endo-lysosomal Niemann-Pick type C1 protein, restricts the host-range of viruses in bats and susceptibility to infections in humans. Lack of NPC1 and its pharmacological suppression inhibits many viral infections including SARS-CoV-1 and Type I Feline Coronavirus Infection. Antiviral effects of NPC1-inhibiting drugs for COVID-19 treatment should be explored.

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Targeted high volume hemofiltration could avoid extracorporeal membrane oxygenation in some patients with severe Hantavirus cardiopulmonary syndrome

2021 , LOPEZ HERNANDEZ, RENE RAMON , Rodrigo Pérez‐Araos , Álvaro Salazar , Mauricio Espinoza , Analia Cuiza , VIAL COX, MARIA CECILIA , VIAL CLARO, PABLO AGUSTIN , GRAF SANTOS, JERÓNIMO

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Platelet Count in Patients with Mild Disease at Admission is Associated with Progression to Severe Hantavirus Cardiopulmonary Syndrome

2019 , LOPEZ HERNANDEZ, RENE RAMON , Mario Calvo , VIAL COX, MARIA CECILIA , Marcela Ferrés , GRAF SANTOS, JERÓNIMO , Gregory Mertz , Analía Cuiza , Begonia Agüero , Dante Aguilera , Diego Araya , Ignacia Pailamilla , Flavia Paratori , Víctor Torres-Torres , VIAL CLARO, PABLO AGUSTIN , DELGADO BECERRA, OROZIMBA IRIS

Background: Hantavirus cardiopulmonary syndrome (HCPS) has a mortality up to 35–40% and its treatment is mainly supportive. A variable to predict progression from mild to severe disease is unavailable. This study was performed in patients with documented infection by Andes orthohantavirus, and the aim was to find a simple variable to predict progression to moderate/severe HCPS in patients with mild disease at admission. Methods: We performed a retrospective analysis of 175 patients between 2001 and 2018. Patients were categorized into mild, moderate, and severe disease according to organ failure and advanced support need at hospital admission (e.g., mechanical ventilation, vasopressors). Progression to moderate/severe disease was defined accordingly. Clinical and laboratory variables associated with progression were explored. Results: Forty patients with mild disease were identified; 14 of them progressed to moderate/severe disease. Only platelet count was different between those who progressed versus those that did not (37 (34–58) vs. 83 (64–177) K/mm3, p < 0.001). A ROC curve analysis showed an AUC = 0.889 (0.78–1.0) p < 0.001, with a platelet count greater than 115K /mm3 ruling out progression to moderate/severe disease. Conclusions: In patients with mild disease at presentation, platelet count could help to define priority of evacuation to tertiary care centers.

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A 19 Year Analysis of Small Mammals Associated with Human Hantavirus Cases in Chile

2019 , VIAL COX, MARIA CECILIA

Small mammals present in areas where hantavirus cardiopulmonary syndrome (HCPS) cases had occurred in central and southern Chile were captured and analyzed to evaluate the abundance of rodents and seroprevalence rates of antibodies to Andes orthohantavirus (ANDV). Sampling areas ranged from the Coquimbo to Aysén regions (30–45° S approx.) regions. Ninety-two sites in peridomestic and countryside areas were evaluated in 19 years of sampling. An antibody against ANDV was detected by strip immunoassay in 58 of 1847 specimens captured using Sherman traps. Of the eleven species of rodents sampled, Abrothrix olivacea, Oligoryzomys longicaudatus and Abrothrix hirta were the most frequently trapped. O. longicaudatus had the highest seropositivity rate, and by logistic regression analysis, O. longicaudatus of at least 60 g had 80% or higher probability to be seropositive. Sex, age and wounds were significantly related to seropositivity only for O. longicaudatus. Across administrative regions, the highest seropositivity was found in the El Maule region (34.8–36.2° S), and the highest number of HCPS cases was registered in the Aysén region. Our results highlight the importance of long term and geographically extended studies, particularly for highly fluctuating pathogens and their reservoirs, to understand the implications of the dynamics and transmission of zoonotic diseases in human populations.

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Sociodemographic risk factors of hantavirus cardiopulmonary syndrome ^[Factores de riesgo socio-demográficos del síndrome]

2019 , VIAL COX, MARIA CECILIA , Francisca Valdivieso R. , Analía Cuiza V. , Iris Delgado B. , Grazielle Ribeiro E. , Elena Llop R. , Marcela Ferrés G. , REPETTO LISBOA, MARIA GABRIELA , Raúl Riquelme O. , M. Luisa Rioseco Z. , Mario Calvo A. , Gregory Mertz , VIAL CLARO, PABLO AGUSTIN

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Deletions in Genes Participating in Innate Immune Response Modify the Clinical Course of Andes Orthohantavirus Infection

2019 , Grazielle Esteves Ribeiro , Luis Edgardo Leon , Ruth Perez , Analia Cuiza , Pablo Agustin Vial , Marcela Ferres , Gregory J. Mertz , VIAL COX, MARIA CECILIA

Andes orthohantavirus (ANDV) is an important human pathogen causing hantavirus cardiopulmonary syndrome (HCPS) with a fatality rate of 30% in Chile. Around 60% of all cases have a severe clinical course, while the others have a mild clinical course. The main goal of this study was to understand if the genetic variation of patients is associated with the clinical course they develop after ANDV infection. For this, the frequency of copy number variants (CNVs, i.e., deletions and duplications) was studied in 195 patients, 88 with mild and 107 with severe HCPS. CNVs were called from intensity data of the Affymetrix Genome-Wide SNP Array 6.0. The analysis of the data was performed with PennCNV, ParseCNV and R softwares; Results: a deletion of 19, 416 bp in the q31.3 region of chromosome 1 is found more frequently in severe patients (p < 0.05). This region contains Complement Factor H Related (CFHR1) and CFHR3 genes, regulators of the complement cascade. A second deletion of 1.81 kb located in the p13 region of chr20 was significantly more frequent in mild patients (p < 0.05). This region contains the SIRPB1 gene, which participates in the innate immune response, more specifically in neutrophil trans-epithelial migration. Both deletions are associated with the clinical course of HCPS, the first being a risk factor and the second being protective. The participation of genes contained in both deletions in ANDV infection pathophysiology deserves further investigation.

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Mother-to-Child Transmission of Andes Virus through Breast Milk, Chile1

2020 , Marcela Ferrés , Constanza Martínez-Valdebenito , Jenniffer Angulo , Carolina Henríquez , Jorge Vera-Otárola , María José Vergara , Javier Pérez , Jorge Fernández , Viviana Sotomayor , María Francisca Valdés , Diego González-Candia , Nicole D. Tischler , VIAL COX, MARIA CECILIA , VIAL CLARO, PABLO AGUSTIN , Gregory Mertz , Nicole Le Corre

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Proteinuria in Hantavirus Cardiopulmonary Syndrome: A Frequent Finding Linked To Mortality

2021 , LOPEZ HERNANDEZ, RENE RAMON , Gregory Mertz , GRAF SANTOS, JERÓNIMO , Mauricio Espinoza , Marcela Ferrés , Mario Calvo , VIAL CLARO, PABLO AGUSTIN , VIAL COX, MARIA CECILIA

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