#Ribavirin and #Interferon #Therapy for Critically Ill Patients With #MERS: A Multicenter Observational Study (Clin Infect Dis., abstract)

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

Clin Infect Dis. 2019 Jun 25. pii: ciz544. doi: 10.1093/cid/ciz544. [Epub ahead of print]

Ribavirin and Interferon Therapy for Critically Ill Patients With Middle East Respiratory Syndrome: A Multicenter Observational Study.

Arabi YM1, Shalhoub S2,3, Mandourah Y4, Al-Hameed F5, Al-Omari A6, Al Qasim E1, Jose J1, Alraddadi B7,8, Almotairi A9, Al Khatib K10, Abdulmomen A11, Qushmaq I7, Sindi AA12, Mady A13,14, Solaiman O15, Al-Raddadi R16, Maghrabi K15, Ragab A17, Al Mekhlafi GA18, Balkhy HH19, Al Harthy A13, Kharaba A20, Gramish JA21, Al-Aithan AM22, Al-Dawood A1, Merson L23, Hayden FG23,24, Fowler R25.

Author information: 1 Intensive Care Department, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, King Abdulaziz Medical City, Riyadh, Saudi Arabia. 2 Department of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Canada. 3 King Fahad Armed Forces Hospital, Jeddah. 4 Military Medical Services, Ministry of Defense, Prince Sultan Military Medical City, Riyadh. 5 Department of Intensive Care, College of Medicine, King Saud bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, King Abdulaziz Medical City, Jeddah. 6 Department of Intensive Care, College of Medicine, Alfaisal University, Dr Sulaiman Al-Habib Group Hospitals, Riyadh. 7 Department of Medicine, King Faisal Specialist Hospital and Research Center, Jeddah. 8 Department of Medicine, University of Jeddah. 9 Department of Critical Care Medicine, King Fahad Medical City, Riyadh. 10 Intensive Care Department, Al-Noor Specialist Hospital, Makkah. 11 Department of Critical Care Medicine, King Saud University, Riyadh. 12 Department of Anesthesia and Critical Care, Faculty of Medicine, King Abdulaziz University, Jeddah. 13 Intensive Care Department, King Saud Medical City, Riyadh, Saudi Arabia. 14 Tanta University Hospitals, Egypt. 15 Intensive Care Department, King Faisal Specialist Hospital and Research Center, Riyadh. 16 Department of Community Medicine, Faculty of Medicine, King Abdulaziz University. 17 Intensive Care Department, King Fahd Hospital, Jeddah. 18 Department of Intensive Care Services, Prince Sultan Military Medical City. 19 Department of Infection Prevention and Control, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, King Abdulaziz Medical City, Riyadh. 20 Department of Critical Care, King Fahad Hospital, Ohoud Hospital, Al-Madinah. 21 Pharmaceutical Care Department, College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, King Abdulaziz Medical City, Riyadh. 22 Department of Medicine, Critical Care Division, King Abdulaziz Hospital, Al Ahsa, Saudi Arabia. 23 International Severe Acute Respiratory and Emerging Infection Consortium, Infectious Diseases Data Observatory, Oxford University, United Kingdom. 24 Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville. 25 Institute of Health Policy Management and Evaluation, University of Toronto, Department of Critical Care Medicine and Department of Medicine, Sunnybrook Hospital, Ontario, Canada.

 

Abstract

BACKGROUND:

The objective of this study was to evaluate the effect of ribavirin and recombinant interferon (RBV/rIFN) therapy on the outcomes of critically ill patients with Middle East respiratory syndrome (MERS), accounting for time-varying confounders.

METHODS:

This is a retrospective cohort study of critically ill patients with laboratory-confirmed MERS from 14 hospitals in Saudi Arabia diagnosed between September 2012 and January 2018. We evaluated the association of RBV/rIFN with 90-day mortality and MERS coronavirus (MERS-CoV) RNA clearance using marginal structural modeling to account for baseline and time-varying confounders.

RESULTS:

Of 349 MERS patients, 144 (41.3%) patients received RBV/rIFN (RBV and/or rIFN-α2a, rIFN-α2b, or rIFN-β1a; none received rIFN-β1b). RBV/rIFN was initiated at a median of 2 days (Q1, Q3: 1, 3 days) from intensive care unit admission. Crude 90-day mortality was higher in patients with RBV/rIFN compared to no RBV/rIFN (106/144 [73.6%] vs 126/205 [61.5%]; P = .02]. After adjusting for baseline and time-varying confounders using a marginal structural model, RBV/rIFN was not associated with changes in 90-day mortality (adjusted odds ratio, 1.03 [95% confidence interval {CI}, .73-1.44]; P = .87) or with more rapid MERS-CoV RNA clearance (adjusted hazard ratio, 0.65 [95% CI, .30-1.44]; P = .29).

CONCLUSIONS:

In this observational study, RBV/rIFN (RBV and/or rIFN-α2a, rIFN-α2b, or rIFN-β1a) therapy was commonly used in critically ill MERS patients but was not associated with reduction in 90-day mortality or in faster MERS-CoV RNA clearance.

© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

KEYWORDS: Middle East respiratory syndrome; coronavirus; interferon; pneumonia; ribavirin

PMID: 31925415 DOI: 10.1093/cid/ciz544

Keywords: Antivirals; Ribavirin; Interferons; MERS-CoV.

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Comparative #therapeutic efficacy of #remdesivir and combination #lopinavir#, ritonavir, and #interferon beta against #MERS-CoV (Nat Commun., abstract)

[Source: Nature Communications, full page: (LINK). Abstract, edited.]

Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV

Timothy P. Sheahan, Amy C. Sims, Sarah R. Leist, Alexandra Schäfer, John Won, Ariane J. Brown, Stephanie A. Montgomery, Alison Hogg, Darius Babusis, Michael O. Clarke, Jamie E. Spahn, Laura Bauer, Scott Sellers, Danielle Porter, Joy Y. Feng, Tomas Cihlar, Robert Jordan, Mark R. Denison & Ralph S. Baric

Nature Communications, volume 11, Article number: 222 (2020)

 

Abstract

Middle East respiratory syndrome coronavirus (MERS-CoV) is the causative agent of a severe respiratory disease associated with more than 2468 human infections and over 851 deaths in 27 countries since 2012. There are no approved treatments for MERS-CoV infection although a combination of lopinavir, ritonavir and interferon beta (LPV/RTV-IFNb) is currently being evaluated in humans in the Kingdom of Saudi Arabia. Here, we show that remdesivir (RDV) and IFNb have superior antiviral activity to LPV and RTV in vitro. In mice, both prophylactic and therapeutic RDV improve pulmonary function and reduce lung viral loads and severe lung pathology. In contrast, prophylactic LPV/RTV-IFNb slightly reduces viral loads without impacting other disease parameters. Therapeutic LPV/RTV-IFNb improves pulmonary function but does not reduce virus replication or severe lung pathology. Thus, we provide in vivo evidence of the potential for RDV to treat MERS-CoV infections.

Keywords: Antivirals; Remdesivir; Lopinavir; Ritonavir; Interferons; MERS-CoV; Animal models.

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#Treatment of #MERS with a #combination of #lopinavir / #ritonavir and #interferon-β1b (#MIRACLE trial): statistical analysis plan for a recursive two-stage group sequential #RCT (Trials, abstract)

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

Trials. 2020 Jan 3;21(1):8. doi: 10.1186/s13063-019-3846-x.

Treatment of Middle East respiratory syndrome with a combination of lopinavir/ritonavir and interferon-β1b (MIRACLE trial): statistical analysis plan for a recursive two-stage group sequential randomized controlled trial.

Arabi YM1,2, Asiri AY3, Assiri AM4, Aziz Jokhdar HA5, Alothman A6,7, Balkhy HH6,8, AlJohani S6,9, Al Harbi S10,11, Kojan S6,7, Al Jeraisy M10,11, Deeb AM12,13, Memish ZA14,15, Ghazal S3, Al Faraj S3, Al-Hameed F16,17, AlSaedi A16,18, Mandourah Y19, Al Mekhlafi GA20, Sherbeeni NM21, Elzein FE21, Almotairi A22, Al Bshabshe A23, Kharaba A24, Jose J25, Al Harthy A26, Al Sulaiman M27, Mady A28,29, Fowler RA30,31, Hayden FG32, Al-Dawood A6,33, Abdelzaher M34,35, Bajhmom W36, Hussein MA13,25; and the Saudi Critical Care Trials group.

Author information: 1 College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia. arabi@ngha.med.sa. 2 Intensive Care Department, Ministry of the National Guard – Health Affairs, ICU 1425, P.O. Box 22490, Riyadh, 11426, Saudi Arabia. arabi@ngha.med.sa. 3 Prince Mohammed bin Abdulaziz Hospital, Riyadh, Saudi Arabia. 4 Infection Prevention and Control, Assistant Deputy Minister, Preventive Health, Ministry of Health, Riyadh, Saudi Arabia. 5 Deputy Minister for Public Health, Ministry of Health, Riyadh, Saudi Arabia. 6 College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia. 7 Department of Medicine, Ministry of the National Guard – Health Affairs, Riyadh, Saudi Arabia. 8 Department of Infection Prevention and Control, Ministry of the National Guard – Health Affairs, Riyadh, Saudi Arabia. 9 Department of Pathology and Laboratory Medicine, Ministry of the National Guard – Health Affairs, Riyadh, Saudi Arabia. 10 College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia. 11 Pharmaceutical Care Department, Ministry of the National Guard – Health Affairs, Riyadh, Saudi Arabia. 12 King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Research Office, Riyadh, Saudi Arabia. 13 Ministry of the National Guard – Health Affairs, Riyadh, Saudi Arabia. 14 Prince Mohammed bin Abdulaziz Hospital, Ministry of Health & College of Medicine, Alfaisal University, Riyadh, Saudi Arabia. 15 Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA. 16 College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Jeddah, Saudi Arabia. 17 Intensive Care Department, Ministry of the National Guard – Health Affairs, Jeddah, Saudi Arabia. 18 Department of Infection Prevention and Control, Ministry of the National Guard – Health Affairs, Jeddah, Saudi Arabia. 19 Military Medical Services, Ministry of Defense, Prince Sultan Military Medical City, Riyadh, Saudi Arabia. 20 Department of Intensive Care Services, Prince Sultan Military Medical City, Riyadh, Saudi Arabia. 21 Infectious Diseases Division, Prince Sultan Military Medical City, Riyadh, Saudi Arabia. 22 Department of Critical Care Medicine, King Fahad Medical City, Riyadh, Saudi Arabia. 23 Department of Critical Care Medicine, King Khalid University, Aseer Central Hospital, Abha, Saudi Arabia. 24 Department of Critical Care, King Fahad Hospital, Ohoud Hospital, Al-Madinah Al-Monawarah, Saudi Arabia. 25 Department Biostatistics and Bioinformatics, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia. 26 Intensive Care Unit, King Saud Medical City, Riyadh, Saudi Arabia. 27 Infectious Disease, King Saud Medical City, Riyadh, Saudi Arabia. 28 Intensive Care Department, King Saud Medical City, Riyadh, Saudi Arabia. 29 Department of Anesthesiology and Intensive Care, Tanta University Hospitals, Tanta, Egypt. 30 Institute of Health Policy Management and Evaluation, University of Toronto, Toronto, Canada. 31 Department of Critical Care Medicine and Department of Medicine, Sunnybrook Hospital, Bayview Avenue, Room D478, Toronto, 2075, Canada. 32 International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC), Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, USA. 33 Intensive Care Department, Ministry of the National Guard – Health Affairs, ICU 1425, P.O. Box 22490, Riyadh, 11426, Saudi Arabia. 34 Critical Care Medicine Department, King Abdullah Medical Complex, Jeddah, Saudi Arabia. 35 Critical Care Medicine Department, Cairo University Hospital, Cairo, Egypt. 36 Internal Medicine Department, King Fahad General Hospital, Ministry of Health, Jeddah, Saudi Arabia.

 

Abstract

The MIRACLE trial (MERS-CoV Infection tReated with A Combination of Lopinavir/ritonavir and intErferon-β1b) investigates the efficacy of a combination therapy of lopinavir/ritonavir and recombinant interferon-β1b provided with standard supportive care, compared to placebo provided with standard supportive care, in hospitalized patients with laboratory-confirmed MERS. The MIRACLE trial is designed as a recursive, two-stage, group sequential, multicenter, placebo-controlled, double-blind randomized controlled trial. The aim of this article is to describe the statistical analysis plan for the MIRACLE trial. The primary outcome is 90-day mortality. The primary analysis will follow the intention-to-treat principle. The MIRACLE trial is the first randomized controlled trial for MERS treatment.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT02845843. Registered on 27 July 2016.

KEYWORDS: Antiviral; Clinical trial; Coronavirus; Interferon-β1b; Lopinavir/ritonavir; MERS; Protocol; Statistical analysis plan

PMID: 31900204 DOI: 10.1186/s13063-019-3846-x

Keywords: MERS-CoV; Antivirals; Interferons; Ritonavir; Lopinavir.

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Control of #Nipah Virus #Infection in Mice by the Host Adaptors Mitochondrial Antiviral Signaling Protein (#MAVS) and Myeloid Differentiation Primary Response 88 (MyD88) (J Infect Dis., abstract)

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

Control of Nipah Virus Infection in Mice by the Host Adaptors Mitochondrial Antiviral Signaling Protein (MAVS) and Myeloid Differentiation Primary Response 88 (MyD88)

Mathieu Iampietro, Noemie Aurine, Kevin P Dhondt, Claire Dumont, Rodolphe Pelissier, Julia Spanier, Audrey Vallve, Herve Raoul, Ulrich Kalinke, Branka Horvat

The Journal of Infectious Diseases, jiz602, https://doi.org/10.1093/infdis/jiz602

Published: 19 December 2019

 

Abstract

Interferon (IFN) type I plays a critical role in the protection of mice from lethal Nipah virus (NiV) infection, but mechanisms responsible for IFN-I induction remain unknown. In the current study, we demonstrated the critical role of the mitochondrial antiviral signaling protein signaling pathway in IFN-I production and NiV replication in murine embryonic fibroblasts in vitro, and the redundant but essential roles of both mitochondrial antiviral signaling protein and myeloid differentiation primary response 88 adaptors, but not TRIF (Toll/Interleukin-1 receptor/Resistance [TIR] domain–containing adaptor–inducing IFN-β), in the control of NiV infection in mice. These results reveal potential novel targets for antiviral intervention and help in understanding NiV immunopathogenesis.

Nipah virus, innate immunity, mice, MAVS, MyD88, TRIF, TLR, interferon

Issue Section: Supplement Article

© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

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: Nipah virus; Immunopathology; Interferons; Animal models.

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#HA #stability regulates #H1N1 #influenza virus #replication and #pathogenicity in mice by modulating type I #interferon responses in dendritic cells (J Virol., abstract)

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

HA stability regulates H1N1 influenza virus replication and pathogenicity in mice by modulating type I interferon responses in dendritic cells

Marion Russier, Guohua Yang, Benoit Briard, Victoria Meliopoulos, Sean Cherry, Thirumala-Devi Kanneganti, Stacey Schultz-Cherry, Peter Vogel, Charles J. Russell

DOI: 10.1128/JVI.01423-19

 

ABSTRACT

Hemagglutinin (HA) stability, or the pH at which HA is activated to cause membrane fusion, has been associated with the replication, pathogenicity, transmissibility, and interspecies adaptation of influenza A viruses. Here, we investigated mechanisms by which a destabilizing HA mutation, Y17H (activation pH 6.0), attenuates virus replication and pathogenicity in DBA/2 mice, compared to wild-type (WT; activation pH 5.5). Extracellular lung pH was measured to be near neutral (pH 6.9–7.5). WT and Y17H viruses had similar environmental stability at pH 7.0; thus, extracellular inactivation was unlikely to attenuate Y17H virus. The Y17H virus had accelerated replication kinetics in MDCK, A549, and Raw264.7 cells when inoculated at an MOI of 3 PFU/cell. The destabilizing mutation also increased early infectivity and type I interferon (IFN) responses in mouse bone marrow–derived dendritic cells (DCs). In contrast, the HA-Y17H mutation reduced replication in murine airway mNEC and mTEC cultures and attenuated virus replication, virus spread, severity of infection, and cellular infiltration in the lungs of mice. Normalizing virus infection and weight loss in mice by inoculating them with Y17H virus at a dose 500-fold higher than that of WT virus revealed that the destabilized mutant virus triggered the upregulation of more host genes and increased type I IFN responses and cytokine expression in DBA/2 mouse lungs. Overall, HA destabilization decreased virulence in mice by boosting early infection in DCs, resulting in greater activation of antiviral responses, including type I IFN. These studies reveal HA stability may regulate pathogenicity by modulating IFN responses.

 

Importance

Diverse influenza A viruses circulate in wild aquatic birds, occasionally infecting farm animals. Rarely, an avian- or swine-origin influenza virus adapts to humans and starts a pandemic. Seasonal and many universal influenza vaccines target the HA surface protein, which is a key component of pandemic influenza. Understanding HA properties needed for replication and pathogenicity in mammals may guide response efforts to control influenza. Some antiviral drugs and broadly reactive influenza vaccines that target the HA protein have suffered resistance due to destabilizing HA mutations that do not compromise replicative fitness in cell culture. Here, we show that despite not compromising fitness in standard cell cultures, a destabilizing H1N1 HA stalk mutation greatly diminishes viral replication and pathogenicity in vivo by modulating type I IFN responses. This encourages targeting the HA stalk with antiviral drugs and vaccines as well as reevaluating previous candidates that were susceptible to destabilizing resistance mutations.

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

Keywords: Influenza A; H1N1; Viral pathogenesis; Interferons.

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#Clinical #outcomes among #hospital #patients with Middle East respiratory syndrome #coronavirus (#MERS-CoV) #infection (BMC Infect Dis., abstract)

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

BMC Infect Dis. 2019 Oct 22;19(1):870. doi: 10.1186/s12879-019-4555-5.

Clinical outcomes among hospital patients with Middle East respiratory syndrome coronavirus (MERS-CoV) infection.

Habib AMG1, Ali MAE1, Zouaoui BR1, Taha MAH1, Mohammed BS2, Saquib N3.

Author information: 1 College of Medicine, Sulaiman Al Rajhi Colleges, P.O. Box 777, Bukayriah, Al-Qassim, Zip code 51941, Saudi Arabia. 2 Buraidah Central Hospital, Buraidah, Saudi Arabia. 3 College of Medicine, Sulaiman Al Rajhi Colleges, P.O. Box 777, Bukayriah, Al-Qassim, Zip code 51941, Saudi Arabia. a.saquib@sr.edu.sa.

 

Abstract

BACKGROUND:

Mortality is high among patients with Middle East Respiratory Syndrome Coronavirus (MERS-CoV) infection. We aimed to determine hospital mortality and the factors associated with it in a cohort of MERS-CoV patients.

METHODS:

We reviewed hospital records of confirmed cases (detection of virus by polymerase chain reaction from respiratory tract samples) of MERS-CoV patients (n = 63) admitted to Buraidah Central Hospital in Al-Qassim, Saudi Arabia between 2014 and 2017. We abstracted data on demography, vital signs, associated conditions presented on admission, pre-existing chronic diseases, treatment, and vital status. Bi-variate comparisons and multiple logistic regressions were the choice of data analyses.

RESULTS:

The mean age was 60 years (SD = 18.2); most patients were male (74.6%) and Saudi citizens (81%). All but two patients were treated with Ribavirin plus Interferon. Hospital mortality was 25.4%. Patients who were admitted with septic shock and/or organ failure were significantly more likely to die than patients who were admitted with pneumonia and/or acute respiratory distress syndrome (OR = 47.9, 95% CI = 3.9, 585.5, p-value 0.002). Age, sex, and presence of chronic conditions were not significantly associated with mortality.

CONCLUSION:

Hospital mortality was 25%; septic shock/organ failure at admittance was a significant predictor of mortality.

KEYWORDS: Interferon alpha; MERS-CoV; Mortality; Ribavirin

PMID: 31640578 DOI: 10.1186/s12879-019-4555-5

Keywords: MERS-CoV; Saudi Arabia; ARDS; Septic shock; Ribavirin; Interferon.

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#Azithromycin Protects against #Zika virus #Infection by Upregulating virus-induced Type I and III #Interferon Responses (Antimicrob Agents Chemother., abstract)

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

Azithromycin Protects against Zika virus Infection by Upregulating virus-induced Type I and III Interferon Responses

Chunfeng Li, Shulong Zu, Yong-Qiang Deng, Dapei Li, Kislay Parvatiyar, Natalie Quanquin, Jingzhe Shang, Nina Sun, Jiaqi Su, Zhenyang Liu, Min Wang, Saba R. Aliyari, Xiao-Feng Li, Aiping Wu, Feng Ma, Yi Shi, Karin Nielsevn-Saines, Jae U. Jung, Frank Xiao-Feng Qin, Cheng-Feng Qin, Genhong Cheng

DOI: 10.1128/AAC.00394-19

 

ABSTRACT

Azithromycin (AZM) is a widely used antibiotic, with additional antiviral and anti-inflammatory properties that remain poorly understood. Although Zika virus (ZIKV) poses a significant threat to global health, there are currently no vaccines or effective therapeutics against it. Herein, we report that AZM effectively suppresses ZIKV infection in vitro by targeting a late stage in the viral life cycle. Besides that, AZM upregulates the expression of host type I and III interferons and several of their downstream interferon-stimulated genes (ISGs) in response to ZIKV infection. In particular, we found that AZM upregulates the expression of MDA5 and RIG-I, pathogen recognition receptors (PRRs) induced by ZIKV infection, and increases the levels of phosphorylated TBK1 and IRF3. Interestingly, AZM treatment upregulates phosphorylation of TBK1, without inducing phosphorylation of IRF3 by itself. These findings highlight the potential use of AZM as a broad antiviral agent to combat viral infection and prevent ZIKV associated devastating clinical outcomes, such as congenital microcephaly.

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

Keywords: Antivirals; Antibiotics; Azithromycin; Zika Virus.

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