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%).

On November 2, 2018, a person-to-person transmission outbreak of Andes virus (Orthohantavirus andesense) began in the small town of Epuyén, Argentina. The strain demonstrated a high capacity for sustained transmission among the human population requiring the implementation of quarantine measures, rigorous contact tracing, isolation of close contacts, and active clinical monitoring to prevent further spread. In this study, we report the isolation of this strain, which we name the ARG-Epuyén strain, directly from a clinical sample after just three passages in cell culture. Complete sequencing revealed only a single amino acid change post-isolation, suggesting that this strain can be considered a non-adapted wild-type Andes virus, marking a critical step toward the development of medical countermeasures against this emerging pathogen. The pathogenicity and transmissibility potential of ARG-Epuyén were evaluated in hamsters, the only animal model for Hantavirus Pulmonary Syndrome. Additionally, this strain was compared with Andes/ARG, an ANDV strain previously isolated from the same geographical area in the Argentinian Patagonia, from a rodent specimen. Our findings revealed high infectiousness and efficient hamster-to-hamster transmission through direct contact experiments, although ARG-Epuyén appeared to be less pathogenic than Andes/ARG.

Hantavirus pulmonary syndrome (HPS) is an American emerging disease caused by the rodent-borne virus genus Orthohantavirus (Family: Hantaviridae: Order: Elliovirales Class: Bunyaviricetes). In Argentina, almost half of the HPS infections occur in the northwestern endemic region. In this study, we monitored rodent abundance during 2022 and 2023 in three sites with different sampling methods (removal trapping, live trapping and hunted rodents by domestic cats) to evaluate their relationship with human infections. We found a similar pattern of variation in rodent abundance across time, and particularly a synchronous rise of rodent abundance that anticipated an HPS outbreak in 2023. Our dynamic regression models revealed a positive relationship between HPS cases and rodent abundance with a three-month lag, as well as rainfall with an eight-month lag. Our results provide a framework for the planning and implementation of public health prevention campaigns based on climatology and rodent monitoring. Domestic cats bringing rodents into houses can be an overlooked risk factor, particularly if viral shedding of infected rodents is magnified by stress. HPS is a disease of public health concern due to its high mortality rate, the lack of a specific therapeutic treatment and no vaccine. Thus, prevention of infections is of the utmost importance.

In this work, we performed the genetic characterization of a new variant of orthohantavirus associated with a fatal case of hantavirus pulmonary syndrome, outside the known endemic region, in northwestern Argentina. We first confirmed an orthohantavirus infection by ELISA, testing for the detection of IgM and IgG antibodies. Then, we extracted RNA from 100 microliters of serum, the only sample available, followed by RT-PCR. The amplicons were sequenced using Sanger and next-generation sequencing technology. We obtained partial sequences of 1253 bp, 799 bp and 1675 bp from the S-, M- and L-segments, respectively, showing low sequence identities with all the previously characterized hantaviruses (10.9%, 13.5% and 15.1% of the divergence, respectively). The phylogenetic analysis showed that this virus belongs to the Orthohantavirus andesense species (ANDV), and among the ANDV-like variants, it is more closely related to the Lechiguanas clade. Similar percentages of divergence were considered sufficient to distinguish AND-like variants in previous works. As the patient had no travel history before the onset of disease was reported, we conducted rodent surveys to confirm the presence of reservoirs. The rodent assemblage was compatible with the transitional zone among different ecoregions (Yungas, Chaco and Monte). Moreover, one of the species captured, Oligoryzomys flavescens, was previously described as a reservoir of hantavirus. This species may either host several variants across its range or encompass a species complex, as proposed by some authors.

Summary: On November 2018, a person-to-person transmission outbreak of Andes virus (ANDV) began in the small town of Epuyen, Argentina. The strain involved demonstrated a high capacity for sustained transmission among the human population requiring the implementation of quarantine measures, rigorous contact tracing, isolation of close contacts, and active clinical monitoring to prevent further spread. In this study, we report the isolation of this strain, which we name the ARG-Epuyen after just three passages in cell culture. Complete sequencing revealed only a single amino acid change post-isolation, revealing that it is a non-adapted, wild-type ANDV strain, and its isolation probably represents a critical step toward the development of medical countermeasures against this emerging pathogen. The pathogenicity and transmissibility potential of ARG-Epuyen were evaluated in hamsters, the only animal model for Hantavirus Pulmonary Syndrome. Additionally, this strain was compared with ARG, an ANDV strain previously isolated from the same geographical area in the Argentinian Patagonia, from a rodent specimen. Our findings revealed high infectiousness and efficient hamster-to-hamster transmission through direct contact experiments, although ARG-Epuyen appeared to be less pathogenic than ARG.

The analysis of the pulmonary microenvironment in six fatal cases of hantavirus pulmonary syndrome (HPS) provides valuable insights into the complex immunological and pathological mechanisms underlying disease severity. HPS is characterized by rapid respiratory deterioration, and understanding local immune responses within lung tissue is essential for elucidating why some infections progress to fatal outcomes. This study highlights several key factors, including cytokine production, immune cell activity, and alterations in pulmonary structure and function. Our findings suggest that excessive production of proinflammatory cytokines, particularly IL-6, together with a robust but dysregulated Th1 immune response, insufficient Treg-mediated immune regulation, and impaired surfactant function, may contribute to disease progression. These observations not only improve our understanding of HPS pathogenesis but also identify potential therapeutic targets, including cytokine modulation and strategies aimed at preserving pulmonary integrity, which may improve clinical outcomes in future patients.