MHC class II transactivator CIITA induces cell resistance to Ebola virus and SARS-like coronaviruses

Anna Bruchez; Ky Sha; Joshua Johnson; Li Chen; Caroline Stefani; Hannah McConnell; Lea Gaucherand; Rachel Prins; Kenneth A Matreyek; Adam J Hume; Elke Mühlberger; Emmett V Schmidt; Gene G Olinger; Lynda M Stuart; Adam Lacy-Hulbert

doi:10.1126/science.abb3753

MHC class II transactivator CIITA induces cell resistance to Ebola virus and SARS-like coronaviruses

Science. 2020 Oct 9;370(6513):241-247. doi: 10.1126/science.abb3753. Epub 2020 Aug 27.

Authors

Anna Bruchez^#¹, Ky Sha^#¹, Joshua Johnson², Li Chen³, Caroline Stefani¹, Hannah McConnell¹, Lea Gaucherand¹, Rachel Prins¹, Kenneth A Matreyek⁴, Adam J Hume^{5

6}, Elke Mühlberger^{5

6}, Emmett V Schmidt⁷, Gene G Olinger^{2

5

6

8}, Lynda M Stuart^{1

9}, Adam Lacy-Hulbert^{10

11}

Affiliations

¹ Benaroya Research Institute, Seattle, WA 98101, USA.
² National Institute of Allergy and Infectious Diseases (NIAID) Integrated Research Facility, Frederick, MD 21702, USA.
³ Massachusetts General Hospital, Boston, MA 02114, USA.
⁴ Department of Genome Sciences, University of Washington, Seattle, WA 98109, USA.
⁵ Boston University School of Medicine, Boston, MA 02118, USA.
⁶ National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA 02118, USA.
⁷ Merck and Co., Inc, Kenilworth, NJ 07033, USA.
⁸ MRIGlobal, Gaithersburg, MD 20878, USA.
⁹ Bill and Melinda Gates Foundation, Seattle, WA 98109, USA.
¹⁰ Benaroya Research Institute, Seattle, WA 98101, USA. alacyhulbert@benaroyaresearch.org.
¹¹ Department of Immunology, University of Washington, Seattle, WA 98109, USA.

^# Contributed equally.

Abstract

Recent outbreaks of Ebola virus (EBOV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have exposed our limited therapeutic options for such diseases and our poor understanding of the cellular mechanisms that block viral infections. Using a transposon-mediated gene-activation screen in human cells, we identify that the major histocompatibility complex (MHC) class II transactivator (CIITA) has antiviral activity against EBOV. CIITA induces resistance by activating expression of the p41 isoform of invariant chain CD74, which inhibits viral entry by blocking cathepsin-mediated processing of the Ebola glycoprotein. We further show that CD74 p41 can block the endosomal entry pathway of coronaviruses, including SARS-CoV-2. These data therefore implicate CIITA and CD74 in host defense against a range of viruses, and they identify an additional function of these proteins beyond their canonical roles in antigen presentation.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Antigens, Differentiation, B-Lymphocyte / genetics
Antigens, Differentiation, B-Lymphocyte / physiology*
Betacoronavirus / physiology*
COVID-19
Cell Line, Tumor
Coronavirus Infections / immunology*
Coronavirus Infections / virology
DNA Transposable Elements
Ebolavirus / physiology*
Endosomes / virology
Genetic Testing
Hemorrhagic Fever, Ebola / immunology*
Hemorrhagic Fever, Ebola / virology
Histocompatibility Antigens Class II / genetics
Histocompatibility Antigens Class II / physiology*
Host-Pathogen Interactions / genetics
Host-Pathogen Interactions / immunology*
Humans
Nuclear Proteins / genetics
Nuclear Proteins / physiology*
Pandemics
Pneumonia, Viral / immunology*
Pneumonia, Viral / virology
SARS-CoV-2
Trans-Activators / genetics
Trans-Activators / physiology*
Transcription, Genetic
Virus Internalization*

Substances

Antigens, Differentiation, B-Lymphocyte
DNA Transposable Elements
Histocompatibility Antigens Class II
MHC class II transactivator protein
Nuclear Proteins
Trans-Activators
invariant chain

Abstract

Publication types

MeSH terms

Substances

Grants and funding