Biology subjects

Palacios, G. F.

Publications and source records attributed to Palacios, G. F..

4 recordsLinked to original sources

bioRxiv2025

Monkeypox Virus Clade IIb Isolate Exhibits Reduced Virulence Relative to Clade IIa Isolates in Multiple Murine Models

Monkeypox virus (MPXV) is the causative agent of mpox disease in humans. The virus is comprised of two clades, Central African clade I and West African clade II with case fatality rates of [~]11 and [~]4%, respectively. Since the discovery of mpox disease in 1970, the virus has been restricted to Africa. However, in 2022, a previously unrecognized subclade IIb caused the largest global outbreak of mpox disease with a case fatality rate of [~]0.2%. The difference in virulence of MPXV subclades in human infection warrants further investigation, however, one critical limitation is the lack of susceptible small animal models. In this study, we investigated the susceptibility of four murine models, including CAST-EiJ and three immunocompromised models (C57BL/6 Ifnar-/-, C57BL/6 Ifngr-/-, and C57BL/6 Ifnar-/-/Ifngr-/-) to MPXV clade IIa (WR 7-61 and US-2003) and IIb (MA-2022) isolates. All four mouse models were susceptible to clade IIa infection, leading to severe disease marked by decreased body temperature, weight loss, and lethality. In contrast, clade IIb infection produced minimal to mild disease at similar doses in all four murine models. The clade IIb isolate produced severe disease (40% lethality) at only the highest dose (8.0 log10 PFU) in the most susceptible immunocompromised mouse model, C57BL/6 Ifnar-/-/Ifngr-/-. This is the first demonstration of lethal disease with clade IIb in a murine model. In addition, these data demonstrate that clade IIa is [~]100- to 100,000-fold more virulent than clade IIb and provide three additional murine models for investigating MPXV infection and pathogenesis. IMPORTANCEMpox is an emerging human disease caused by four distinct MPXV subclades (Ia, Ib, IIa, and IIb). Despite genetic similarities, the case fatality rate varies considerably between the subclades: Ia ([~]11%), Ib and IIa ([~]4%), and IIb ([~]0.2%). Since 2022, multiple mpox outbreaks have occurred due to previously unrecognized subclades, leading to the declaration of two public health emergencies by the World Health Organization. This unprecedented global spread, coupled with the variation in severity of human disease, underscores the importance of research into the pathogenesis of emerging MPXV subclades. However, a critical limitation is the lack of suitable small animal models. This study identifies three additional murine models susceptible to MPXV clade II infection and demonstrates significant virulence differences between clade IIa and IIb. These models will enable rapid characterization of previously unrecognized subclades and will facilitate countermeasure development.

microbiology↗

bioRxiv2025

ISG15 Differentially Modulates Clade Ib and II MPXV Infection in MEF cells

The unprecedented human-to-human transmission of Clade IIb monkeypox virus (MPXV) during the 2022 outbreak has renewed focus on host determinants of viral fitness. Interferon-stimulated gene 15 (ISG15) encodes a ubiquitin-like protein with broad immunomodulatory functions, yet its role in MPXV infection remains unclear. Using representative strains from recent and historical outbreaks spanning Clades I and II, we show that ISG15 deficiency enhances viral replication and protein production in murine cells. Given that rodents are considered potential natural reservoirs of MPXV, these findings highlight the importance of studying murine models to understand virus-host interactions. Notably, the 2024 Democratic Republic of Congo strain displays reduced sensitivity to ISG15, suggesting clade-specific adaptation. ISG15 also influences viral immune evasion, as knockout cells infected with Clade II viruses expressed fewer immunomodulatory proteins and exhibited marked reductions in host protein phosphorylation. These results identify ISG15 as a determinant of MPXV infection and underscore evolutionary differences between clades.

microbiology↗

bioRxiv2024

Orthohantavirus Diversity in Central-East Argentina: Insights from Complete Genomic Sequencing on Phylogenetics, Geographic patterns and Transmission scenarios.

Hantavirus Pulmonary Syndrome (HPS), characterized by its high fatality rate, poses a significant public health concern in the Americas. Phylogenetic relationships of orthohantaviruses in the country were inferred from partial genomic sequences. The objectives of this work were to report new complete viral genomes of the known viral variants associated with HPS cases in Central-East region of Argentina, to assess viral diversity, phylogenetic relationships, and to elucidate the geographic patterns of distribution of each variant. To accomplish this, a detailed analysis was conducted of the geographic distribution of reported cases within the most impacted province of the region. The phylogenetic analysis defined clearly separated clades in the country according to their geographic origin. Andes virus (ANDV) segregated from the rest of the sequences, and those representative from the Central East region, Buenos Aires (BAV) and Lechiguanas virus (LECV), were grouped in the same cluster but segregated in two different branches. ImportanceIn Argentina, most of the HPS cases were associated with ANDV and closely related viruses distributed in four endemic regions. This work focused on obtaining and studying the complete genome of the orthohantaviruses present in the Central East (CE) region (BAV and LECV). Both viruses were responsible for major and minor outbreaks of person- to-person transmission in the country, and the findings may pave the way to study the impact of genetic determinants of viral transmission and to consider the reclassification of the species Orthohantavirus andesense.

genomics↗

bioRxiv2023

Andes virus genome mutations that are likely associated with animal-model attenuation and human person-to-person transmission

STRUCTURED ABSTRACTO_ST_ABSAbstractC_ST_ABSWe 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; 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. Mutations in the ANDV nucleocapsid protein, glycoprotein, and small nonstructural protein open reading frames correlated with mutations typical for ANDV strains associated with increased pathogenesis 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 person-to-person efficient transmission. Our results indicate that there are virulence-associated and transmission-associated single-nucleotide polymorphisms that could be used to predict strain-specific ANDV virulence and/or transmissibility. ImportanceSeveral 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.

microbiology↗