Association between HLA genotype and ferritin levels in COVID-19 infection: a study of a Saudi cohort.

BACKGROUND: An elevation in serum ferritin levels through an unknown mechanism was observed in COVID-19 infected patients. This study examined the association between patients' HLA genotype and serum ferritin level modulation and also assessed the effect of serum ferritin levels on infection severity/mortality. MATERIALS AND METHODS: One hundred and thirty-six COVID-19 Saudi patients were divided into two groups according to their ferritin levels: group 1 (<500 ng/mL, N = 67) and group 2 (>500 ng/mL, N = 69). HLA genotyping (class I and II) was carried out through the rPCR-SSO method. RESULTS: High serum ferritin levels were associated with a significant increase in infection severity, as 75% of ICU patients showed high levels of ferritin compared to 43% of patients with moderate symptoms, p = .002. This elevation indicated a gender skew in that 56% of the infected male patients displayed high ferritin levels compared to 36.6% of the female patients, p = .03. In terms of mortality, 74% of patients with fatal outcomes had a high level of serum ferritin compared to 47% of recovered patients, p = .039. There was a significant difference in the HLA frequency between the two groups, with a predominance of HLA-A*01 in the low-ferritin group (19.4 vs. 6.5%, p = .002, pc = .016) and predominance of C*03 in the high ferritin group (10.9 vs. 3%, p = .047, pc = .27). CONCLUSION: High serum ferritin levels are associated with an increase in COVID-19 severity, which may be affected by HLA polymorphism.

Scaffold Hopping of α-Rubromycin Enables Direct Access to FDA-Approved Cromoglicic Acid as a SARS-CoV-2 MPro Inhibitor.

The COVID-19 pandemic is still active around the globe despite the newly introduced vaccines. Hence, finding effective medications or repurposing available ones could offer great help during this serious situation. During our anti-COVID-19 investigation of microbial natural products (MNPs), we came across α-rubromycin, an antibiotic derived from Streptomyces collinus ATCC19743, which was able to suppress the catalytic activity (IC50 = 5.4 µM and Ki = 3.22 µM) of one of the viral key enzymes (i.e., MPro). However, it showed high cytotoxicity toward normal human fibroblasts (CC50 = 16.7 µM). To reduce the cytotoxicity of this microbial metabolite, we utilized a number of in silico tools (ensemble docking, molecular dynamics simulation, binding free energy calculation) to propose a novel scaffold having the main pharmacophoric features to inhibit MPro with better drug-like properties and reduced/minimal toxicity. Nevertheless, reaching this novel scaffold synthetically is a time-consuming process, particularly at this critical time. Instead, this scaffold was used as a template to explore similar molecules among the FDA-approved medications that share its main pharmacophoric features with the aid of pharmacophore-based virtual screening software. As a result, cromoglicic acid (aka cromolyn) was found to be the best hit, which, upon in vitro MPro testing, was 4.5 times more potent (IC50 = 1.1 µM and Ki = 0.68 µM) than α-rubromycin, with minimal cytotoxicity toward normal human fibroblasts (CC50 > 100 µM). This report highlights the potential of MNPs in providing unprecedented scaffolds with a wide range of therapeutic efficacy. It also revealed the importance of cheminformatics tools in speeding up the drug discovery process, which is extremely important in such a critical situation.

Association between the HLA genotype and the severity of COVID-19 infection among South Asians.

Regional variations are found in the incidence and severity of the COVID-19 infection. Human leukocyte antigen (HLA) polymorphism is one of the genetic factors that might have an impact on the outcome of the disease. This study explored the association between the HLA genotype and the severity of COVID-19 among patients from South Asia. Blood samples from 95 Asians (Bangladeshis, Indians, and Pakistanis) with COVID-19 were collected. The patients were divided according to the severity of their infection: mild (N = 64), severe (N = 31), and fatal (N = 20). DNA was extracted from all samples, and HLA genotyping was performed for both class I (A, B, and C) and class II (DRB1, DQA1, and DQB1) using the PCR-rSSO (polymerase chain reaction-reverse sequence-specific oligonucleotide) molecular method. The frequency of HLA-B*51 was significantly higher among patients in the fatal group than among those in the mild infection group (15% vs. 4.7%, p = 0.027). Additionally, the frequency of HLA-B*35 was significantly higher in the mild infection group than in the fatal group (21.1% vs. 7.5%, p = 0.050 [a borderline p-value]). In terms of HLA class II, DRB1*13 was significantly observed in the fatal group than in the mild infection group (17.5% vs. 11.3%, p = 0.049). However, the p-value for all alleles became insignificant after a statistical correction for the p-values (pc = 0.216, pc = 0.4, and pc = 0.49, respectively). Compared with all published data, this study highlights that the association between the HLA system and the COVID-19 outcome might be ethnic-dependent. Genetic variation between populations must be examined on a wider scale to assess infection prognosis and vaccine effectiveness.

Frequency of HLA alleles among COVID-19 infected patients: Preliminary data from Saudi Arabia.

HLA polymorphism is one of the genetic factors that may be associated with variations in susceptibility to COVID-19 infection. In this study, the frequency of HLA alleles among Saudi patients infected with COVID-19 was examined. The association with infection susceptibility and mortality was evaluated. This study included 135 Saudi COVID-19-infected patients (106 recovered and 29 died) who were admitted to hospitals because of their symptoms, and 135 healthy controls. HLA class I (A, B, C) and class II (DRB1, DQB1) genotyping was performed using the molecular method (PCR-rSSO). In this study, there was a significant increase in the frequency of HLA-A*01, B*56 and C*01 among infected patients compared to the control group (12.1% vs. 5.2%, p = 0.004, 3.7% vs. 0%, p = 0.006, 4.4% vs. 1.5%, p = 0.042, respectively). Moreover, there was a significant increase in the frequency of HLA-A*03 and C*06 among fatal patients compared to infected patients (13.8% vs. 5.7%, p = 0.036, 32.8% vs. 17.5%, p = 0.011, respectively). In terms of HLA class II, HLA-DRB1*04 was significantly higher in the control group compared to infected patients (27.4% vs. 16.3%, p = 0.002), while HLA-DRB1*08 was significantly higher in the infected group compared to the control (4.8% vs. 0.7%, p = 0.004). After statistical correction of the p value, A*01, B*56, DRB1*04 and DRB1*08 remained statistically significant (pc = 0.04, pc = 0.03, pc = 0.014 and pc = 0.028). This initial data suggested that individual HLA genotypes might play a role in determining susceptibility to COVID-19 infection and infection outcome. However, examining a larger sample size from different populations is required to determine a powerful association for clinical application.