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In Memory of Stefan Kunz

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A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "General Virology".

Deadline for manuscript submissions: closed (31 May 2021) | Viewed by 43834

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Special Issue Editors

Prof. Dr. Michael B.A. Oldstone

*
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Guest Editor

The Scripps Research Institute, La Jolla, Emeritus Professor Department of Immunology and Microbiology
Interests: viral pathogenesis; immune responses to viral infections; autoimmune diseases; history of viral plagues and their control
* Emeritus Professor Department of Immunology and Microbiology; Founder of the Laboratory of Virus-Immunobiology; Elected Member U.S.A. National Academy of Sciences, and National Academy of Medicine; Author of Viruses, Plagues and History [Oxford Press]

Prof. Dr. Juan De la Torre

E-Mail Website
Guest Editor

Department of Immunology and Microbiology IMM-6, The Scripps Research Institute, La Jolla Campus, 10466 North Torrey Pines Road, La Jolla, CA 92037, USA
Interests: molecular, cell biology and pathogenesis of mammarenaviruses; virus-host cell interactions; antivirals; live attenuated vaccines
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Stefan Kunz was a dear scientific colleague and friend that passed away too early in life. During his scientific career, Stefan made major contributions to the field of virology, working on how mammarenaviruses gain access to their target cells. Stefan made seminal contributions to the structural basis and molecular interactions between Old World mammarenaviruses Lassa virus (LASV) and lymphocytic choriomeningitis virus (LCMV) and their cell entry receptor alpha-dystroglycan (a-DG).

LASV is an important human pathogen, whereas LCMV provides investigators with a highly tractable experimental system for the investigation of virus–host interactions and associated disease. LASV is the causative agent of Lassa fever (LF), a viral hemorrhagic fever (HF) disease endemic to Western Africa where the virus infects hundreds of thousands of individuals yearly, resulting in a high number of LF cases that are associated with high morbidity and a high case fatality rate among hospitalized patients. LCMV has been a Rosetta Stone in the fields of viral immunology and pathogenesis, including the investigation of virus persistence, T cell responses, T cell exhaustion, and virus-induced autoimmune diseases. In addition to his discoveries in the area of mammarenavirus cell entry, Stefan made also important contributions to our understanding of the processing of the virus glycoprotein precursor (GPC) by the cellular protease subtilisin kexin isozyme-1/site-1 protease (SKI-1/S1P), which is a critical step in the completion of the mammarenavirus life cycle. Works by Stefan uncovered that targeting the activity of the SKI-1/S1P protease represents a very attractive antiviral strategy against human pathogenic mammarenaviruses.

This Special Issue of Viruses contains articles by those who knew and worked with Stefan and will cover different aspects of the basic molecular and cell biology of the mammarenavirus life cycle and the implications for the development of antiviral strategies. Stefan’s numerous high-quality publications speak of his talent for research, but they do not capture his also great human qualities and collegiality. Those of us who worked with Stefan will miss his generosity in sharing reagents and methods, and disposition, which included sharing new ideas and participating in collaborative research studies.

Dr. Juan De la Torre
Prof. Dr. Michael B.A. Oldstone
Guest Editors

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Published Papers (14 papers)

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1 pages, 130 KiB

Open AccessObituary

Tribute to Professor Stefan Kunz

by Manuel Pascual

Viruses 2021, 13(9), 1862; https://0-doi-org.brum.beds.ac.uk/10.3390/v13091862 - 18 Sep 2021

Viewed by 2069

Abstract

It has been a year since Stefan Kunz, a Full Professor since 2017 at the Faculty of Biology and Medicine of the University of Lausanne, Switzerland, passed away [...] Full article

(This article belongs to the Special Issue In Memory of Stefan Kunz)

2 pages, 329 KiB

Open AccessObituary

In Tribute to Stefan Kunz

by Mar Perez

Viruses 2021, 13(9), 1840; https://0-doi-org.brum.beds.ac.uk/10.3390/v13091840 - 15 Sep 2021

Viewed by 1599

Abstract

We do not always remember the exact moment in which we first met our friends [...] Full article

(This article belongs to the Special Issue In Memory of Stefan Kunz)

21 pages, 2020 KiB

Open AccessArticle

Lymphocytic Choriomeningitis Virus Alters the Expression of Male Mouse Scent Proteins

by Michael B. A. Oldstone, Brian C. Ware, Amanda Davidson, Mark C. Prescott, Robert J. Beynon and Jane L. Hurst

Viruses 2021, 13(6), 1180; https://0-doi-org.brum.beds.ac.uk/10.3390/v13061180 - 21 Jun 2021

Cited by 5 | Viewed by 2450

Abstract

Mature male mice produce a particularly high concentration of major urinary proteins (MUPs) in their scent marks that provide identity and status information to conspecifics. Darcin (MUP20) is inherently attractive to females and, by inducing rapid associative learning, leads to specific attraction to the individual male’s odour and location. Other polymorphic central MUPs, produced at much higher abundance, bind volatile ligands that are slowly released from a male’s scent marks, forming the male’s individual odour that females learn. Here, we show that infection of C57BL/6 males with LCMV WE variants (v2.2 or v54) alters MUP expression according to a male’s infection status and ability to clear the virus. MUP output is substantially reduced during acute adult infection with LCMV WE v2.2 and when males are persistently infected with LCMV WE v2.2 or v54. Infection differentially alters expression of darcin and, particularly, suppresses expression of a male’s central MUP signature. However, following clearance of acute v2.2 infection through a robust virus-specific CD8 cytotoxic T cell response that leads to immunity to the virus, males regain their normal mature male MUP pattern and exhibit enhanced MUP output by 30 days post-infection relative to uninfected controls. We discuss the likely impact of these changes in male MUP signals on female attraction and mate selection. As LCMV infection during pregnancy can substantially reduce embryo survival and lead to lifelong infection in surviving offspring, we speculate that females use LCMV-induced changes in MUP expression both to avoid direct infection from a male and to select mates able to develop immunity to local variants that will be inherited by their offspring. Full article

(This article belongs to the Special Issue In Memory of Stefan Kunz)

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9 pages, 931 KiB

Open AccessArticle

Prevention of CD8 T Cell Deletion during Chronic Viral Infection

by David G. Brooks, Antoinette Tishon, Michael B. A. Oldstone and Dorian B. McGavern

Viruses 2021, 13(7), 1189; https://0-doi-org.brum.beds.ac.uk/10.3390/v13071189 - 22 Jun 2021

Cited by 3 | Viewed by 2214

Abstract

During chronic viral infections, CD8 T cells rapidly lose antiviral and immune-stimulatory functions in a sustained program termed exhaustion. In addition to this loss of function, CD8 T cells with the highest affinity for viral antigen can be physically deleted. Consequently, treatments designed to restore function to exhausted cells and control chronic viral replication are limited from the onset by the decreased breadth of the antiviral T cell response. Yet, it remains unclear why certain populations of CD8 T cells are deleted while others are preserved in an exhausted state. We report that CD8 T cell deletion during chronic viral infection can be prevented by therapeutically lowering viral replication early after infection. The initial resistance to deletion enabled long-term maintenance of antiviral cytolytic activity of the otherwise deleted high-affinity CD8 T cells. In combination with decreased virus titers, CD4 T cell help and prolonged interactions with costimulatory molecules B7-1/B7-2 were required to prevent CD8 T cell deletion. Thus, therapeutic strategies to decrease early virus replication could enhance virus-specific CD8 T cell diversity and function during chronic infection. Full article

(This article belongs to the Special Issue In Memory of Stefan Kunz)

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18 pages, 1046 KiB

Open AccessReview

Progress in Anti-Mammarenavirus Drug Development

by Yu-Jin Kim, Victor Venturini and Juan C. de la Torre

Viruses 2021, 13(7), 1187; https://0-doi-org.brum.beds.ac.uk/10.3390/v13071187 - 22 Jun 2021

Cited by 5 | Viewed by 2655

Abstract

Mammarenaviruses are prevalent pathogens distributed worldwide, and several strains cause severe cases of human infections with high morbidity and significant mortality. Currently, there is no FDA-approved antiviral drugs and vaccines against mammarenavirus and the potential treatment option is limited to an off-label use of ribavirin that shows only partial protective effect and associates with side effects. For the past few decades, extensive research has reported potential anti-mammarenaviral drugs and their mechanisms of action in host as well as vaccine candidates. This review describes current knowledge about mammarenavirus virology, progress of antiviral drug development, and technical strategies of drug screening. Full article

(This article belongs to the Special Issue In Memory of Stefan Kunz)

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11 pages, 1191 KiB

Open AccessArticle

The Antiviral Effect of the Chemical Compounds Targeting DED/EDh Motifs of the Viral Proteins on Lymphocytic Choriomeningitis Virus and SARS-CoV-2

by Mya Myat Ngwe Tun, Kouichi Morita, Takeshi Ishikawa and Shuzo Urata

Viruses 2021, 13(7), 1220; https://0-doi-org.brum.beds.ac.uk/10.3390/v13071220 - 24 Jun 2021

Cited by 6 | Viewed by 2488

Abstract

Arenaviruses and coronaviruses include several human pathogenic viruses, such as Lassa virus, Lymphocytic choriomeningitis virus (LCMV), SARS-CoV, MERS-CoV, and SARS-CoV-2. Although these viruses belong to different virus families, they possess a common motif, the DED/EDh motif, known as an exonuclease (ExoN) motif. In this study, proof-of-concept studies, in which the DED/EDh motif in these viral proteins, NP for arenaviruses, and nsp14 for coronaviruses, could be a drug target, were performed. Docking simulation studies between two structurally different chemical compounds, ATA and PV6R, and the DED/EDh motifs in these viral proteins indicated that these compounds target DED/EDh motifs. The concentration which exhibited modest cell toxicity was used with these compounds to treat LCMV and SARS-CoV-2 infections in two different cell lines, A549 and Vero 76 cells. Both ATA and PV6R inhibited the post-entry step of LCMV and SARS-CoV-2 infection. These studies strongly suggest that DED/EDh motifs in these viral proteins could be a drug target to combat two distinct viral families, arenaviruses and coronaviruses. Full article

(This article belongs to the Special Issue In Memory of Stefan Kunz)

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24 pages, 1389 KiB

Open AccessReview

How Do Enveloped Viruses Exploit the Secretory Proprotein Convertases to Regulate Infectivity and Spread?

by Nabil G. Seidah, Antonella Pasquato and Ursula Andréo

Viruses 2021, 13(7), 1229; https://0-doi-org.brum.beds.ac.uk/10.3390/v13071229 - 25 Jun 2021

Cited by 17 | Viewed by 3614

Abstract

Inhibition of the binding of enveloped viruses surface glycoproteins to host cell receptor(s) is a major target of vaccines and constitutes an efficient strategy to block viral entry and infection of various host cells and tissues. Cellular entry usually requires the fusion of the viral envelope with host plasma membranes. Such entry mechanism is often preceded by “priming” and/or “activation” steps requiring limited proteolysis of the viral surface glycoprotein to expose a fusogenic domain for efficient membrane juxtapositions. The 9-membered family of Proprotein Convertases related to Subtilisin/Kexin (PCSK) serine proteases (PC1, PC2, Furin, PC4, PC5, PACE4, PC7, SKI-1/S1P, and PCSK9) participate in post-translational cleavages and/or regulation of multiple secretory proteins. The type-I membrane-bound Furin and SKI-1/S1P are the major convertases responsible for the processing of surface glycoproteins of enveloped viruses. Stefan Kunz has considerably contributed to define the role of SKI-1/S1P in the activation of arenaviruses causing hemorrhagic fever. Furin was recently implicated in the activation of the spike S-protein of SARS-CoV-2 and Furin-inhibitors are being tested as antivirals in COVID-19. Other members of the PCSK-family are also implicated in some viral infections, such as PCSK9 in Dengue. Herein, we summarize the various functions of the PCSKs and present arguments whereby their inhibition could represent a powerful arsenal to limit viral infections causing the present and future pandemics. Full article

(This article belongs to the Special Issue In Memory of Stefan Kunz)

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15 pages, 3766 KiB

Open AccessArticle

Screening and Identification of Lujo Virus Inhibitors Using a Recombinant Reporter Virus Platform

by Stephen R. Welch, Jessica R. Spengler, Sarah C. Genzer, Payel Chatterjee, Mike Flint, Éric Bergeron, Joel M. Montgomery, Stuart T. Nichol, César G. Albariño and Christina F. Spiropoulou

Viruses 2021, 13(7), 1255; https://0-doi-org.brum.beds.ac.uk/10.3390/v13071255 - 28 Jun 2021

Cited by 6 | Viewed by 2708

Abstract

Lujo virus (LUJV), a highly pathogenic arenavirus, was first identified in 2008 in Zambia. To aid the identification of effective therapeutics for LUJV, we developed a recombinant reporter virus system, confirming reporter LUJV comparability with wild-type virus and its utility in high-throughput antiviral screening assays. Using this system, we evaluated compounds with known and unknown efficacy against related arenaviruses, with the aim of identifying LUJV-specific and potential new pan-arenavirus antivirals. We identified six compounds demonstrating robust anti-LUJV activity, including several compounds with previously reported activity against other arenaviruses. These data provide critical evidence for developing broad-spectrum antivirals against high-consequence arenaviruses. Full article

(This article belongs to the Special Issue In Memory of Stefan Kunz)

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13 pages, 3211 KiB

Open AccessReview

Viral Control of Glioblastoma

by Nicole Mihelson and Dorian B. McGavern

Viruses 2021, 13(7), 1264; https://0-doi-org.brum.beds.ac.uk/10.3390/v13071264 - 29 Jun 2021

Cited by 8 | Viewed by 2842

Abstract

Glioblastoma multiforme (GBM) is a universally lethal cancer of the central nervous system. Patients with GBM have a median survival of 14 months and a 5-year survival of less than 5%, a grim statistic that has remained unchanged over the last 50 years. GBM is intransigent for a variety of reasons. The immune system has a difficult time mounting a response against glioblastomas because they reside in the brain (an immunologically dampened compartment) and generate few neoantigens relative to other cancers. Glioblastomas inhabit the brain like sand in the grass and display a high degree of intra- and inter-tumoral heterogeneity, impeding efforts to therapeutically target a single pathway. Of all potential therapeutic strategies to date, virotherapy offers the greatest chance of counteracting each of the obstacles mounted by GBM. Virotherapy can xenogenize a tumor that is deft at behaving like “self”, triggering adaptive immune recognition in an otherwise immunologically quiet compartment. Viruses can also directly lyse tumor cells, creating damage and further stimulating secondary immune reactions that are detrimental to tumor growth. In this review, we summarize the basic immune mechanisms underpinning GBM immune evasion and the recent successes achieved using virotherapies. Full article

(This article belongs to the Special Issue In Memory of Stefan Kunz)

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11 pages, 1689 KiB

Open AccessArticle

The Protein Kinase Receptor Modulates the Innate Immune Response against Tacaribe Virus

by Hector Moreno and Stefan Kunz

Viruses 2021, 13(7), 1313; https://0-doi-org.brum.beds.ac.uk/10.3390/v13071313 - 07 Jul 2021

Cited by 6 | Viewed by 2059

Abstract

The New World (NW) mammarenavirus group includes several zoonotic highly pathogenic viruses, such as Junin (JUNV) or Machupo (MACV). Contrary to the Old World mammarenavirus group, these viruses are not able to completely suppress the innate immune response and trigger a robust interferon (IFN)-I response via retinoic acid-inducible gene I (RIG-I). Nevertheless, pathogenic NW mammarenaviruses trigger a weaker IFN response than their nonpathogenic relatives do. RIG-I activation leads to upregulation of a plethora of IFN-stimulated genes (ISGs), which exert a characteristic antiviral effect either as lone effectors, or resulting from the combination with other ISGs or cellular factors. The dsRNA sensor protein kinase receptor (PKR) is an ISG that plays a pivotal role in the control of the mammarenavirus infection. In addition to its well-known protein synthesis inhibition, PKR further modulates the overall IFN-I response against different viruses, including mammarenaviruses. For this study, we employed Tacaribe virus (TCRV), the closest relative of the human pathogenic JUNV. Our findings indicate that PKR does not only increase IFN-I expression against TCRV infection, but also affects the kinetic expression and the extent of induction of Mx1 and ISG15 at both levels, mRNA and protein expression. Moreover, TCRV fails to suppress the effect of activated PKR, resulting in the inhibition of a viral titer. Here, we provide original evidence of the specific immunomodulatory role of PKR over selected ISGs, altering the dynamic of the innate immune response course against TCRV. The mechanisms for innate immune evasion are key for the emergence and adaptation of human pathogenic arenaviruses, and highly pathogenic mammarenaviruses, such as JUNV or MACV, trigger a weaker IFN response than nonpathogenic mammarenaviruses. Within the innate immune response context, PKR plays an important role in sensing and restricting the infection of TCRV virus. Although the mechanism of PKR for protein synthesis inhibition is well described, its immunomodulatory role is less understood. Our present findings further characterize the innate immune response in the absence of PKR, unveiling the role of PKR in defining the ISG profile after viral infection. Moreover, TCRV fails to suppress activated PKR, resulting in viral progeny production inhibition. Full article

(This article belongs to the Special Issue In Memory of Stefan Kunz)

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17 pages, 2157 KiB

Open AccessReview

The Interplay between Bluetongue Virus Infections and Adaptive Immunity

by Daniel Rodríguez-Martín, Andrés Louloudes-Lázaro, Miguel Avia, Verónica Martín, José M. Rojas and Noemí Sevilla

Viruses 2021, 13(8), 1511; https://0-doi-org.brum.beds.ac.uk/10.3390/v13081511 - 31 Jul 2021

Cited by 9 | Viewed by 3391

Abstract

Viral infections have long provided a platform to understand the workings of immunity. For instance, great strides towards defining basic immunology concepts, such as MHC restriction of antigen presentation or T-cell memory development and maintenance, have been achieved thanks to the study of lymphocytic choriomeningitis virus (LCMV) infections. These studies have also shaped our understanding of antiviral immunity, and in particular T-cell responses. In the present review, we discuss how bluetongue virus (BTV), an economically important arbovirus from the Reoviridae family that affects ruminants, affects adaptive immunity in the natural hosts. During the initial stages of infection, BTV triggers leucopenia in the hosts. The host then mounts an adaptive immune response that controls the disease. In this work, we discuss how BTV triggers CD8⁺ T-cell expansion and neutralizing antibody responses, yet in some individuals viremia remains detectable after these adaptive immune mechanisms are active. We present some unpublished data showing that BTV infection also affects other T cell populations such as CD4⁺ T-cells or γδ T-cells, as well as B-cell numbers in the periphery. This review also discusses how BTV evades these adaptive immune mechanisms so that it can be transmitted back to the arthropod host. Understanding the interaction of BTV with immunity could ultimately define the correlates of protection with immune mechanisms that would improve our knowledge of ruminant immunology. Full article

(This article belongs to the Special Issue In Memory of Stefan Kunz)

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11 pages, 473 KiB

Open AccessArticle

The Origins and Future of Sentinel: An Early-Warning System for Pandemic Preemption and Response

by Yolanda Botti-Lodovico, Parvathy Nair, Dolo Nosamiefan, Matthew Stremlau, Stephen Schaffner, Sebastian V. Agignoae, John Oke Aiyepada, Fehintola V. Ajogbasile, George O. Akpede, Foday Alhasan, Kristian G. Andersen, Danny A. Asogun, Oladele Oluwafemi Ayodeji, Aida S. Badiane, Kayla Barnes, Matthew R. Bauer, Antoinette Bell-Kareem, Muoebonam Ekene Benard, Ebo Ohomoime Benevolence, Osiemi Blessing, Chloe K. Boehm, Matthew L. Boisen, Nell G. Bond, Luis M. Branco, Michael J. Butts, Amber Carter, Andres Colubri, Awa B. Deme, Katherine C. DeRuff, Younousse Diédhiou, Akhilomen Patience Edamhande, Siham Elhamoumi, Emily J. Engel, Philomena Eromon, Mosoka Fallah, Onikepe A. Folarin, Ben Fry, Robert Garry, Amy Gaye, Michael Gbakie, Sahr M. Gevao, Gabrielle Gionet, Adrianne Gladden-Young, Augustine Goba, Jules Francois Gomis, Anise N. Happi, Mary Houghton, Chikwe Ihekwuazu, Christopher Ojemiega Iruolagbe, Jonathan Jackson, Simbirie Jalloh, Jeremy Johnson, Lansana Kanneh, Adeyemi Kayode, Molly Kemball, Ojide Chiedozie Kingsley, Veronica Koroma, Dylan Kotliar, Samar Mehta, Hayden C. Metsky, Airende Michael, Marzieh Ezzaty Mirhashemi, Kayvon Modjarrad, Mambu Momoh, Cameron A. Myhrvold, Okonofua Grace Naregose, Tolla Ndiaye, Mouhamadou Ndiaye, Aliou Ndiaye, Erica Normandin, Ikponmwosa Odia, Judith Uche Oguzie, Sylvanus A. Okogbenin, Peter O. Okokhere, Johnson Okolie, Idowu B. Olawoye, Testimony J. Olumade, Paul E. Oluniyi, Omigie Omoregie, Daniel J. Park, Mariétou Faye Paye, Brittany Petros, Anthony A. Philippakis, Abechi Priscilla, Alan Ricks, Anne Rimoin, John Demby Sandi, John S. Schieffelin, Monica Schreiber, Mame Cheikh Seck, Sameed Siddiqui, Katherine Siddle, Allison R. Smither, Mouhamad Sy, Ngayo Sy, Christopher H. Tomkins-Tinch, Oyewale Tomori, Chinedu Ugwu, Jessica N. Uwanibe, Eghosasere Anthonia Uyigue, Dada Ireti Victoria, Anika Vinzé, Megan E. Vodzak, Nicole Welch, Haja Isatta Wurie, Daba Zoumarou, Donald S. Grant, Daouda Ndiaye, Bronwyn MacInnis, Pardis C. Sabeti and Christian Happi Show full author list Hide full author list

Viruses 2021, 13(8), 1605; https://0-doi-org.brum.beds.ac.uk/10.3390/v13081605 - 13 Aug 2021

Cited by 5 | Viewed by 5762

Abstract

While investigating a signal of adaptive evolution in humans at the gene LARGE, we encountered an intriguing finding by Dr. Stefan Kunz that the gene plays a critical role in Lassa virus binding and entry. This led us to pursue field work to test our hypothesis that natural selection acting on LARGE—detected in the Yoruba population of Nigeria—conferred resistance to Lassa Fever in some West African populations. As we delved further, we conjectured that the “emerging” nature of recently discovered diseases like Lassa fever is related to a newfound capacity for detection, rather than a novel viral presence, and that humans have in fact been exposed to the viruses that cause such diseases for much longer than previously suspected. Dr. Stefan Kunz’s critical efforts not only laid the groundwork for this discovery, but also inspired and catalyzed a series of events that birthed Sentinel, an ambitious and large-scale pandemic prevention effort in West Africa. Sentinel aims to detect and characterize deadly pathogens before they spread across the globe, through implementation of its three fundamental pillars: Detect, Connect, and Empower. More specifically, Sentinel is designed to detect known and novel infections rapidly, connect and share information in real time to identify emerging threats, and empower the public health community to improve pandemic preparedness and response anywhere in the world. We are proud to dedicate this work to Stefan Kunz, and eagerly invite new collaborators, experts, and others to join us in our efforts. Full article

(This article belongs to the Special Issue In Memory of Stefan Kunz)

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7 pages, 1060 KiB

Open AccessReview

Lassa Fever Virus Binds Matriglycan—A Polymer of Alternating Xylose and Glucuronate—On α-Dystroglycan

by Soumya Joseph and Kevin P. Campbell

Viruses 2021, 13(9), 1679; https://0-doi-org.brum.beds.ac.uk/10.3390/v13091679 - 25 Aug 2021

Cited by 6 | Viewed by 2984

Abstract

Lassa fever virus (LASV) can cause life-threatening hemorrhagic fevers for which there are currently no vaccines or targeted treatments. The late Prof. Stefan Kunz, along with others, showed that the high-affinity host receptor for LASV, and other Old World and clade-C New World mammarenaviruses, is matriglycan—a linear repeating disaccharide of alternating xylose and glucuronic acid that is polymerized uniquely on α-dystroglycan by like-acetylglucosaminyltransferase-1 (LARGE1). Although α-dystroglycan is ubiquitously expressed, LASV preferentially infects vascular endothelia and professional phagocytic cells, which suggests that viral entry requires additional cell-specific factors. In this review, we highlight the work of Stefan Kunz detailing the molecular mechanism of LASV binding and discuss the requirements of receptors, such as tyrosine kinases, for internalization through apoptotic mimicry. Full article

(This article belongs to the Special Issue In Memory of Stefan Kunz)

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19 pages, 635 KiB

Open AccessReview

Type I Interferon Induction and Exhaustion during Viral Infection: Plasmacytoid Dendritic Cells and Emerging COVID-19 Findings

by Trever T. Greene and Elina I. Zuniga

Viruses 2021, 13(9), 1839; https://0-doi-org.brum.beds.ac.uk/10.3390/v13091839 - 15 Sep 2021

Cited by 22 | Viewed by 4104

Abstract

Type I Interferons (IFN-I) are a family of potent antiviral cytokines that act through the direct restriction of viral replication and by enhancing antiviral immunity. However, these powerful cytokines are a caged lion, as excessive and sustained IFN-I production can drive immunopathology during infection, and aberrant IFN-I production is a feature of several types of autoimmunity. As specialized producers of IFN-I plasmacytoid (p), dendritic cells (DCs) can secrete superb quantities and a wide breadth of IFN-I isoforms immediately after infection or stimulation, and are the focus of this review. Notably, a few days after viral infection pDCs tune down their capacity for IFN-I production, producing less cytokines in response to both the ongoing infection and unrelated secondary stimulations. This process, hereby referred to as “pDC exhaustion”, favors viral persistence and associates with reduced innate responses and increased susceptibility to secondary opportunistic infections. On the other hand, pDC exhaustion may be a compromise to avoid IFN-I driven immunopathology. In this review we reflect on the mechanisms that initially induce IFN-I and subsequently silence their production by pDCs during a viral infection. While these processes have been long studied across numerous viral infection models, the 2019 coronavirus disease (COVID-19) pandemic has brought their discussion back to the fore, and so we also discuss emerging results related to pDC-IFN-I production in the context of COVID-19. Full article

(This article belongs to the Special Issue In Memory of Stefan Kunz)

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