ABSTRACT
COVID-19 is a highly contagious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The case-fatality rate is significantly higher in older patients and those with diabetes, cancer or cardiovascular disorders. The human proteins, angiotensin-converting enzyme 2 (ACE2), transmembrane protease serine 2 (TMPRSS2) and basigin (BSG), are involved in high-confidence host-pathogen interactions with SARS-CoV-2 proteins. We considered these three proteins as seed nodes and applied the random walk with restart method on the human interactome to construct a protein-protein interaction sub-network, which captures the effects of viral invasion. We found that 'Insulin resistance', 'AGE-RAGE signaling in diabetic complications' and 'adipocytokine signaling' were the common pathways associated with diabetes, cancer and cardiovascular disorders. The association of these critical pathways with aging and its related diseases explains the molecular basis of COVID-19 fatality. We further identified drugs that have effects on these proteins/pathways based on gene expression studies. We particularly focused on drugs that significantly downregulate ACE2 along with other critical proteins identified by the network-based approach. Among them, COL-3 had earlier shown activity against acute lung injury and acute respiratory distress, while entinostat and mocetinostat have been investigated for non-small-cell lung cancer. We propose that these drugs can be repurposed for COVID-19.
Subject(s)
COVID-19/mortality , SARS-CoV-2 , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/genetics , Antiviral Agents/therapeutic use , COVID-19/epidemiology , COVID-19/therapy , Cardiovascular Diseases/epidemiology , Comorbidity , Computational Biology , Drug Repositioning , Gastrointestinal Diseases/epidemiology , Gene Expression Profiling/statistics & numerical data , Host Microbial Interactions/drug effects , Host Microbial Interactions/genetics , Host Microbial Interactions/physiology , Humans , Pandemics , Protein Interaction Maps/drug effects , Respiratory Tract Diseases/epidemiology , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity , SARS-CoV-2/physiology , COVID-19 Drug TreatmentABSTRACT
Coronavirus disease 2019 is a global pandemic, and to deal with the unexpected, enormous burden on healthcare system, liver transplantation (LT) services have been suspended in many centers. Development of robust and successful protocols in preventing the disease among the recipients, donors and healthcare workers would help in re-starting the LT programs. We adapted a protocol at our center, which is predominantly a living donor liver transplant center based in north India, and continued the service as the pandemic unfolded and peaked in India with good results and shared the experience of the same. Between March 24 and June 7, 2020, during the government-enforced public curfew-"lockdown"-7 children received LT. The protocols of infection control were drafted in our team by local customization of published guidelines. The number of pediatric LT done during the lockdown period in 2020 was similar to that done in corresponding pre-COVID period in 2019. The outcomes were of 100% survival, and none of recipients developed COVID. One potential donor was asymptomatic positive for COVID, responded well to conservative treatment, and was later accepted as a donor. LT program during the COVID pandemic can successfully function after putting in place standard protocols for infection control. These can be implemented with minimal extra involvement of healthcare infrastructure, hence without diversion of resources from COVID management. In conclusion, pediatric liver transplantation services can be continued amid COVID-19 pandemic after establishing a properly observed protocol with minimum additional resources.