#Enterovirus D68–Associated Acute Flaccid #Myelitis – Rising to the #Clinical and #Research #Challenges (JAMA, summary)

[Source: JAMA, full page: (LINK). Summary, edited.]

February 15, 2019

Enterovirus D68–Associated Acute Flaccid MyelitisRising to the Clinical and Research Challenges

Kevin Messacar, MD1,2; Kenneth L. Tyler, MD3,4

Author Affiliations: 1 Hospital Medicine and Pediatric Infectious Disease Sections, Department of Pediatrics, University of Colorado, Aurora; 2 Children’s Hospital Colorado, Aurora; 3 Neuroinfectious Disease Section, Department of Neurology, University of Colorado, Aurora; 4 Departments of Medicine and Immunology-Microbiology, University of Colorado, Aurora

JAMA. Published online February 15, 2019. doi:10.1001/jama.2019.1016



In the summer of 2014, the emergence of an upsurge in cases of a poliomyelitis-like paralytic syndrome in the United States, designated acute flaccid myelitis (AFM), generated substantial concern among the medical community and the public. There were 120 confirmed AFM cases in 34 states in the summer and fall of 2014. In 2016, this increased to 149 cases in 39 states, and in 2018 there were at least 210 confirmed cases from 40 states (as of February 10, 2019).1 These numbers compare to a likely baseline incidence of 22 to 35 cases per year scattered throughout the intervening years of 2015 and 2017.1



Corresponding Author: Kenneth L. Tyler, MD, University of Colorado Denver Health Sciences Center, 12700 E 19th Ave, Aurora, CO 80045 (ken.tyler@ucdenver.edu).

Published Online: February 15, 2019. doi:10.1001/jama.2019.1016

Conflict of Interest Disclosures: Dr Messacar reported receiving grants from NIAID during the conduct of the study and is a member of the CDC Acute Flaccid Myelitis Task Force. Dr Tyler reported receiving grants from NINDS and from Taiga Biotechnologies during the conduct of the study; personal fees from DNAtrix, grants from the Department of Veterans Affairs, and grants from NIH outside the submitted work. Dr Tyler is also a member of the CDC Acute Flaccid Myelitis Task Force.

Funding/Support: The authors acknowledge support from NIH grants 1K23AI128069 (Dr Messacar) and 1R01NS101208 (Dr Tyler).

Role of the Funder/Sponsor: Funding agencies had no role in the preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: This Viewpoint is not intended to represent the views of the CDC or CDC Task Force.

Additional Contributions: We thank Mark J. Abzug, MD, and Samuel R. Dominguez, MD (Infectious Diseases Section, Department of Pediatrics, University of Colorado School of Medicine and Children’s Hospital Colorado), for their suggestions and critical review of the manuscript.

Keywords: Enterovirus; AFM; AFP; EV-D68.



Cyclical #adaptation of #measles virus #quasispecies to #epithelial and #lymphocytic cells: To V, or not to V (PLoS Pathog., abstract)

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


Cyclical adaptation of measles virus quasispecies to epithelial and lymphocytic cells: To V, or not to V

Ryan C. Donohue, Christian K. Pfaller, Roberto Cattaneo

Published: February 15, 2019 / DOI: https://doi.org/10.1371/journal.ppat.1007605 / This is an uncorrected proof.



Measles virus (MeV) is dual-tropic: it replicates first in lymphatic tissues and then in epithelial cells. This switch in tropism raises the question of whether, and how, intra-host evolution occurs. Towards addressing this question, we adapted MeV either to lymphocytic (Granta-519) or epithelial (H358) cells. We also passaged it consecutively in both human cell lines. Since passaged MeV had different replication kinetics, we sought to investigate the underlying genetic mechanisms of growth differences by performing deep-sequencing analyses. Lymphocytic adaptation reproducibly resulted in accumulation of variants mapping within an 11-nucleotide sequence located in the middle of the phosphoprotein (P) gene. This sequence mediates polymerase slippage and addition of a pseudo-templated guanosine to the P mRNA. This form of co-transcriptional RNA editing results in expression of an interferon antagonist, named V, in place of a polymerase co-factor, named P. We show that lymphocytic-adapted MeV indeed produce minimal amounts of edited transcripts and V protein. In contrast, parental and epithelial-adapted MeV produce similar levels of edited and non-edited transcripts, and of V and P proteins. Raji, another lymphocytic cell line, also positively selects V-deficient MeV genomes. On the other hand, in epithelial cells V-competent MeV genomes rapidly out-compete the V-deficient variants. To characterize the mechanisms of genome re-equilibration we rescued four recombinant MeV carrying individual editing site-proximal mutations. Three mutations interfered with RNA editing, resulting in almost exclusive P protein expression. The fourth preserved RNA editing and a standard P-to-V protein expression ratio. However, it altered a histidine involved in Zn2+ binding, inactivating V function. Thus, the lymphocytic environment favors replication of V-deficient MeV, while the epithelial environment has the opposite effect, resulting in rapid and thorough cyclical quasispecies re-equilibration. Analogous processes may occur in natural infections with other dual-tropic RNA viruses.


Author summary

Key questions in infectious disease are how pathogens adapt to different cells of their hosts, and how the interplay between the virus and host factors controls the outcome of infection. Human measles virus (MeV) and related animal morbilliviruses provide important models of pathogenesis because they are dual-tropic: they replicate first in immune cells for spread through the body, and then in epithelial cells for transmission. We sought here to define the underlying molecular and evolutionary processes that allow MeV to spread rapidly in either lymphocytic or epithelial cells. We discovered unexpectedly rapid and thorough genome adaptation to these two tissues. Genome variants that cannot express functional V protein, an innate immunity control protein, are rapidly selected in lymphocytic cells. These variants express only the P protein, a polymerase co-factor, instead of expressing P and V at similar levels. Upon passaging in epithelial cells, V-competent MeV genome variants rapidly re-gain dominance. These results suggest that cyclical quasispecies re-equilibration may occur in acute MeV infections of humans, and that suboptimal variants in one environment constitute a low frequency reservoir for adaptation to the other, where they become dominant.


Citation: Donohue RC, Pfaller CK, Cattaneo R (2019) Cyclical adaptation of measles virus quasispecies to epithelial and lymphocytic cells: To V, or not to V. PLoS Pathog 15(2): e1007605. https://doi.org/10.1371/journal.ppat.1007605

Editor: Diane E. Griffin, Johns Hopkins Bloomberg School of Public Health, UNITED STATES

Received: November 26, 2018; Accepted: January 29, 2019; Published: February 15, 2019

Copyright: © 2019 Donohue 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: RNAseq data, selected analyses, and reference sequences were deposited in the GEO database under accession number GSE126126.

Funding: RC received the award, 5R21AI128037-02, from National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID) https://projectreporter.nih.gov/project_info_description.cfm?aid=9406235&icde=39429219. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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

Keywords: Morbillivirus; Measles; Viral pathogenesis.


Prevalence of #Wēnzhōu virus in small #mammals in #Yunnan Province, #China (PLoS Negl Trop Dis., abstract)

[Source: PLoS Neglected Tropical Diseases, full page: (LINK). Abstract, edited.]


Prevalence of Wēnzhōu virus in small mammals in Yunnan Province, China

Jinxia Wang , Xinglou Yang , Haizhou Liu, Li Wang, Jihua Zhou, Xi Han, Yan Zhu, Weihong Yang, Hong Pan, Yunzhi Zhang , Zhengli Shi

Published: February 15, 2019 / DOI: https://doi.org/10.1371/journal.pntd.0007049 / This is an uncorrected proof.




Mammarenaviruses are associated with human hemorrhagic fever diseases in Africa and America. Recently, a rodent mammarenavirus, Wēnzhōu virus (WENV) and related viruses, have been reported in China, Cambodia, and Thailand. Moreover, in Cambodia, these viruses were suspected to be associated with human disease. In China, Yunnan Province is famous for its abundant animal and plant diversity and is adjacent to several South-eastern Asia countries. Therefore, it is necessary to know whether WENV-related viruses, or other mammarenaviruses, are prevalent in this province.

Methodology/Principal findings

Small mammals were trapped, euthanized, and sampled. Mammarenavirus RNA was detected using a nested reverse transcription polymerase chain reaction (RT-PCR) and quantified by real-time RT-PCR. A total of 1040 small mammals belonging to 13 genera and 26 species were trapped in Yunnan Province. WENV-related mammarenaviruses were detected in 41 rodent liver samples, mainly in brown rats (Rattus norvegicus) and oriental house rats (R. tanezumi).Viral nucleocapsid protein was detected in liver sections by indirect immunofluorescence assay. Full-length-genomes were amplified by RT-PCR and used for phylogenetic analysis with the MEGA package. Recombination analysis was performed using the SimPlot and Recombination Detection Program.


WENV related viruses circulated in small mammals in Yunnan Province. Whole genome sequence analysis of five selected viral strains showed that these viruses are closely related to WENVs discovered in Asia and form an independent branch in the phylogenetic tree in the WENV clade. Paying attention to investigate the influence of these viruses to public health is essential in the epidemic regions.


Author summary

Rodents are natural reservoirs of mammarenavirus. Lymphocytic choriomeningitis virus (LCMV), isolated in Asian countries during the 1990s, has a worldwide distribution and was the first mammarenavirus isolated. In 2014, a second mammarenavirus, Wēnzhōu virus (WENV), was identified in rodents in Zhejiang Province of China and later in Guangdong, Shandong, and Hainan Provinces. Most importantly, WENV or related viruses were reported in Thailand and Cambodia. In Cambodia, the isolated virus was associated with human respiratory diseases. In this study, we detected WENV or related viruses in Yunnan Province and found a high prevalence in rats of two species (Rattus norvegicus and R. tanezumi). Phylogenetic analysis of the complete L and S segments of five strains showed that these viruses form an independent phylogenetic branch in WENV clade most closely related to WENVs found in China and Cambodia. Considering the wide spread distribution of rats and altered distribution patterns due to ecological changes, we propose that these viruses may have a wider prevalence and be found in countries from South-eastern Asia to China. Given that WENV may be associated with human diseases, it is necessary to improve surveillances of these viruses in their natural reservoirs and in humans.


Citation: Wang J, Yang X, Liu H, Wang L, Zhou J, Han X, et al. (2019) Prevalence of Wēnzhōu virus in small mammals in Yunnan Province, China. PLoS Negl Trop Dis 13(2): e0007049. https://doi.org/10.1371/journal.pntd.0007049

Editor: Townsend Peterson, The University of Kansas, UNITED STATES

Received: April 29, 2018; Accepted: December 4, 2018; Published: February 15, 2019

Copyright: © 2019 Wang 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 paper and its Supporting Information files.

Funding: This work was jointly funded by the National Natural Science Foundation of China (81874274 and 81660558), a Scientific and Technological Basis Special Project grant (2013FY113500) from the Ministry of Science and Technology of PR China, Yunnan health training project of high level talents (L-2017027). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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

Keywords: Mammarenavirus; LCMV; Wenzhou virus; Human; Wildlife; Yunnan; China.


#Postmortem evidence of disseminated #Zika virus #infection in an #adult patient (Int J Infect Dis., abstract)

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

Int J Infect Dis. 2019 Feb 11. pii: S1201-9712(19)30060-8. doi: 10.1016/j.ijid.2019.01.047. [Epub ahead of print]

Postmortem evidence of disseminated Zika virus infection in an adult patient.

Rajahram GS1, Hale G2, Bhatnagar J2, Hiu J3, Thayan R4, William T5, Wong KT6, Tambyah PA7, Yeo TW8.

Author information: 1 Infectious Diseases Unit, Department of Medicine, Queen Elizabeth Hospital, Kota Kinabalu, Sabah, Malaysia; Clinical Research Centre, Queen Elizabeth Hospital, Kota Kinabalu, Sabah, Malaysia. 2 Infectious Diseases Pathology Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA. 3 Department of Forensic Medicine, Queen Elizabeth Hospital, Kota Kinabalu, Sabah, Malaysia. 4 Virology Unit, Infectious Disease Research Centre, Institute of Medical Research, Kuala Lumpur, Malaysia. 5 Jesselton Medical Centre, Kota Kinabalu, Sabah Malaysia. 6 Department of Pathology, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia. 7 Department of Medicine, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore. 8 Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; Institute of Infectious Disease and Epidemiology, Tan Tock Seng Hospital, Singapore.



Zika virus infections in immunocompetent adults typically are asymptomatic or cause mild symptoms, but have also been associated with neurological complications including Guillain-Barre Syndrome. Zika virusassociated non-neurological fatalities in adults are rare. Herein, we describe a decedent with multiple commodities who developed an acute febrile illness with rash days prior to death. A post-mortem evaluation detected molecular evidence of disseminated Zika virus. Further testing by Zika virus in-situ hybridization identified genomic and replicative Zika viral RNA in renal tubular epithelial cells, and cardiomyocytes, providing insights into organ-specific viral reservoirs.

Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.

KEYWORDS: Zika Virus Post-Mortem Myocarditis Renal Tubule In-situ hybridisation

PMID: 30763620 DOI: 10.1016/j.ijid.2019.01.047

Keywords: Zika Virus.


#Compressed #Influenza #Vaccination in #US Older Adults: A Decision Analysis (Am J Prev Med., abstract)

[Source: American Journal of Preventive Medicine, full page: (LINK). Abstract, edited.]

Compressed Influenza Vaccination in U.S. Older Adults: A Decision Analysis

Kenneth J. Smith, MD, MS, Glenson France, MA, Mary Patricia Nowalk, PhD, Jonathan M. Raviotta, MPH, Jay DePasse, BS, Angela Wateska, MPH, Eunha Shim, PhD, Richard K. Zimmerman, MD, MPH

DOI: https://doi.org/10.1016/j.amepre.2018.11.015

Published online: February 14, 2019




Tradeoffs exist between efforts to increase influenza vaccine uptake, including early season vaccination, and potential decreased vaccine effectiveness if protection wanes during influenza season. U.S. older adults increasingly receive vaccination before October. Influenza illness peaks vary from December to April.


A Markov model compared influenza likelihood in older adults with (1) status quo vaccination (August–May) to maximize vaccine uptake or (2) vaccination compressed to October–May (to decrease waning vaccine effectiveness impact). The Centers for Disease Control and Prevention data were used for influenza incidence and vaccination parameters. Prior analyses showed that absolute vaccine effectiveness decreased by 6%–11% per month, favoring later season vaccination. However, compressed vaccination could decrease overall vaccine uptake. Influenza incidence was based on average monthly incidence with earlier and later peaks also examined. Influenza strain distributions from two seasons were modeled in separate scenarios. Sensitivity analyses were performed to test result robustness. Data were collected and analyzed in 2018.


Compressed vaccination would avert ≥11,400 influenza cases in older adults during a typical season if it does not decrease vaccine uptake. However, if compressed vaccination decreases vaccine uptake or there is an early season influenza peak, more influenza can result. In probabilistic sensitivity analyses, compressed vaccination was never favored if it decreased absolute vaccine uptake by >5.5% in any scenario; when influenza peaked early, status quo vaccination was favored.


Compressed vaccination could decrease waning vaccine effectiveness and decrease influenza cases in older adults. However, this positive effect is negated when early season influenza peaks occur and diminished by decreased vaccine uptake that could occur with shortening the vaccination season.

© 2018 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.

Keywords: Seasonal Influenza; Vaccines; USA.


Principal #Controversies in #Vaccine #Safety in the #USA (Clin Infect Dis., abstract)

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

Clin Infect Dis. 2019 Feb 12. doi: 10.1093/cid/ciz135. [Epub ahead of print]

Principal Controversies in Vaccine Safety in the United States.

DeStefano F1, Bodenstab HM2, Offit PA3.

Author information: 1 Immunization Safety Office, Centers for Disease Control and Prevention, Atlanta, GA. 2 Department of Pharmacy Services, The Children’s Hospital of Philadelphia, Philadelphia, PA. 3 Division of Infectious Diseases, The Children’s Hospital of Philadelphia, Philadelphia, PA.



Concerns about vaccine safety can lead to decreased acceptance of vaccines and resurgence of vaccine-preventable diseases. We summarize the key evidence on some of the main current vaccine safety controversies in the United States, including: 1) MMR vaccine and autism; 2) thimerosal, a mercury-based vaccine preservative, and the risk of neurodevelopmental disorders; 3) vaccine-induced Guillain-Barré Syndrome (GBS); 4) vaccine-induced autoimmune diseases; 5) safety of HPV vaccine; 6) aluminum adjuvant-induced autoimmune diseases and other disorders; and 7) too many vaccines given early in life predisposing children to health and developmental problems. A possible small increased risk of GBS following influenza vaccination has been identified, but the magnitude of the increase is less than the risk of GBS following influenza infection. Otherwise, the biological and epidemiologic evidence does not support any of the reviewed vaccine safety concerns.

PMID:  30753348  DOI: 10.1093/cid/ciz135

Keywords: Society; Vaccines; USA.


In vitro characterization and in vivo effectiveness of #Ebola virus specific #equine #polyclonal F(ab’)2 (J Infect Dis., abstract)

[Source: Journal of Infectious Diseases, full page: (LINK). Abstract, edited.]

In vitro characterization and in vivo effectiveness of Ebola virus specific equine polyclonal F(ab’)2

Trina Racine, Mélanie Denizot, Delphine Pannetier, Ludovic Nguyen, Anaïs Pasquier, Hervé Raoul, Jean-François Saluzzo, Gary Kobinger, Francisco Veas, Cécile H Herbreteau

The Journal of Infectious Diseases, jiz068, https://doi.org/10.1093/infdis/jiz068

Published: 14 February 2019



There is no vaccine or approved therapy against lethal Ebola virus (EBOV). We investigated a proven technology platform to produce polyclonal IgG fragments, F(ab’)2, against EBOV. Horses immunized with virus-like-particles (VLPs) harboring surface glycoprotein trimers of EBOV-Zaire/Makona produced anti-Ebola IgG polyclonal antibodies with high neutralization activity. Highly-purified equine anti-Ebola F(ab’)2 showed strong cross-neutralization of two Zaire EBOV strains (Gabon 2001 and Makona) and in vivothree or five daily F(ab’)2 intraperitoneal injections provided 100% protection to BALB/c mice against lethal EBOV challenge. Rapid preparation of purified equine anti-Ebola F(ab’)2 offers a potentially efficient therapeutic approach against EBOV disease in humans.

Ebola, immunoglobulins, equine, F(ab’)2 fragments

Issue Section: Brief Report

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This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Keywords: Ebola; Ebola Makona; Immunoglobulins.