SARS-CoV-2: Understanding the Transcriptional Regulation of ACE2 and TMPRSS2 and the Role of Single Nucleotide Polymorphism (SNP) at Codon 72 of p53 in the Innate Immune Response against Virus Infection

Abstract

Human ACE2 and the serine protease TMPRSS2 of novel SARS-CoV-2 are primary entry receptors in host cells. Expression of these genes at the transcriptional level has not been much discussed in detail. The ISRE elements of the ACE2 promoter are a binding site for the ISGF3 complex of the JAK/STAT signaling pathway. TMPRSS2, including IFNβ, STAT1, and STAT2, has the PARP1 binding site near to TSS either up or downstream promoter region. It is well documented that PARP1 regulates gene expression at the transcription level. Therefore, to curb virus infection, both promoting type I IFN signaling to boost innate immunity and prevention of virus entry by inhibiting PARP1, ACE2 or TMPRSS2 are safe options. Most importantly, our aim is to attract the attention of the global scientific community towards the codon 72 Single Nucleotide Polymorphism (SNP) of p53 and its underneath role in the innate immune response against SARS-CoV-2. Here, we discuss codon 72 SNP of human p53′s role in the different innate immune response to restrict virus-mediated mortality rate only in specific parts of the world. In addition, we discuss potential targets and emerging therapies using bioengineered bacteriophage, anti-sense, or CRISPR strategies.

Ibuprofen, Flurbiprofen, Etoricoxib or Paracetamol Do Not Influence ACE2 Expression and Activity In Vitro or in Mice and Do Not Exacerbate In-Vitro SARS-CoV-2 Infection

“…TMPRSS2 has a poly(ADP-ribose) polymerase 1 (PARP1) binding site near to the promoter region. Since PARP1 regulates gene expression at the transcription level, Lodhi et al speculated that virus entry can be blocked by inhibiting PARP1 [25]. It is possible that PARP1 reactivates the transcription of TMPRSS2 during viral infection [26].…”

p53/NF-kB Balance in SARS-CoV-2 Infection: From OMICs, Genomics and Pharmacogenomics Insights to Tailored Therapeutic Perspectives (COVIDomics)

“…These studies have shown that genes related to immune and apoptosis-related functions were deregulated, and further analysis revealed that p53 signaling was one of the most enriched pathway upon SARS-CoV-2 infection. Moreover, additional studies emphasized the role of single nucleotide polymorphism (SNP) of p53 on host immune response against the virus as a potential predictor of the outcome in SARS-CoV-2 infected patients ( Lodhi et al, 2021 ).…”

“…Recent studies ascribed to the P72-allele a significantly enhanced response to inflammatory stimuli compared to R72-allele, and studies in knock-in humanized p53 mice showed altered degree of NF-kB-dependent apoptosis in P72 or R72 mice ( Azzam et al, 2011 ). In addition, P72 and R72 alleles show a dramatically different response to the innate immunity stress also against SARS-CoV-2 infection ( Leu et al, 2013 ; Lodhi et al, 2021 ). Interestingly, these differences are regulated by NF-kB target genes that are better activated by the P72 variant accounting for intriguing personalized feedbacks in the different populations ( Frank et al, 2011 ).…”

Network Pharmacology and Comparative Transcriptome Reveals Biotargets and Mechanisms of Curcumol Treating Lung Adenocarcinoma Patients With COVID-19

“…These seven targets, namely, CCNB1, CCNB2, CCNE1, CCNE2, AURKA, CDK1, and TTK, have been reported to play critical roles in the carcinogenesis and development of LUAD. These targets mediate signaling pathways, such as PI3K/AKT and p53, that are associated with the Warburg effect, which supports SARS-CoV-2 replication and inflammatory response ( 30 , 31 ). Four cyclin family members (CCNB1, CCNB2, CCNE1, and CCNE2) were identified as core targets in our analysis.…”