#Risk of #Zika #microcephaly correlates with features of #maternal #antibodies (J Exp Med., abstract)

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

Risk of Zika microcephaly correlates with features of maternal antibodies

Davide F. Robbiani, Priscilla C. Olsen, Federico Costa,Qiao Wang, Thiago Y. Oliveira, Nivison Nery, Adeolu Aromolaran, Mateus S. do Rosário, Gielson A. Sacramento, Jaqueline S. Cruz, Ricardo Khouri, Elsio A. Wunder, Adriana Mattos, Bruno de Paula Freitas, Manoel Sarno, Gracinda Archanjo, Dina Daltro, Gustavo B.S. Carvalho, Kleber Pimentel, Isadora C. de Siqueira, João R.M. de Almeida, Daniele F. Henriques, Juliana A. Lima, Pedro F.C. Vasconcelos, Dennis Schaefer-Babajew, Stephanie A. Azzopardi, Leonia Bozzacco, Anna Gazumyan, Rubens Belfort, Ana P. Alcântara, Gustavo Carvalho, Licia Moreira, Katiaci Araujo, Mitermayer G. Reis, Rebekah I. Keesler, Lark L. Coffey, Jennifer Tisoncik-Go, Michael Gale, Lakshmi Rajagopal, Kristina M. Adams Waldorf, Dawn M. Dudley, Heather A. Simmons, Andres Mejia, David H. O’Connor, Rosemary J. Steinbach, Nicole Haese, Jessica Smith, Anne Lewis, Lois Colgin, Victoria Roberts, Antonio Frias, Meredith Kelleher, Alec Hirsch, Daniel N. Streblow, Charles M. Rice, Margaret R. MacDonald, Antonio R.P. de Almeida, Koen K.A. Van Rompay, Albert I. Ko, Michel C. Nussenzweig

DOI: 10.1084/jem.20191061 | Published August 14, 2019

 

Abstract

Zika virus (ZIKV) infection during pregnancy causes congenital abnormalities, including microcephaly. However, rates vary widely, and the contributing risk factors remain unclear. We examined the serum antibody response to ZIKV and other flaviviruses in Brazilian women giving birth during the 2015–2016 outbreak. Infected pregnancies with intermediate or higher ZIKV antibody enhancement titers were at increased risk to give birth to microcephalic infants compared with those with lower titers (P < 0.0001). Similarly, analysis of ZIKV-infected pregnant macaques revealed that fetal brain damage was more frequent in mothers with higher enhancement titers. Thus, features of the maternal antibodies are associated with and may contribute to the genesis of ZIKV-associated microcephaly.

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Keywords: Zika virus; Pregnancy; Immunopathology; Microcephaly.

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An #influenza virus-triggered SUMO switch orchestrates co-opted endogenous #retroviruses to stimulate host antiviral #immunity (Proc Natl Acad Sci USA, abstract)

[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]

An influenza virus-triggered SUMO switch orchestrates co-opted endogenous retroviruses to stimulate host antiviral immunity

Nora Schmidt, Patricia Domingues, Filip Golebiowski, Corinna Patzina, Michael H. Tatham, Ronald T. Hay, and Benjamin G. Hale

PNAS first published August 7, 2019 / DOI: https://doi.org/10.1073/pnas.1907031116

Edited by Stephen P. Goff, Columbia University Medical Center, New York, NY, and approved July 15, 2019 (received for review April 24, 2019)

 

Significance

Primary host defenses against viruses involve specific cellular recognition of non-self nucleic acids as pathogen-associated molecular patterns (PAMPs) that trigger induction of cytokine-mediated antiviral responses. Thus, ability to discriminate between “self” and “non-self” nucleic acids, and prevent aberrant immunopathology, is a key tenet of immunity. Here, we identify self-derived endogenous retroviral RNAs as host-encoded PAMPs that are up-regulated during influenza virus infections, and which stimulate antiviral immunity. Normally, endogenous retroviruses are tightly repressed transcriptionally by host TRIM28, but infection triggers changes in the modification status of TRIM28 to alleviate repression. This provides an example of how endogenous retroviruses integrated within the host genome have been functionally co-opted by a regulatory switch to aid defense against newly invading pathogens.

 

Abstract

Dynamic small ubiquitin-like modifier (SUMO) linkages to diverse cellular protein groups are critical to orchestrate resolution of stresses such as genome damage, hypoxia, or proteotoxicity. Defense against pathogen insult (often reliant upon host recognition of “non-self” nucleic acids) is also modulated by SUMO, but the underlying mechanisms are incompletely understood. Here, we used quantitative SILAC-based proteomics to survey pan-viral host SUMOylation responses, creating a resource of almost 600 common and unique SUMO remodeling events that are mounted during influenza A and B virus infections, as well as during viral innate immune stimulation. Subsequent mechanistic profiling focused on a common infection-induced loss of the SUMO-modified form of TRIM28/KAP1, a host transcriptional repressor. By integrating knockout and reconstitution models with system-wide transcriptomics, we provide evidence that influenza virus-triggered loss of SUMO-modified TRIM28 leads to derepression of endogenous retroviral (ERV) elements, unmasking this cellular source of “self” double-stranded (ds)RNA. Consequently, loss of SUMO-modified TRIM28 potentiates canonical cytosolic dsRNA-activated IFN-mediated defenses that rely on RIG-I, MAVS, TBK1, and JAK1. Intriguingly, although wild-type influenza A virus robustly triggers this SUMO switch in TRIM28, the induction of IFN-stimulated genes is limited unless expression of the viral dsRNA-binding protein NS1 is abrogated. This may imply a viral strategy to antagonize such a host response by sequestration of induced immunostimulatory ERV dsRNAs. Overall, our data reveal that a key nuclear mechanism that normally prevents aberrant expression of ERV elements (ERVs) has been functionally co-opted via a stress-induced SUMO switch to augment antiviral immunity.

influenza – SUMO – endogenous retroviruses – dsRNA – interferon

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Keywords: Influenza A; Retrovirus; Immunopathology; Viral pathogenesis.

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#Zika Virus-Immune #Plasmas from Symptomatic and Asymptomatic Individuals Enhance Zika #Pathogenesis in #Adult and #Pregnant Mice (mBio, abstract)

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

Zika Virus-Immune Plasmas from Symptomatic and Asymptomatic Individuals Enhance Zika Pathogenesis in Adult and Pregnant Mice

Byoung-Shik Shim, Young-Chan Kwon, Michael J. Ricciardi, Mars Stone, Yuka Otsuka, Fatma Berri, Jaclyn M. Kwal, Diogo M. Magnani, Cody B. Jackson, Audrey S. Richard, Philip Norris,Michael Busch, Christine L. Curry, Michael Farzan, David Watkins, Hyeryun Choe

Mark R. Denison, Editor

DOI: 10.1128/mBio.00758-19

 

ABSTRACT

Preexisting immunity against dengue virus or West Nile virus was previously reported to mediate antibody-dependent enhancement (ADE) of Zika virus (ZIKV) infection in a mouse model. We show here that ZIKV-immune plasma samples from both symptomatic and asymptomatic individuals mediated ZIKV ADE of infection in vitro and in mice. In a lethal infection model with a viral inoculum 10 times higher, both ADE and protection were observed, depending on the amount of infused immune plasma. In a vertical-transmission model, ZIKV-immune plasma infused to timed pregnant mice increased fetal demise and decreased the body weight of surviving fetuses. Depletion of IgG from an immune plasma abolished ADE of infection, and the presence of purified IgG alone mediated ADE of infection. Higher viral loads and proinflammatory cytokines were detected in mice treated with ZIKV-immune plasma samples compared to those receiving control plasma. Together, these data show that passive immunization with homotypic ZIKV antibodies, depending on the concentration, could either worsen or limit a subsequent ZIKV infection.

 

IMPORTANCE

Antibody-dependent enhancement (ADE) of virus infection is common to many viruses and is problematic when plasma antibody levels decline to subneutralizing concentrations. ADE of infection is especially important among flaviviruses, many of which are the cause of global health problems. Recently, human plasma samples immune to heterologous flaviviruses were shown to promote Zika virus (ZIKV) infection. Here we showed in immunocompromised mouse models that homologous immune plasma samples protect mice from subsequent infection at high antibody concentrations but that they mediate ADE of infection and increase ZIKV pathogenesis in adult mice and fetal demise during pregnancy at low concentrations.

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Keywords: Zika Virus; ADE; Pregnancy; Immunopathology; Animal models.

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Characterization of #antibody and memory T cell response in #H7N9 #survivors: A cross-sectional analysis (Clin Microbiol Infect., abstract)

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

Clin Microbiol Infect. 2019 Jun 20. pii: S1198-743X(19)30338-6. doi: 10.1016/j.cmi.2019.06.013. [Epub ahead of print]

Characterization of antibody and memory T cell response in H7N9 survivors: A cross-sectional analysis.

Ma MJ1, Wang XX2, Wu MN3, Wang XJ4, Bao CJ5, Zhang HJ6, Yang Y7, Xu K5, Wang GL8, Zhao M9, Cheng W2, Chen WJ3, Zhang WH8, Fang LQ8, Liu WJ10, Chen EF11, Cao WC8.

Author information: 1 State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China. Electronic address: mjma@163.com. 2 Department of Acute Infectious Disease Control and Prevention, Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, China. 3 State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China; Department of Acute Infectious Disease Control and Prevention, Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, China. 4 Department of Acute Infectious Disease Control and Prevention, Shandong Provincial Center for Disease Control and Prevention, Jinan, China. 5 Department of Acute Infectious Disease Control and Prevention, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China. 6 National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China. 7 Department of Biostatistics, University of Florida, Gainesville; Emerging Pathogens Institute, University of Florida, FL 32610, Gainesville, USA. 8 State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China. 9 CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China. 10 National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China. Electronic address: liujun@ivdc.chinacdc.cn. 11 Department of Acute Infectious Disease Control and Prevention, Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, China. Electronic address: enfchen@cdc.zj.cn.

 

Abstract

OBJECTIVES:

Despite the importance of immunological memory for protective immunity against viral infection, whether H7N9-specific antibodies and memory T-cell responses remain detectable years after the original infection is unknown.

METHODS:

A cross-sectional study was conducted to investigate the immune memory responses of H7N9 patients who contracted the disease and survived during the 2013-2016 epidemics in China. Sustainability of antibodies and T-cell memory to H7N9 virus were examined. Healthy subjects receiving routine medical examination in physical examination center were recruited as control.

RESULTS:

A total of 75 survivors were enrolled and classified into four groups based on the time elapsed from illness onset to specimen collection: three months (n=14), 14 months (n=14), 26 months (n=28), and 36 months (n=19). Approximately 36 months after infection, the geometric mean titers of virus-specific antibodies were significantly lower than titers in patients of three months after infection, but 16 of 19 (84.2%) survivors in the 36-month interval had microneutralization (MN) titer > 40. Despite the overall declining trend, the percentages of virus-specific cytokines-secreting memory CD4+ and CD8+ T-cells remained higher in survivors at nearly all time points in comparison with control subjects. Linear regression analysis showed that severe disease (mean titer ratio 2.77, 95%CI 1.17-6.49) was associated with higher hemagglutination inhibition (HI) titer, and female sex for both HI (1.92, 1.02-3.57) and MN (3.33, 1.26-9.09) antibody, whereas female sex (mean percentage ratio 1.69, 95%CI 1.08-2.63), underlying medical conditions (1.94, 95%CI 1.09-3.46), and lack of antiviral therapy (2.08, 95%CI 1.04-4.17) were predictors for higher T-cell responses.

CONCLUSIONS:

Survivors from H7N9 virus infection produced long-term antibodies and memory T-cells responses. Our findings warrant further serological investigation in general and high-risk populations and have important implications for vaccine design and development.

Copyright © 2019 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

KEYWORDS: Antibodies; H7N9; Immune Memory; Influenza; Survivors; T-Cells

PMID: 31229595 DOI: 10.1016/j.cmi.2019.06.013

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Keywords: Avian Influenza; H7N9; Human; Immunology; Immunopathology.

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Characterization of #Antibody Response in #Patients with Acute and Chronic #Chikungunya Virus Disease (J Clin Virol., abstract)

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

Journal of Clinical Virology / Available online 10 June 2019 / In Press, Accepted Manuscript

Characterization of Antibody Response in Patients with Acute and Chronic Chikungunya Virus Disease

Fatih Anfasa a,b, Stephanie M. Lim c, Susan Fekken c, Robert Wever d, Albert D.M.E. Osterhaus c,e, Byron E.E. Martina a,c

{a} Department of Viroscience, Erasmus Medical Center, Rotterdam, the Netherlands; {b} Department of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia; {c} Artemis One Health Research Institute, Utrecht, the Netherlands; {d} Medical Laboratory Services, Dutch Caribbean, Curaçao; {e} Center for Infection Medicine and Zoonoses Research (RIZ), University of Veterinary Medicine, Hannover, Germany

Received 29 November 2018, Revised 29 May 2019, Accepted 8 June 2019, Available online 10 June 2019. DOI: https://doi.org/10.1016/j.jcv.2019.06.001

 

Highlights

• We found no difference between homologous and heterologous cross-neutralization of chikungunya virus.
• There was a significant difference in the complement-dependent virus neutralization titers between patients with acute and chronic chikungunya infection when high viral load was used.
• Patients with acute chikungunya infection were found to have a significantly higher antibody avidity index compared to those with chronic infection.

(…)

© 2019 Published by Elsevier B.V.

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Keywords: Chikungunya fever; Immunopathology.

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#Phage #therapy of #pneumonia is not associated with an over stimulation of the #inflammatory response compared to #antibiotic treatment in mice (Antimicrob Agents Chemother., abstract)

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

Phage therapy of pneumonia is not associated with an over stimulation of the inflammatory response compared to antibiotic treatment in mice

Nicolas Dufour, Raphaëlle Delattre, Anne Chevallereau, Jean-Damien Ricard, Laurent Debarbieux

DOI: 10.1128/AAC.00379-19

 

ABSTRACT

Background.

Supported by years of clinical use in some countries and more recently by literature on experimental models as well as compassionate use in Europe and in USA, bacteriophage (phage) therapy is providing a solution for difficult to treat bacterial infections. However, studies of the impact of such treatments on the host remain scarce.

Methods.

Murine acute pneumonia initiated by intranasal instillation of two pathogenic strains of Escherichia coli (536 and LM33) were treated by two specific bacteriophages (536_P1 and LM33_P1; intranasal) or antibiotics (Ceftriaxone, Cefoxitin, Imipenem-Cilastatin; intraperitoneal). Healthy mice also received phages alone. Severity of pulmonary edema, acute inflammatory cytokines (blood and lung homogenates), complete blood count, bacteria and bacteriophages counts were obtained at early (≤12h) and late (≥20h) time points.

Results.

Bacteriophage’s efficacy to decrease bacterial load was faster than antibiotics, but both displayed similar endpoints. Bacteriophage treatment was not associated with an over-inflammation but in contrast tended to lower inflammation and provided a faster correction of blood cell count abnormalities compared to antibiotics. In absence of bacterial infection, bacteriophage 536_P1 promoted a weak increase in the production of anti-viral cytokines (INF-γ and IL-12) and chemokines in the lungs, but not in the blood. However, such variations were no longer observed when bacteriophage 536_P1 was administered to treat infected animals.

Conclusions.

The rapid lysis of bacteria by bacteriophages in vivo does not increase the innate inflammatory response compared to an antibiotic treatment.

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

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Keywords: Bacteriophages; Pneumonia; Animal models.

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#H7N9 #influenza A virus activation of necroptosis in #human #monocytes links innate and adaptive immune responses (Cell Death Dis., abstract)

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

Cell Death Dis. 2019 Jun 5;10(6):442. doi: 10.1038/s41419-019-1684-0.

H7N9 influenza A virus activation of necroptosis in human monocytes links innate and adaptive immune responses.

Lee ACY1, Zhang AJX1,2,3,4, Chu H1,2,3,4, Li C1, Zhu H1, Mak WWN1, Chen Y1, Kok KH1,2,3,4, To KKW1,2,3,4, Yuen KY5,6,7,8.

Author information: 1 Department of Microbiology, The University of Hong Kong, Hong Kong, China. 2 State Key Laboratory of Emerging Infectious Diseases, Hong Kong, China. 3 Carol Yu Centre for infection, Hong Kong, China. 4 Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong, China. 5 Department of Microbiology, The University of Hong Kong, Hong Kong, China. kyyuen@hku.hk. 6 State Key Laboratory of Emerging Infectious Diseases, Hong Kong, China. kyyuen@hku.hk. 7 Carol Yu Centre for infection, Hong Kong, China. kyyuen@hku.hk. 8 Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong, China. kyyuen@hku.hk.

 

Abstract

We previously demonstrated that avian influenza A H7N9 virus preferentially infected CD14+ monocyte in human peripheral blood mononuclear cells (PBMCs), which led to apoptosis. To better understand H7N9 pathogenesis in relation to monocyte cell death, we showed here that extensive phosphorylation of mixed lineage kinase domain-like (MLKL) protein occurred concurrently with the activation of caspases-8, -9 and -3 in H7N9-infected monocytes at 6 h post infection (hpi), indicating that apoptosis and necroptosis pathways were simultaneously activated. The apoptotic morphology was readily observed in H7N9-infected monocytes with transmission electron microscopy (TEM), while the pan-caspase inhibitor, IDN6556 (IDN), accelerated cell death through necroptosis as evidenced by the increased level of pMLKL accompanied with cell swelling and plasma membrane rupture. Most importantly, H7N9-induced cell death could only be stopped by the combined treatment of IDN and necrosulfonamide (NSA), a pMLKL membrane translocation inhibitor, but not by individual inhibition of caspase or RIPK3. Our data further showed that activation of apoptosis and necroptosis pathways in monocytes differentially contributed to the immune response of monocytes upon H7N9 infection. Specifically, caspase inhibition significantly enhanced, while RIPK3 inhibition reduced the early expression of type I interferons and cytokine/chemokines in H7N9-infected monocytes. Moreover, culture supernatants from IDN-treated H7N9-infected monocyte promoted the expression of co-stimulatory molecule CD80, CD83 and CD86 on freshly isolated monocytes and monocyte-derived dendritic cells (MDCs) and enhanced the capacity of MDCs to induce CD3+ T-cell proliferation in vitro. In contrast, these immune stimulatory effects were abrogated by using culture supernatants from H7N9-infected monocyte with RIPK3 inhibition. In conclusion, our findings indicated that H7N9 infection activated both apoptosis and necroptosis in monocytes. An intact RIPK3 activity is required for upregulation of innate immune responses, while caspase activation suppresses the immune response.

PMID: 31165725 DOI: 10.1038/s41419-019-1684-0

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Keywords: Avian Influenza; H7N9; Immunopathology.

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