Promising use of immune cell-derived exosomes in the treatment of SARS-CoV-2 infections

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is persistently threatening the lives of thousands of individuals globally. It triggers pulmonary oedema, driving to dyspnoea and lung failure. Viral infectivity of coronavirus disease 2019 (COVID-19) is a genuine challenge due to the mutagenic genome and mysterious immune-pathophysiology. Early reports highlighted that extracellular vesicles (exosomes, Exos) work to enhance COVID-19 progression by mediating viral transmission, replication and mutations. Furthermore, recent studies revealed that Exos derived from immune cells play an essential role in the promotion of immune cell exhaustion by transferring regulatory lncRNAs and miRNAs from exhausted cells to the active cells. Fortunately, there are great chances to modulate the immune functions of Exos towards a sustained repression of COVID-19. Engineered Exos hold promising immunotherapeutic opportunities for remodelling cytotoxic T cells' function. Immune cell-derived Exos may trigger a stable epigenetic repression of viral infectivity, restore functional cytokine-producing T cells and rebalance immune response in severe infections by inducing functional T regulatory cells (Tregs). This review introduces a view on the current outcomes of immunopathology, and immunotherapeutic applications of immune cell-derived Exos in COVID-19, besides new perspectives to develop novel patterns of engineered Exos triggering novel anti-SARS-CoV-2 immune responses.

Keywords: SARS-CoV-2; epigenetics; exhaustion; exosomes; immunotherapy.

FIGURE 1

Site of mutations and potential targeting by Exos. Schematic diagram presents the structure of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2)‐SPs, with a focus on mutation positions on the spike proteins (SPs). The S1 subunit is made up of two active parts: S1‐CTDcore, which screens and senses binding active sites; and S1‐CTDmotif, which binds the S1 domain to the active sites of angiotensin‐converting enzyme 2 (ACE2) on the host cell. The potential interaction of Exos with target sites on ACE2 receptors to prevent viral entry

FIGURE 2

Schematic diagram presents the role of Exos in severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) transmission. SARS‐CoV‐2 particles use furin to induce spike proteins (SPs) cleavage and bind the S1 subunit to the angiotensin‐converting enzyme 2 (ACE2) binding unit to mediate cell entry. SARS‐CoV‐2 begins to replicate after entry, utilizing ribosomes and endoplasmic reticulum to construct virus units. Exos cargo, which includes completed virus units, viral RNA polymerase and uncombined units, is released extracellularly and transmits cargo to healthy cells.

FIGURE 3

Schematic diagram describes the role of Th17 in Coronavirus disease 2019 (COVID‐19) and the immune modulation effects of Exos. Th17 cells are involved in the progression of COVID‐19 hyperinflammation through inducing repression of Th1 and Tregs. Engineered Exos mediate Th17 cell inhibition and thereby induce functional T effector cell responses and balance the function of active Tregs. Furthermore, Exos enriched with lncRNAs can efficiently induce targeting of virally infected cells by a reactivation of cytotoxic T cells.

FIGURE 4

A diagram depicts epigenetic changes in host cell receptors and viral RNA polymerase. The first section demonstrates that Exos enriched in EZH2 mediate chromatin methylation to reduce angiotensin‐converting enzyme 2 (ACE2) expression by activating H3K27me3. The second section demonstrates how Exos enriched in methyltransferase 3 mediate DNA methylation to inhibit ACE2 expression. The third section shows Exos enriched with RNA methyltransferase 3 to induce viral mRNA methylation, which inhibits viral RNA polymerase expression and thus prevents viral replication.