Repurposing of drugs targeting the cytokine storm induced by SARS-CoV-2.

A cytokine storm is one of the leading causes of acute respiratory distress syndrome (ARDS) and sepsis-associated multiple organ failure in many respiratory viral infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The coronavirus disease 2019 (COVID-19) pandemic has caused millions of deaths worldwide, resulting in an urgent need for effective therapeutic interventions. Repurposing immunosuppressive drugs that target cytokines with immunomodulatory properties is a promising approach to counteract SARS-CoV-2-induced ARDS at the infective and post-infective stages. In this minireview, we examine drugs targeting IL-1ß, IL-4/IL-13, IL-6 and TNF-α tested in COVID-19 patients.

Ocular tropism of SARS-CoV-2 in animal models with retinal inflammation via neuronal invasion following intranasal inoculation.

Although ocular manifestations are reported in patients with COVID-19, consensus on ocular tropism of SARS-CoV-2 is lacking. Here, we infect K18-hACE2 transgenic mice with SARS-CoV-2 using various routes. We observe ocular manifestation and retinal inflammation with production of pro-inflammatory cytokines in the eyes of intranasally (IN)-infected mice. Intratracheal (IT) infection results in dissemination of the virus from the lungs to the brain and eyes via trigeminal and optic nerves. Ocular and neuronal invasions are confirmed using intracerebral (IC) infection. Notably, the eye-dropped (ED) virus does not cause lung infection and becomes undetectable with time. Ocular and neurotropic distribution of the virus in vivo is evident in fluorescence imaging with an infectious clone of SARS-CoV-2-mCherry. The ocular tropic and neuroinvasive characteristics of SARS-CoV-2 are confirmed in wild-type Syrian hamsters. Our data can improve the understanding regarding viral transmission and clinical characteristics of SARS-CoV-2 and help in improving COVID-19 control procedures.

The Delta SARS-CoV-2 Variant of Concern Induces Distinct Pathogenic Patterns of Respiratory Disease in K18-hACE2 Transgenic Mice Compared to the Ancestral Strain from Wuhan.

Compared to the original ancestral strain of SARS-CoV-2, the Delta variant of concern has shown increased transmissibility and resistance toward COVID-19 vaccines and therapies. However, the pathogenesis of the disease associated with Delta is still not clear. In this study, using K18-hACE2 transgenic mice, we assessed the pathogenicity of the Delta variant by characterizing the immune response following infection. We found that Delta induced the same clinical disease manifestations as the ancestral SARS-CoV-2, but with significant dissemination to multiple tissues, such as brain, intestine, and kidney. Histopathological analysis showed that tissue pathology and cell infiltration in the lungs of Delta-infected mice were the same as in mice infected with the ancestral SARS-CoV-2. Delta infection caused perivascular inflammation in the brain and intestinal wall thinning in K18-hACE2 transgenic mice. Increased cell infiltration in the kidney was observed in both ancestral strain- and Delta-infected mice, with no clear visible tissue damage identified in either group. Interestingly, compared with mice infected with the ancestral strain, the numbers of CD45+ cells, T cells, B cells, inflammatory monocytes, and dendritic cells were all significantly lower in the lungs of the Delta-infected mice, although there was no significant difference in the levels of proinflammatory cytokines between the two groups. Our results showed distinct immune response patterns in the lungs of K18-hACE2 mice infected with either the ancestral SARS-CoV-2 or Delta variant of concern, which may help to guide therapeutic interventions for emerging SARS-CoV-2 variants. IMPORTANCE SARS-CoV-2 variants, with the threat of increased transmissibility, infectivity, and immune escape, continue to emerge as the COVID-19 pandemic progresses. Detailing the pathogenesis of disease caused by SARS-CoV-2 variants, such as Delta, is essential to better understand the clinical threat caused by emerging variants and associated disease. This study, using the K18-hACE2 mouse model of severe COVID-19, provides essential observation and analysis on the pathogenicity and immune response of Delta infection. These observations shed light on the changing disease profile associated with emerging SARS-CoV-2 variants and have potential to guide COVID-19 treatment strategies.

Comorbidities in SARS-CoV-2 Patients: a Systematic Review and Meta-Analysis.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread across the globe at unprecedented speed and is showing no signs of slowing down. The outbreak of coronavirus disease 2019 (COVID-19) has led to significant health burden in infected patients especially in those with underlying comorbidities. The aim of this study was to evaluate the correlation between comorbidities and their role in the exacerbation of disease in COVID-19 patients leading to fatal outcomes. A systematic review was conducted using data from MEDLINE, Scopus, Web of Science, and EMBASE databases published from 1 December 2019 to 15 September 2020. Fifty-three articles were included in the systematic review. Of those 53 articles, 8 articles were eligible for meta-analysis. Hypertension, obesity, and diabetes mellitus were identified to be the most prevalent comorbidities in COVID-19 patients. Our meta-analysis showed that cancer, chronic kidney diseases, diabetes mellitus, and hypertension were independently associated with mortality in COVID-19 patients. Chronic kidney disease was statistically the most prominent comorbidity leading to death. However, despite having high prevalence, obesity was not associated with mortality in COVID-19 patients.IMPORTANCE COVID-19 has plagued the world since it was first identified in December 2019. Previous systematic reviews and meta-analysis were limited by various factors such as the usage of non-peer reviewed data and were also limited by the lack of clinical data on a global scale. Comorbidities are frequently cited as risk factors for severe COVID-19 outcomes. However, the degree to which specific comorbidities impact the disease is debatable. Our study selection involves a global reach and covers all comorbidities that were reported to be involved in the exacerbation of COVID-19 leading to fatal outcomes, which allows us to identify the specific comorbidities that have higher risk in patients. The study highlights COVID-19 high-risk groups. However, further research should focus on the status of comorbidities and prognosis in COVID-19 patients.

Development of vaccines for SARS-CoV-2.

COVID-19 emerged in late 2019 and has rapidly spread through many countries globally. The causative SARS-CoV-2 virus was not known until recently, and there is little or no natural immunity in human populations. There is an urgent need for vaccines and drugs to combat this new pandemic. In just a few months, huge efforts and resources by government, academia, and industry have been thrown into the race to develop a vaccine. This brief review summarizes and discusses the array of technologies being applied to vaccine development, highlighting the strengths and weaknesses of the various approaches.