EV-VIRUS

Physical and chemical characteristics of many EVs, as well as their biogenesis pathways, resemble those of retroviruses. Moreover, EVs generated by virus-infected cells can incorporate viral proteins and fragments of viral RNA.
EVs, depending on the proteins and genetic material incorporated in them, play a significant role in viral infection, both facilitating and suppressing it. Deciphering the mechanisms of EV-cell interactions may facilitate the design of EVs that inhibit viral infection.

PNAS August 16, 2016 113 (33) 9155-9161; first published July 18, 2016 https://doi.org/10.1073/pnas.1605146113

TOPIC 1. VIRUSES USE EVs TO SPREAD DISEASE AND TO MODULATE HOST RESPONCES

1. Epstein-Barr virus noncoding RNAs from the extracellular vesicles of nasopharyngeal carcinoma (NPC) cells promote angiogenesis via TLR3/RIG-I-mediated VCAM-1 expression.

Biochim Biophys Acta Mol Basis Dis. 2019 Jun 1;1865(6):1201-1213.

https://doi.org/10.1016/j.bbadis.2019.01.015 

2. HPV DNA Associates With Breast Cancer Malignancy and It Is Transferred to Breast Cancer Stromal Cells by Extracellular Vesicles.

De Carolis S, et al. Front Oncol. 2019.

This paper shows how EB virus induces a distant modulation of angiogenesis trough lncRNAs coded by itself and vehicled trough EVs.

3. Extracellular Vesicles Deliver Host and Virus RNA and Regulate Innate Immune Response. Int J Mol Sci. 2017 Mar 20;18(3)

DOI: 10.3390/ijms18030666 

Kouwaki et al. Review the mechanisms by which Hepatitis-B virus utilizes the EVs and host microRNAs to counteract the antiviral innate immune response

TOPIC 3. SARS-CoV-2 ENTRY RECEPTORS AND SIALYLATION  

1. The level of sialylation of ACE2 is key for the SARS-CoV and SARS-CoV2 entry

WANG et al., 2020 - https://doi.org/10.1038/s41422-020-0282-0; Vincent et al., 2005 - doi:10.1186/1743-422X-2-69


2. Cell-surface sialoglycoconjugates can serve as MERS-CoV attachment factors, as pretreatment of human mucin with sialidase completely inhibited binding by MERS-CoV S1A and IAV HA
Li et al., 2017 - www.pnas.org/cgi/doi/10.1073/pnas.1712592114

3. NH4Cl and chloroquine both impaired the terminal glycosylation (sialylation) of ACE2
Vincent et al., 2005 - doi:10.1186/1743-422X-2-69

4. Hydroxychloroquine is currently under investigation in clinical trials for pre-exposure or post-exposure prophylaxis of SARS-CoV-2 infection, and treatment of patients with mild, moderate, and severe COVID-19
(https://clinicaltrials.gov/ct2/results?cond=covid&term=chloroquine&cntry=&state=&city=&dist=; Liu et al., 2020 - https://doi.org/10.1038/s41421-020-0156-0

TOPIC 2. AN ANTI-VIRAL EFFECT OF EVS AND SUGGESTION FOR POSSIBLE THERAPEUTIC STRATEGY BASED ON THIS APPROACH.

1. Extracellular vesicles from symbiotic vaginal lactobacilli inhibit HIV-1 infection of human tissues

Nat Commun. 2019; 10: 5656.

Published online 2019 Dec 11. doi: 10.1038/s41467-019-13468-9

Palomino et al. hypothesize that EVs released by lactobacilli contribute to the symbiotic vaginal lactobacilli -mediated protection of vaginal viral infection. This protection is mediated, in part, by inhibition of viral attachment and entry to target cells due to diminished exposure of Env on EV-treated HIV-1 virions Furthermore, using proteomic and metabolomic analysis, they identify several EV-associated bacterial proteins and metabolites that may play a role in this protective effect against HIV-1 infection.

2. Monocyte-derived exosomes upon exposure to cigarette smoke condensate alter their characteristics and show protective effect against cytotoxicity and HIV-1 replication

Sci Rep. 2017; 7: 16120.

Published online 2017 Nov 23. doi: 10.1038/s41598-017-16301-9

The progression of smoking-associated diseases is more rapid in HIV-1 infected than in uninfected smokers.. Furthermore, several reports also support that smoking enhances HIV-1 infectivity, replication, and its progression to AIDS. Exosomes from lymphocytic and monocytic cells are shown to contain miRNA, viral transactivators, and cytokines that affect the course of HIV-1 infection.
Haque et al. investigate examine how exosomes from monocytes communicate with the neighboring HIV-1 infected and uninfected cells to protect smoking-mediated cellular toxicity and viral replication in HIV-1 infected macrophages.

3. Monocyte-derived exosomes upon exposure to cigarette smoke condensate alter their characteristics and show protective effect against cytotoxicity and HIV-1 replication.

Antiviral Res. 2016 Oct; 134: 167–171.

Published online 2016 Aug 3. doi: 10.1016/j.antiviral.2016.07.013

In an early work, this group had showed that TLR3 signalling of human brain microvascular endothelial cells (HBMECs) could produce the antiviral factors that inhibit HIV replication in macrophages. The present study examine whether exosomes from TLR3-activated HBMECs mediate the intercellular transfer of antiviral factors to macrophages. HBMECs-derived exosomes contained multiple antiviral factors, and their depletion from TLR3-activated HBMECs culture supernatant diminished HBMECs-mediated anti-HIV activity in macrophages. In conclusion, they demonstrate that exosomes shed by HBMECs are able to transport the antiviral molecules to macrophages. This finding suggests the possibility that HIV nonpermissive BBB cells (HBMECs) can help to restore the antiviral state in HIV-infected macrophages, which may be a defense mechanism against HIV neuroinvasion.

TOPIC 4. SIALYLATION, PULMONARY FRIBROSIS AND EXTRACELLULAR VESICLES

1. Excessive exosome release is the pathogenic pathway linking a lysosomal deficiency to generalized fibrosis

the pathogenic process leading to the fibrotic disease in the sialidosis mice, lacking NEU1 expression, is initiated and perpetuated by the relentless, excessive extracellular vesicle release of NEU1-deficient myofibroblasts. NEU1 is down-regulated in a cohort of human idiopathic pulmonary fibrosis IPF fibroblasts, suggesting a role for NEU1 deficiency/down-regulation in causing or hastening the course of a fibrotic disease in the adult human population

van de Vlekkert et al., 2019 - doi: 10.1126/sciadv.aav3270

2. The role of epidermal growth factor receptor (EGFR) signaling in SARS coronavirus-induced pulmonary fibrosis.

Although pulmonary fibrotic changes are occasionally observed as sequelae of other respiratory viral infections, they appear to be more common following SARS coronavirus (SARS-CoV) infection

Venkataraman and Frieman 2017 https://doi.org/10.1016/j.antiviral.2017.03.022

Clinical Trial using mSC-Exo for COVID-19

The purpose of this single-arm design, open label, combined interventional clinical trial, therefore, is to explore the safety and efficiency of aerosol inhalation of the exosomes derived from allogenic adipose mesenchymal stem cells (MSCs-Exo) in the treatment of severe patients hospitalized with novel coronavirus pneumonia (NCP).

https://clinicaltrials.gov/ct2/show/NCT04276987