Genetic characterization of the Patois Serogroup (Genus Orthobunyavirus; Family Peribunyaviridae) and evidence that Estero Real Virus is a member of the Genus Orthonairovirus

F31 AI124662/AI/NIAID NIH HHS/United States R24 AI120942/AI/NIAID NIH HHS/United StatesUniversity of Texas Medical Branch. Department of Pathology. Galveston, Texas, USA / Institute for Human Infection and Immunity. Galveston, Texas, USA / Center for Tropical Diseases. Galveston, Texas, USA.University of São Paulo. School of Medicine of Ribeirão Preto. Virology Research Center. Ribeirão Preto, SP, Brazil.University of Texas Medical Branch. Department of Pathology. Galveston, Texas, USA / Institute for Human Infection and Immunity. Galveston, Texas, USA / Center for Tropical Diseases. Galveston, Texas, USA.University of Texas Medical Branch. Department of Biochemistry and Molecular Biology. Galveston, Texas, USA.University of Texas Medical Branch. Department of Biochemistry and Molecular Biology. Galveston, Texas, USA.University of São Paulo. School of Medicine of Ribeirão Preto. Virology Research Center. Ribeirão Preto, SP, Brazil.Ministério da Saúde. Secretaria de Vigilância em Saúde. Instituto Evandro Chagas. Ananindeua, PA, Brasil.Estero Real virus (ERV) was isolated in 1980 from Ornithodoros tadaridae ticks collected in El Estero Real, Sancti Spiritus, Cuba. Antigenic characterization of the isolate based on serological methods found a relationship with Abras and Zegla viruses and, consequently, the virus was classified taxonomically within the Patois serogroup. Given the fact that genetic characterization of Patois serogroup viruses has not yet been reported and that ERV is the only virus within the Patois serogroup isolated from ticks, we recently conducted nearly complete genome sequencing in an attempt to gain further insight into the genetic relationship of ERV with other Patois serogroup viruses and members of Peribunyaviridae family (Bunyavirales order). With the exception of ERV, our sequencing and phylogenetic studies revealed the close relationship of the Patois serogroup viruses to each other, forming a clear divergent clade from other members of the Orthobunyavirus genus (Peribunyaviridae family). Notably, our analysis also revealed that ERV forms a monophyletic clade that is closely related to species of the Orthonairovirus genus (Nairoviridae family) in all the genome segments. In light of these findings, we believe that the taxonomic classification of ERV should be revised

Long-Term Arthralgia after Mayaro Virus Infection Correlates with Sustained Pro-inflammatory Cytokine Response

<div><p>Mayaro virus (MAYV), an alphavirus similar to chikungunya virus (CHIKV), causes an acute debilitating disease which results in the development of long-term arthralgia in more than 50% of infected individuals. Currently, the immune response and its role in the development of MAYV-induced persistent arthralgia remain unknown. In this study, we evaluated the immune response of individuals with confirmed MAYV infection in a one-year longitudinal study carried out in Loreto, Peru. We report that MAYV infection elicits robust immune responses that result in the development of a strong neutralizing antibody response and the secretion of pro-inflammatory immune mediators. The composition of these inflammatory mediators, in some cases, differed to those previously observed for CHIKV. Key mediators such as IL-13, IL-7 and VEGF were strongly induced following MAYV infection and were significantly increased in subjects that eventually developed persistent arthralgia. Although a strong neutralizing antibody response was observed in all subjects, it was not sufficient to prevent the long-term outcomes of MAYV infection. This study provides initial immunologic insight that may eventually contribute to prognostic tools and therapeutic treatments against this emerging pathogen.</p></div

Neutralizing antibody titers to alphaviruses and disease profile of study patients.

<p>Plaque reduction neutralization tests were carried-out in convalescent phase samples collected at follow up visit 20 (±10) days after Mayaro (MAYV) infection. EEEV = Eastern equine encephalitis virus; VEEV = Venezuelan equine encephalitis virus.</p><p>*Persistent arthralgia was defined as the presence of arthralgia for at least three months after the acute presentation.</p><p>Neutralizing antibody titers to alphaviruses and disease profile of study patients.</p

Induction of cytokine/chemokine immune mediators in MAYV-infected subjects with or without persistent arthralgia.

<p>Serum samples were collected at the acute visit as well as the convalescent visit (20±10 days), at 90±10 days, at 180±15 days, and at 360±30 days after the acute visit. The serum concentrations of a variety of cytokines were assessed by a cytokine bead array. The cytokine concentrations in subjects with (open circles) or without (closed circles) persistent arthralgia were compared to healthy donor controls by a 2-tailed Mann-Whitney test. An asterisk (*) indicates statistical significance (p<0.05) when compared to healthy controls. Comparisons between MAYV infected groups were also performed by a 2-tailed Mann-Whitney test. No statistical significance (p<0.05) between the MAYV infected groups was found. The horizontal dotted line represents the median cytokine values for the healthy donor controls. Each circle corresponds to the cytokine concentration of an individual subject and the solid horizontal line represents the mean cytokine concentration of the group.</p

Kinetic profile of cytokines and chemokines significantly affected following MAYV infection.

<p>Serum samples were collected at the acute visit as well as the convalescent visit (20±10 days), at 90±10 days, at 180±15 days, and at 360±30 days after the acute visit. The serum concentrations of a variety of cytokines were assessed by a multiplex cytokine bead array. Three kinetic profiles are presented based on the peak of cytokine expression: <b>Acute:</b> cytokines/chemokines that peak during the acute phase (upon enrollment); <b>Convalescent:</b> cytokines/chemokines that peak during the convalescent phase 20 (±10) days post enrollment and may remain elevated for few months after MAYV infection; and <b>Sustained:</b> cytokines/chemokines whose expression remain elevated up to 12 months following MAYV infection. The box plot denotes the median, 25^th percentile, and 75^th percentile cytokine levels. The whiskers denote the minimum and maximum cytokine levels observed at each time point. The horizontal dotted line represents the median cytokine values for the healthy donor controls. Data sets were evaluated by using Wilcoxon non-parametric tests to evaluate the evolution of cytokine levels at each time point post-infection (*p<0.05).</p

Kinetic profile of cytokines and chemokines similar to the concentrations detected in healthy donor controls following MAYV infection.

<p>Serum samples were collected at the acute visit as well as the convalescent visit (20±10 days), at 90±10 days, at 180±15 days, and at 360±30 days after the acute visit. The serum concentrations of a variety of cytokines were assessed by a multiplex cytokine bead array. The box plot denotes the median, 25^th percentile, and 75^th percentile cytokine levels. The whiskers denote the minimum and maximum cytokine levels observed at each time point. The horizontal dotted line represents the median cytokine values for the healthy donor controls. Comparisons between MAYV infected subjects and healthy donors were performed by a 2-tailed Mann-Whitney test (*p<0.05).</p

Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms.

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a grave threat to public health and the global economy. SARS-CoV-2 is closely related to the more lethal but less transmissible coronaviruses SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV). Here, we have carried out comparative viral-human protein-protein interaction and viral protein localization analyses for all three viruses. Subsequent functional genetic screening identified host factors that functionally impinge on coronavirus proliferation, including Tom70, a mitochondrial chaperone protein that interacts with both SARS-CoV-1 and SARS-CoV-2 ORF9b, an interaction we structurally characterized using cryo-electron microscopy. Combining genetically validated host factors with both COVID-19 patient genetic data and medical billing records identified molecular mechanisms and potential drug treatments that merit further molecular and clinical study

Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms

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