Filling the gaps in the Argentinian distribution of orthohantavirus: First finding of Lechiguanas virus in rodents from Corrientes, Argentina.

Hantavirus Pulmonary Syndrome (HPS) is an emerging infectious disease caused by orthohantaviruses in the Americas. In Argentina, since 1995, several reservoirs and virus variants have been described, but the northeastern and central endemic zones in the country include an area without human or rodent infections, despite sharing rodent species with areas with that disease. The aim of this study was to search for orthohantavirus in rodent communities that inhabit this area, which borders two endemic areas of HPS. Small rodents were captured in June of 2022 through a total effort of 644 trap nights distributed in five grids located in the Iberá National Park, Corrientes, Northeastern Argentina. All rodents were sexed, weighed, and the species was recorded. Blood samples were extracted to detect ANDV-specific immunoglobulin G (IgG), and to extract the RNA virus. Trimmed sequences were mapped against reference sequences from GenBank. We captured a total of 36 Oligoryzomys flavescens and 15 Oxymycterus rufus. We detected the O. flavescens species infected with Lechiguanas orthohantavirus in the camping area of the National Park. A nucleotide comparison with previously published sequences shows a 98.34% similarity to the virus obtained from a human case of HPS reported in the adjacent Misiones province. This study demonstrated, for the first time, that O. flavescens is a host of the Lechiguanas orthohantavirus in this zone and contributes to closing information gaps on the distribution of orthohantavirus in Argentina. Additionally, the high similarity with the hantavirus found in the human case of Misiones suggests that the reservoir in that province would also be O. flavescens (not previously confirmed). This information permits us to focus on the preventive measurements to protect the human population.

Orthohantavirus Infection in Two Rodent Species that Inhabit Wetlands in Argentina.

Previous research conducted in central-east region of Argentina recorded potential orthohantavirus host rodents in diverse environments, but no research has focused particularly on islands, the environments that present the greatest risk to humans. For this reason, the aims of this research were to determine the orthohantavirus host in the rodent community focused on islands of Paraná River Delta, central-east region of Argentina, to identify temporal and spatial factors associated with orthohantavirus prevalence variations, to compare the functional traits of seropositive and seronegative rodents, and to explore the association between orthohantavirus prevalence and rodent community characteristics between August 2014 and May 2018. With a trapping effort of 14,600 trap-nights, a total of 348 sigmodontine rodent specimens belonging to seven species were captured 361 times. The overall antibody prevalence was 4.9%. Particularly, 14.9% of Oligoryzomys flavescens and 1.5% of Oxymycterus rufus, mainly reproductively active adult males, had antibodies against orthohantavirus. Even though O. flavescens inhabit all islands, our results suggest spatial heterogeneity in the viral distribution, with two months after periods of low temperature presenting increases in seroprevalence. This could be a response to the increased proportion of adults present in the rodent population. In addition, an association was found between the high seroprevalence and the diversity of the rodent assemblage. We also found 1.5% of O. rufus exposed to orthohantavirus, which shows us that further investigation of the ecology of the virus is needed to answer whether this species act as a spillover or a new competent host.

Andes Virus Genome Mutations That Are Likely Associated with Animal Model Attenuation and Human Person-to-Person Transmission.

We performed whole-genome sequencing with bait enrichment techniques to analyze Andes virus (ANDV), a cause of human hantavirus pulmonary syndrome. We used cryopreserved lung tissues from a naturally infected long-tailed colilargo, including early, intermediate, and late cell culture, passages of an ANDV isolate from that animal, and lung tissues from golden hamsters experimentally exposed to that ANDV isolate. The resulting complete genome sequences were subjected to detailed comparative genomic analysis against American orthohantaviruses. We identified four amino acid substitutions related to cell culture adaptation that resulted in attenuation of ANDV in the typically lethal golden hamster animal model of hantavirus pulmonary syndrome. Changes in the ANDV nucleocapsid protein, glycoprotein, and small nonstructural protein open reading frames correlated with mutations typical for ANDV strains associated with increased virulence in the small-animal model. Finally, we identified three amino acid substitutions, two in the small nonstructural protein and one in the glycoprotein, that were only present in the clade of viruses associated with efficient person-to-person transmission. Our results indicate that there are single-nucleotide polymorphisms that could be used to predict strain-specific ANDV virulence and/or transmissibility. IMPORTANCE Several orthohantaviruses cause the zoonotic disease hantavirus pulmonary syndrome (HPS) in the Americas. Among them, HPS caused by Andes virus (ANDV) is of great public health concern because it is associated with the highest case fatality rate (up to 50%). ANDV is also the only orthohantavirus associated with relatively robust evidence of person-to-person transmission. This work reveals nucleotide changes in the ANDV genome that are associated with virulence attenuation in an animal model and increased transmissibility in humans. These findings may pave the way to early severity predictions in future ANDV-caused HPS outbreaks.

Expanded distribution of orthohantavirus Pergamino genotype: First record in Entre Rios province, Argentina / Ampliación de la distribución del Orthohantavirus genotipo Pergamino: Primer registro en la Provincia de Entre Ríos, Argentina

Abstract Hantavirus Pulmonary Syndrome (HPS) is an emerging infectious disease of the Americas. Eight native rodent species have been identified as HPS virus reservoirs in Argentina. The aim of this work was to detect the orthohantavirus genotypes present in a rodent commu-nity that inhabits a zone where a fatal HPS case occurred within an endemic locality of Central Argentina. We captured 27 rodents with a trapping effort of 723 trap nights. We detected 14.3% of infected Akodon azarae with the Pergamino genotype. This result expands the known distribution of this orthohantavirus. Although the Pergamino genotype has not been associated with human cases, the information about its distribution is relevant for risk assessment against potential changes in the virus infectivity.

Resumen El síndrome pulmonar por hantavirus (SPH) es una enfermedad infecciosa emergente en América. Ocho especies de roedores nativos han sido identificadas como reservorios del virus causante del SPH en la Argentina. El objetivo de este trabajo fue detectar los genotipos de orthohantavirus presentes en una comunidad de roedores que habita en una zona donde ocurrió un caso fatal de SPH, en una localidad endémica de Argentina central. Se capturaron 27 individuos con un esfuerzo de 723 trampas-noche. Se detectó un 14,3% de Akodon azarae infectados con el genotipo pergamino. Este resultado amplía el conocido rango de distribución de este orthohantavirus. A pesar de que el genotipo pergamino no ha sido asociado con casos humanos hasta el momento, la información sobre su distribución es relevante para analizar el riesgo ante un potencial cambio en la infectividad del virus.

Hantavirus Pulmonary Syndrome in a COVID-19 Patient, Argentina, 2020.

We describe a patient in Argentina with severe acute respiratory syndrome coronavirus 2 infection and hantavirus pulmonary syndrome (HPS). Although both coronavirus disease and HPS can be fatal when not diagnosed and treated promptly, HPS is much more lethal. This case report may contribute to improved detection of co-infections in HPS-endemic regions.

Delayed viral clearance despite high number of activated T cells during the acute phase in Argentinean patients with hantavirus pulmonary syndrome.

BACKGROUND: The hallmarks of HPS are increase of vascular permeability and endothelial dysfunction. Although an exacerbated immune response is thought to be implicated in pathogenesis, clear evidence is still elusive. As orthohantaviruses are not cytopathic CD8+ T cells are believed to be the central players involved in pathogenesis. METHODS: Serum and blood samples from Argentinean HPS patients were collected from 2014 to 2019. Routine white blood cell analyses, quantification and characterization of T-cell phenotypic profile, viral load, neutralizing antibody response and quantification of inflammatory mediators were performed. FINDINGS: High numbers of activated CD4+ and CD8+ T cells were found in all HPS cases independently of disease severity. We found increased levels of some proinflammatory mediators during the acute phase of illness. Nonetheless, viral RNA remained high, showing a delay in clearance from blood up to late convalescence, when titers of neutralizing antibodies reached a high level. INTERPRETATION: The high activated phenotypic profile of T cells seems to be unable to resolve infection during the acute and early convalescent phases, and it was not associated with the severity of the disease. Thus, at least part of the activated T cells could be induced by the dysregulated inflammatory response in an unspecific manner. Viral clearance seems to have been more related to high titers of neutralizing antibodies than to the T-cell response. FUNDING: This work was supported mainly by the Administración Nacional de Laboratorios e Institutos de Salud (ANLIS) "Dr. Carlos Malbrán". Further details of fundings sources is included in the appendix.

Expanded distribution of orthohantavirus Pergamino genotype: First record in Entre Rios province, Argentina.

Hantavirus Pulmonary Syndrome (HPS) is an emerging infectious disease of the Americas. Eight native rodent species have been identified as HPS virus reservoirs in Argentina. The aim of this work was to detect the orthohantavirus genotypes present in a rodent community that inhabits a zone where a fatal HPS case occurred within an endemic locality of Central Argentina. We captured 27 rodents with a trapping effort of 723 trap nights. We detected 14.3% of infected Akodon azarae with the Pergamino genotype. This result expands the known distribution of this orthohantavirus. Although the Pergamino genotype has not been associated with human cases, the information about its distribution is relevant for risk assessment against potential changes in the virus infectivity.

Emerging hantaviruses in Central Argentina: First case of Hantavirus Pulmonary Syndrome caused by Alto Paraguay virus, and a novel orthohantavirus in Scapteromys aquaticus rodent.

Orthohantaviruses are emerging rodent-borne pathogens that cause Hantavirus Pulmonary Syndrome in humans. They have a wide range of rodent reservoir hosts and are transmitted to humans through aerosolized viral particles generated by the excretions of infected individuals. Since the first description of HPS in Argentina, new hantaviruses have been reported throughout the country, most of which are pathogenic to humans. We present here the first HPS case infected with Alto Paraguay virus reported in Argentina. Until now, Alto Paraguay virus was considered a non-pathogenic orthohantavirus since it was identified in a rodent, Holochilus chacarius. In addition to this, with the goal of identifying potential hantavirus host species in the province of Santa Fe, we finally describe a novel orthohantavirus found in the native rodent Scapteromys aquaticus, which differed from other hantaviruses described in the country so far. Our findings implicate an epidemiological warning regarding these new orthohantaviruses circulating in Central Argentina as well as new rodent species that must be considered as hosts from now on.

"Super-Spreaders" and Person-to-Person Transmission of Andes Virus in Argentina.

BACKGROUND: From November 2018 through February 2019, person-to-person transmission of Andes virus (ANDV) hantavirus pulmonary syndrome occurred in Chubut Province, Argentina, and resulted in 34 confirmed infections and 11 deaths. Understanding the genomic, epidemiologic, and clinical characteristics of person-to-person transmission of ANDV is crucial to designing effective interventions. METHODS: Clinical and epidemiologic information was obtained by means of patient report and from public health centers. Serologic testing, contact-tracing, and next-generation sequencing were used to identify ANDV infection as the cause of this outbreak of hantavirus pulmonary syndrome and to reconstruct person-to-person transmission events. RESULTS: After a single introduction of ANDV from a rodent reservoir into the human population, transmission was driven by 3 symptomatic persons who attended crowded social events. After 18 cases were confirmed, public health officials enforced isolation of persons with confirmed cases and self-quarantine of possible contacts; these measures most likely curtailed further spread. The median reproductive number (the number of secondary cases caused by an infected person during the infectious period) was 2.12 before the control measures were enforced and decreased to 0.96 after the measures were implemented. Full genome sequencing of the ANDV strain involved in this outbreak was performed with specimens from 27 patients and showed that the strain that was present (Epuyén/18-19) was similar to the causative strain (Epilink/96) in the first known person-to-person transmission of hantavirus pulmonary syndrome caused by ANDV, which occurred in El Bolsón, Argentina, in 1996. Clinical investigations involving patients with ANDV hantavirus pulmonary syndrome in this outbreak revealed that patients with a high viral load and liver injury were more likely than other patients to spread infection. Disease severity, genomic diversity, age, and time spent in the hospital had no clear association with secondary transmission. CONCLUSIONS: Among patients with ANDV hantavirus pulmonary syndrome, high viral titers in combination with attendance at massive social gatherings or extensive contact among persons were associated with a higher likelihood of transmission. (Funded by the Ministerio de Salud y Desarrollo Social de la Nación Argentina and others.).

Hantavirus pulmonary syndrome outbreaks associated with climate variability in Northwestern Argentina, 1997-2017.

BACKGROUND: Rodent-borne hantaviruses (genus Orthohantavirus) are the etiologic agents causing two human diseases: hemorrhagic fever with renal syndrome (HFRS) in Euroasia; and hantavirus pulmonary syndrome (HPS) in North and South America. In South America fatality rates of HPS can reach up to 35%-50%. The transmission of pathogenic hantaviruses to humans occurs mainly via inhalation of aerosolized excreta from infected rodents. Thus, the epidemiology of HPS is necessarily linked to the ecology of their rodent hosts and the contact with a human, which in turn may be influenced by climatic variability. Here we examined the relationship between climatic variables and hantavirus transmission aim to develop an early warning system of potential hantavirus outbreaks based on ecologically relevant climatic factors. METHODOLOGY AND MAIN FINDINGS: We compiled reported HPS cases in northwestern Argentina during the 1997-2017 period and divided our data into biannual, quarterly, and bimestrial time periods to allow annual and shorter time delays to be observed. To evaluate the relationship of hantavirus transmission with mean temperature and precipitation we used dynamic regression analysis. We found a significant association between HPS incidence and lagged rainfall and temperature with a delay of 2 to 6 months. For the biannual and quarterly models, hantavirus transmission was positively associated with lagged rainfall and temperature; whereas the bimestrial models indicate a direct relationship with the rainfall but inverse for temperature in the second lagged period. CONCLUSIONS/SIGNIFICANCE: This work demonstrates that climate variability plays a significant role in the transmission of hantavirus in northwestern Argentina. The model developed in this study provides a basis for the forecast of potential HPS outbreaks based on climatic parameters. Our findings are valuable for the development of public health policies and prevention strategies to mitigate possible outbreaks. Nonetheless, a surveillance program on rodent population dynamics would lead to a more accurate forecast of HPS outbreaks.

Person-to-Person Transmission of Andes Virus in Hantavirus Pulmonary Syndrome, Argentina, 2014.

Andes virus is unique among hantaviruses because it can be transmitted from person to person. This mechanism was previously supported by epidemiologic data and genetic evidence based only on partial sequences. We used full-length virus sequencing to confirm person-to-person transmission of this virus in a cluster of 3 cases in Argentina in 2014.

New data about home range and movements of Oligoryzomys flavescens (Rodentia: Cricetidae) help to understand the spread and transmission of Andes virus that causes Hantavirus Pulmonary Syndrome.

Hantavirus pulmonary syndrome is an emerging infectious disease caused by viruses of the genus Orthohantavirus. The rodent Oligoryzomys flavescens is distributed along four countries of South America. In Argentina, O. flavescens acts as a reservoir of three genotypes of ANDV orthohantavirus. The aims of this work were to estimate home range size and movements-with spool-and-line and radiotelemetry-of infected and non-infected O. flavescens in order to understand the spread and transmission of the virus. O. flavescens use a wide area to satisfice its requirements, reaching a home range of 1.82 ha during spring. Orthohantavirus infection did not change the behaviour of individuals. We observed a great overlapping in the home range of infected and non-infected individuals resulting in a high probability of virus dispersion on rodent population. These results show that human health risks could be high on island environments and knowledge about the movement ecology of O. flavescens provides useful information on prevention.

Epidemiological description, case-fatality rate, and trends of Hantavirus Pulmonary Syndrome: 9 years of surveillance in Argentina.

Hantavirus pulmonary syndrome (HPS) is an endemic disease in Argentina, one of the most affected countries in the Americas. Andes virus (ANDV) is the main Orthohantavirus species causing HPS in Argentina. In this study, the geographical distribution, clinical presentation, and epidemiological features of HPS from all endemic regions of Argentina were analyzed. We focused on the clinical and epidemiological data from 533 HPS cases confirmed during the period 2009 to 2017 by the National Reference Laboratory for Hantavirus. A case-fatality rate of 21.4% was registered, and most of the cases presented a severe clinical picture requiring intensive care treatment (84%). Since HPS first detection in 1995 the case-fatality rate showed a general trend towards a decrease. After more than 22 years of experience in HPS diagnosis and surveillance, we discuss some possible factors implicated in this tendency. This clinical and epidemiological analysis gives a global perspective, being useful to detect trends and patterns, to update preventive actions at a national level, and evaluate their impact on public health.