Treatment of Highly Pathogenic #H7N9 Virus-Infected Mice with #Baloxavir Marboxil (Viruses, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Viruses. 2019 Nov 15;11(11). pii: E1066. doi: 10.3390/v11111066.

Treatment of Highly Pathogenic H7N9 Virus-Infected Mice with Baloxavir Marboxil.

Kiso M1, Yamayoshi S1, Furusawa Y1, Imai M1, Kawaoka Y1,2,3.

Author information: 1 Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan. 2 Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA. 3 Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.

 

Abstract

Viral neuraminidase inhibitors show limited efficacy in mice infected with H7N9 influenza A viruses isolated from humans. Although baloxavir marboxil protected mice from lethal challenge infection with a low pathogenic avian influenza H7N9 virus isolated from a human, its efficacy in mice infected with a recent highly pathogenic version of H7N9 human isolates is unknown. Here, we examined the efficacy of baloxavir marboxil in mice infected with a highly pathogenic human H7N9 virus, A/Guangdong/17SF003/2016. Treatment of infected mice with a single 1.5 mg/kg dose of baloxavir marboxil protected mice from the highly pathogenic human H7N9 virus infection as effectively as oseltamivir treatment at 50 mg/kg twice a day for five days. Daily treatment for five days at 15 or 50 mg/kg of baloxavir marboxil showed superior therapeutic efficacy, largely preventing virus replication in respiratory organs. These results indicate that baloxavir marboxil is a valuable candidate treatment for human patients suffering from highly pathogenic H7N9 virus infection.

KEYWORDS: H7N9; baloxavir marboxil; highly pathogenic; influenza

PMID: 31731678 DOI: 10.3390/v11111066

Keywords: Antivirals; Avian Influenza; H7N9; Baloxavir Marboxil; Animal models.

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#Erythromycin Estolate Inhibits #Zika Virus #Infection by Blocking Viral Entry as a Viral Inactivator (Viruses, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Viruses. 2019 Nov 15;11(11). pii: E1064. doi: 10.3390/v11111064.

Erythromycin Estolate Inhibits Zika Virus Infection by Blocking Viral Entry as a Viral Inactivator.

Wang X1, Xia S1, Zou P1, Lu L1.

Author information: 1 Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Shanghai Medical College, Fudan University, Shanghai 200032, China.

 

Abstract

Recently, Zika virus (ZIKV) has attracted much attention in consideration of its association with severe neurological complications including fetal microcephaly. However, there are currently no prophylactic vaccines or therapeutic drugs approved for clinical treatments of ZIKV infection. To determine the potential anti-ZIKV inhibitors, we screened a library of clinical drugs with good safety profiles. Erythromycin estolate (Ery-Est), one of the macrolide antibiotics, was found to effectively inhibit ZIKV infection in different cell types and significantly protect A129 mice from ZIKV-associated neurological signs and mortality. Through further investigation, Ery-Est was verified to inhibit ZIKV entry by disrupting the integrity of the viral membrane which resulted in the loss of ZIKV infectivity. Furthermore, Ery-Est also showed inhibitory activity against dengue virus (DENV) and yellow fever virus (YFV). Thus, Ery-Est may be a promising drug for patients with ZIKV infection, particularly pregnant women.

KEYWORDS: ZIKV; erythromycin estolate; inactivator; viral entry inhibitor

PMID: 31731598 DOI: 10.3390/v11111064

Keywords: Zika Virus; Antibiotics; Macrolides; Erythromycin.

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#Hemagglutinin head-specific responses dominate over stem-specific responses following prime boost with mismatched #vaccines (JCI Insight, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

JCI Insight. 2019 Nov 14;4(22). pii: 129035. doi: 10.1172/jci.insight.129035.

Hemagglutinin head-specific responses dominate over stem-specific responses following prime boost with mismatched vaccines.

Jegaskanda S1,2, Andrews SF3, Wheatley AK2,3, Yewdell JW4, McDermott AB3, Subbarao K1.

Author information: 1 Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA. 2 Department of Microbiology and Immunology, University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia. 3 Vaccine Research Center and. 4 Laboratory of Viral Diseases, National Institute of Allergy and Infectious Disease, NIH, Bethesda, Maryland, USA.

 

Abstract

Broadly neutralizing Abs targeting the HA stem can provide broad protection against different influenza subtypes, raising the question of how best to elicit such Abs. We have previously demonstrated that vaccination with pandemic live-attenuated influenza vaccine (pLAIV) establishes immune memory for HA head-specific Abs. Here, we determine the extent to which matched versus mismatched LAIV-inactivated subunit vaccine (IIV) prime-boost vaccination elicits stem-specific memory B cells and Abs. We vaccinated African green monkeys with H5N1 pLAIV-pIIV or H5N1 pLAIV followed by seasonal IIV (sIIV) or with H5N1 pLAIV alone and measured Abs and HA-specific B cell responses. While we observed an increase in stem-specific memory B cells, head-specific memory B cell responses were substantially higher than stem-specific responses and were dominant even following boost with mismatched IIV. Neutralizing Abs against heterologous influenza viruses were undetectable. Head-specific B cells from draining lymph nodes exhibited germinal center markers, while stem-specific B cells found in the spleen and peripheral blood did not. Thus, although mismatched prime-boost generated a pool of stem-specific memory B cells, head-specific B cells and serum Abs substantially dominated the immune response. These findings have implications for including full-length native HA in prime-boost strategies intended to induce stem-specific Abs for universal influenza vaccination.

KEYWORDS: Infectious disease; Influenza; Vaccines

PMID: 31723058 DOI: 10.1172/jci.insight.129035

Keywords: Influenza A; H5N1; Vaccines.

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#Subclinical in #utero #Zika virus #infection is associated with #interferon alpha #sequelae and sex-specific molecular #brain #pathology in asymptomatic porcine offspring (PLoS Pathog., abstract)

[Source: PLoS Pathogens, full page: (LINK). Abstract, edited.]

OPEN ACCESS /  PEER-REVIEWED / RESEARCH ARTICLE

Subclinical in utero Zika virus infection is associated with interferon alpha sequelae and sex-specific molecular brain pathology in asymptomatic porcine offspring

Ivan Trus , Daniel Udenze, Brian Cox , Nathalie Berube, Rebecca E. Nordquist, Franz Josef van der Staay, Yanyun Huang, Gary Kobinger, David Safronetz, Volker Gerdts, Uladzimir Karniychuk

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Published: November 14, 2019 / DOI: https://doi.org/10.1371/journal.ppat.1008038

 

Abstract

Zika virus (ZIKV) infection during human pregnancy may lead to severe fetal pathology and debilitating impairments in offspring. However, the majority of infections are subclinical and not associated with evident birth defects. Potentially detrimental life-long health outcomes in asymptomatic offspring evoke high concerns. Thus, animal models addressing sequelae in offspring may provide valuable information. To induce subclinical infection, we inoculated selected porcine fetuses at the mid-stage of development. Inoculation resulted in trans-fetal virus spread and persistent infection in the placenta and fetal membranes for two months. Offspring did not show congenital Zika syndrome (e.g., microcephaly, brain calcifications, congenital clubfoot, arthrogryposis, seizures) or other visible birth defects. However, a month after birth, a portion of offspring exhibited excessive interferon alpha (IFN-α) levels in blood plasma in a regular environment. Most affected offspring also showed dramatic IFN-α shutdown during social stress providing the first evidence for the cumulative impact of prenatal ZIKV exposure and postnatal environmental insult. Other eleven cytokines tested before and after stress were not altered suggesting the specific IFN-α pathology. While brains from offspring did not have histopathology, lesions, and ZIKV, the whole genome expression analysis of the prefrontal cortex revealed profound sex-specific transcriptional changes that most probably was the result of subclinical in utero infection. RNA-seq analysis in the placenta persistently infected with ZIKV provided independent support for the sex-specific pattern of in utero-acquired transcriptional responses. Collectively, our results provide strong evidence that two hallmarks of fetal ZIKV infection, altered type I IFN response and molecular brain pathology can persist after birth in offspring in the absence of congenital Zika syndrome.

 

Author summary

A number of studies showed that Zika virus (ZIKV) can cause severe abnormalities in fetuses, e.g., brain lesions, and subsequently life-long developmental and cognitive impairment in children. However, the majority of infections in pregnant women are subclinical and are not associated with developmental abnormalities in fetuses and newborns. It is known that disruptions to the in utero environment during fetal development can program increased risks for disease in adulthood. For this reason, children affected in utero even by mild ZIKV infection can appear deceptively healthy at birth but develop immune dysfunction and brain abnormalities during postnatal development. Here, we used the porcine model of subclinical fetal ZIKV infection to determine health sequelae in offspring which did not show apparent signs of the disease. We demonstrated that subclinical fetal infection was associated with abnormal immunological responses in apparently healthy offspring under normal environmental conditions and during social stress. We also showed silent sex-specific brain pathology as represented by altered gene expression. Our study provides new insights into potential outcomes of subclinical in utero ZIKV infection. It also emphasizes that further attempts to better understand silent pathology and develop alleviative interventions in ZIKV-affected offspring should take into account interactions of host factors, like sex, and environmental insults, like social stress.

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Citation: Trus I, Udenze D, Cox B, Berube N, Nordquist RE, van der Staay FJ, et al. (2019) Subclinical in utero Zika virus infection is associated with interferon alpha sequelae and sex-specific molecular brain pathology in asymptomatic porcine offspring. PLoS Pathog 15(11): e1008038. https://doi.org/10.1371/journal.ppat.1008038

Editor: Ted C. Pierson, NIH, UNITED STATES

Received: May 8, 2019; Accepted: August 21, 2019; Published: November 14, 2019

Copyright: © 2019 Trus et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript and its Supporting Information files.

Funding: Financial support was provided by Genome Canada, Emerging Issue Program grant #418402, the Public Health Agency of Canada and the Government of Saskatchewan through Innovation Saskatchewan #418836. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. https://www.genomecanada.ca/ https://innovationsask.ca/research/saskatchewan-advantage-innovation-fund

Competing interests: The authors have declared that no competing interests exist.

Keywords: Zika Virus; Pregnancy; Zika Congenital Infection; Zika Congenital Syndrome; Animal models.

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Blocking #transmission of Middle East respiratory syndrome #coronavirus (#MERS-CoV) in #llamas by #vaccination with a recombinant spike protein (Emerg Microbes Infect., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Emerg Microbes Infect. 2019;8(1):1593-1603. doi: 10.1080/22221751.2019.1685912.

Blocking transmission of Middle East respiratory syndrome coronavirus (MERS-CoV) in llamas by vaccination with a recombinant spike protein.

Rodon J1, Okba NMA2, Te N1, van Dieren B3, Bosch BJ3, Bensaid A1, Segalés J4,5, Haagmans BL2, Vergara-Alert J1.

Author information: 1 IRTA, Centre de Recerca en Sanitat Animal (CReSA, IRTA-UAB), Bellaterra (Cerdanyola del Vallès), Spain. 2 Department of Viroscience, Erasmus Medical Centre, Rotterdam, The Netherlands. 3 Virology Division, Department of Infectious Diseases & Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands. 4 UAB, Centre de Recerca en Sanitat Animal (CReSA, IRTA-UAB), Bellaterra (Cerdanyola del Vallès), Spain. 5 Departament de Sanitat i Anatomia Animals, Facultat de Veterinària, UAB, Bellaterra (Cerdanyola del Vallès), Spain.

 

Abstract

The ongoing Middle East respiratory syndrome coronavirus (MERS-CoV) outbreaks pose a worldwide public health threat. Blocking MERS-CoV zoonotic transmission from dromedary camels, the animal reservoir, could potentially reduce the number of primary human cases. Here we report MERS-CoV transmission from experimentally infected llamas to naïve animals. Directly inoculated llamas shed virus for at least 6 days and could infect all in-contact naïve animals 4-5 days after exposure. With the aim to block virus transmission, we examined the efficacy of a recombinant spike S1-protein vaccine. In contrast to naïve animals, in-contact vaccinated llamas did not shed infectious virus upon exposure to directly inoculated llamas, consistent with the induction of strong virus neutralizing antibody responses. Our data provide further evidence that vaccination of the reservoir host may impede MERS-CoV zoonotic transmission to humans.

KEYWORDS: Animal model; MERS-CoV; Middle East respiratory syndrome coronavirus; S1-protein-based vaccine; llama; virus transmission

PMID: 31711379 DOI: 10.1080/22221751.2019.1685912

Keywords: MERS-CoV; Vaccines; Animal models.

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Activity of Aerosolized #Levofloxacin Against #Burkholderia cepacia in a Mouse Chronic #Lung #Infection Model (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Activity of Aerosolized Levofloxacin Against Burkholderia cepacia in a Mouse Chronic Lung Infection Model

Mojgan Sabet, David C. Griffith

DOI: 10.1128/AAC.01988-19

 

ABSTRACT

Burkholderia cepacia complex is an opportunistic pathogen capable of causing chronic pulmonary infections. These studies were conducted to demonstrate the activity of aerosolized levofloxacin in a chronic mouse lung infection model caused by B. cepacia isolates from cystic fibrosis patients. Treatment with aerosolized levofloxacin for four days produced at least one log CFU of bacterial killing against all strains tested and suggests possible utility in the treatment of lung infections caused by B. cepacia.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Burkholderia cepacia; Levofloxacin; Animal models.

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Efficacy of #bacteriophages in a S. aureus non-diabetic or #diabetic #foot #infection murine model (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Efficacy of bacteriophages in a S. aureus non-diabetic or diabetic foot infection murine model

S. Albac, M. Medina, D. Labrousse, D. Hayez, D. Bonnot, N. Anzala, F. Laurent, T. Ferry, A. Dublanchet, P. Chavanet, C. Fevre, D. Croisier

DOI: 10.1128/AAC.01870-19

 

ABSTRACT

This study investigated the in vivo efficiency of three combined bacteriophages compared to linezolid, in two mouse models (non-diabetic or diabetic) of S. aureus foot infection. In both models, a single injection of bacteriophages showed a significant antibacterial efficacy in the hindpaw. Linezolid was as effective as bacteriophages in non-diabetic animals but ineffective in diabetic animals. These findings support further preclinical and clinical studies for the development of phage therapy.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Staphylococcus aureus; Diabetes; Bacteriophages.

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