key: cord-0849282-117impah
authors: Butowt, Rafal; Pyrc, Krzysztof; von Bartheld, Christopher S.
title: Battle at the entrance gate: CIITA as a weapon to prevent the internalization of SARS-CoV-2 and Ebola viruses
date: 2020-11-24
journal: Signal Transduct Target Ther
DOI: 10.1038/s41392-020-00405-2
sha: c4f3edec2772ecdd763cc55a76c97a1f1488e726
doc_id: 849282
cord_uid: 117impah

nan

The findings by Bruchez et al. also suggest that genetic manipulation and/or novel drugs manipulating the levels of CIITA and CD74p41 could be more effective than direct chemical inhibitors of cathepsin such as teicoplanin derivatives, but with less toxicity.

Bruchez et al. report the accumulation of the pseudotyped Ebola virus in multivesicular bodies (MVBs) in vitro. MVBs are intermediate endosomal compartments, which may fuse with lysosomes for degradation but may also release exosomes. This suggests that pseudotyped Ebola virus in MVBs, and possibly also SARS-CoV-2, may be released to the extracellular environment. Thus, MVBs may contribute to the intercellular transfer of SARS-CoV-2 independent of angiotensin convertase enzyme 2 (ACE2), the SARS-CoV entry protein (Fig. 1 ). This may have important implications for some tissues, including the brain, where low ACE2 levels are present, but intercellular virus transfer was documented postmortem. Whether the action of cathepsins on CoVs and Ebola virus surface glycoproteins occurs in late endosomes, in MVBs, or exclusively in lysosomes requires further investigation. Cathepsins were shown to be present not only in lysosomes but also in late endosomes, and the activation of viral spike protein by cathepsins likely takes place in this compartment (Fig. 1) .

But how can therapies be implemented when the virus has already infected cells and is replicating? The brain typically shows delayed neurological symptoms because it is not an immediate target of SARS-CoV-2 infection. The findings of Bruchez et al. may be particularly important for brain infection where microglia, the brain's innate immune cells (similar to peripheral blood monocytes and macrophages), express the ACE2 SARS-CoV-2 receptors as well as the CIITA transcription factor, according to large-scale transcriptomic data. Some macrophages in the periphery, e.g., in the alveoli, are infected by SARS-CoV-2, and this contributes to the lung damage. Proinflammatory IFN/cytokine stimulation may increase levels of CIITA in the microglia, thereby protecting these cells from infection with SARS-CoV-2. Once microglial cells become infected, immediate neuronal damage can be expected, emphasizing the need for protection of these cells. Moreover, TMPRSS2 protease, which was shown to be the key player in the lungs and is the main SARS-CoV-2 spike protein priming enzyme, is not or only minimally expressed in the adult brain. It remains to be determined whether other cell surface proteases are able to carry out this process-triggering the virus fusion on the cell surface, or whether the cathepsin levels in the brain are sufficient to mediate endosomal entry. Depending on the outcome, therapeutic strategies aimed to increase CIITA and/or CD74p41 may be particularly suitable to reduce brain damage and to prevent long-term neurological symptoms observed in COVID-19.

We must emphasize that any therapeutic strategy designed for the current COVID-19 pandemic may have side effects. Some antiviral strategies to inhibit viral entry based on LY6E protein (Fig. 1 ) may protect from one group of viruses such as CoVs and Ebola virus, but may facilitate cell entrance and infection by other virus types such as flaviviruses or influenza A virus. 2 This potential double-edged nature of antiviral therapies must be considered in future approaches targeting the CIITA/CD74p41 pathway. Furthermore, antiviral effects need to be confirmed in additional cell lines in vitro, and many antivirals have failed to be effective in human trials. Mutational changes in the SARS-CoV-2 genome, such as the D614G alteration, may reflect an adaptive virus response to these cellular mechanisms. It was shown in recent studies that the D614G mutation in the spike protein increases the efficiency of SARS-CoV-2 cell entry and infection rate in vitro and in vivo, 5 which may counteract the above described cellular strategies.

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons. org/licenses/by/4.0/. © The Author(s) 2020 Fig. 1 Interference of coronavirus invasion by preventing fusion of viral and host membranes in the endosomal pathway. The coronavirus (SARS-CoV) enters host cells by binding to ACE2 (1), followed by endocytosis (2) and cathepsin-mediated cleavage of the viral glycoproteins. Glycoprotein cleavage allows fusion of viral membranes with endosomal membranes (3) and release of viral RNA into the cytoplasm. CIITA (class II major histocompatibility complex transactivator) upregulates the CD74p41 isoform, which inhibits cathepsins and prevents genome release into the cytoplasm, instead redirecting the virus into a degradation pathway in multivesicular bodies (MVBs) or lysosomes (4). This mechanism aborts or reduces viral transcription/translation, assembly, and virus release (5-7, right side)

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

LY6E impairs coronavirus fusion and confers immune control of viral disease

Inhibiting Ebola virus and SARS-CoV-2 entry

Glycopeptide antibiotics potently inhibit Cathepsin L in the late endosome/lysosome and block the entry of Ebola virus, Middle East respiratory syndrome coronavirus (MERS-CoV), and severe acute respiratory syndrome coronavirus (SARS-CoV)

Chemosensory dysfunction in COVID-19: Integration of genetic and epidemiological data points to D614G spike protein variant as a contributing factor

ACKNOWLEDGEMENTS R.B. is supported by the "Excellence Initiative-Research University" program at the Nicolaus Copernicus University; K.P. is supported by the subsidy from the Polish Ministry of Science and Higher Education for the research on the SARS-CoV-2 and a grant from the National Science Center UMO-2017/27/B/NZ6/02488; and C.S.v.B. is supported by grant GM103554 from the National Institutes of Health.

R.B., K.P., and C.S.v.B. contributed to the writing of this paper.

Competing interests: The authors declare no competing interests.