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The use of mesenchymal stromal cells in the treatment of coronavirus disease 2019.

ABSTRACT: More than seven months into the coronavirus disease -19 (COVID-19) pandemic, infection from the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to over 21.2 million cases and resulted in over 760,000 deaths worldwide so far. As a result, COVID-19 has changed all our lives as we battle to curtail the spread of the infection in the absence of specific therapies against coronaviruses and in anticipation of a proven safe and efficacious vaccine. Common with previous outbreaks of coronavirus infections, SARS and Middle East respiratory syndrome, COVID-19 can lead to acute respiratory distress syndrome (ARDS) that arises due to an imbalanced immune response. While several repurposed antiviral and host-response drugs are under examination as potential treatments, other novel therapeutics are also being explored to alleviate the effects on critically ill patients. The use of mesenchymal stromal cells (MSCs) for COVID-19 has become an attractive avenue down which almost 70 different clinical trial teams have ventured. Successfully trialled for the treatment of other conditions such as multiple sclerosis, osteoarthritis and graft versus host disease, MSCs possess both regenerative and immunomodulatory properties, the latter of which can be harnessed to reduce the severity and longevity of ARDS in patients under intensive care due to SARS-CoV-2 infection.

SUBMITTER: Canham MA

PROVIDER: S-EPMC7503434 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Medicines for the treatment of 2019-novel coronavirus (2019-nCoV) infections are urgently needed. However, drug screening using live 2019-nCoV requires high-level biosafety facilities, which imposes an obstacle for those institutions without such facilities or 2019-nCoV. This study aims to repurpose the clinically approved drugs for the treatment of coronavirus disease 2019 (COVID-19) in a 2019-nCoV-related coronavirus model. METHODS:A 2019-nCoV-related pangolin coronavirus GX_P2V/pangolin/2017/Guangxi was described. Whether GX_P2V uses angiotensin-converting enzyme 2 (ACE2) as the cell receptor was investigated by using small interfering RNA (siRNA)-mediated silencing of ACE2. The pangolin coronavirus model was used to identify drug candidates for treating 2019-nCoV infection. Two libraries of 2406 clinically approved drugs were screened for their ability to inhibit cytopathic effects on Vero E6 cells by GX_P2V infection. The anti-viral activities and anti-viral mechanisms of potential drugs were further investigated. Viral yields of RNAs and infectious particles were quantified by quantitative real-time polymerase chain reaction (qRT-PCR) and plaque assay, respectively. RESULTS:The spike protein of coronavirus GX_P2V shares 92.2% amino acid identity with that of 2019-nCoV isolate Wuhan-hu-1, and uses ACE2 as the receptor for infection just like 2019-nCoV. Three drugs, including cepharanthine (CEP), selamectin, and mefloquine hydrochloride, exhibited complete inhibition of cytopathic effects in cell culture at 10 ?mol/L. CEP demonstrated the most potent inhibition of GX_P2V infection, with a concentration for 50% of maximal effect [EC50] of 0.98 ?mol/L. The viral RNA yield in cells treated with 10 ?mol/L CEP was 15,393-fold lower than in cells without CEP treatment ([6.48?±?0.02]?×?10vs. 1.00?±?0.12, t?=?150.38, P?<?0.001) at 72 h post-infection (p.i.). Plaque assays found no production of live viruses in media containing 10 ?mol/L CEP at 48 h p.i. Furthermore, we found CEP had potent anti-viral activities against both viral entry (0.46?±?0.12, vs.1.00?±?0.37, t?=?2.42, P?<?0.05) and viral replication ([6.18?±?0.95]?×?10vs. 1.00?±?0.43, t?=?3.98, P?<?0.05). CONCLUSIONS:Our pangolin coronavirus GX_P2V is a workable model for 2019-nCoV research. CEP, selamectin, and mefloquine hydrochloride are potential drugs for treating 2019-nCoV infection. Our results strongly suggest that CEP is a wide-spectrum inhibitor of pan-betacoronavirus, and further study of CEP for treatment of 2019-nCoV infection is warranted.

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The use of mesenchymal stromal cells in the treatment of coronavirus disease 2019.

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