Endothelial contribution to COVID-19: an update on mechanisms and therapeutic implications.

The global propagation of SARS-CoV-2 leads to an unprecedented public health emergency. Despite that the lungs are the primary organ targeted by COVID-19, systemic endothelial inflammation and dysfunction is observed particularly in patients with severe COVID-19, manifested by elevated endothelial injury markers, endotheliitis, and coagulopathy. Here, we review the clinical characteristics of COVID-19 associated endothelial dysfunction; and the likely pathological mechanisms underlying the disease including direct cell entry or indirect immune overreactions after SARS-CoV-2 infection. In addition, we discuss potential biomarkers that might indicate the disease severity, particularly related to the abnormal development of thrombosis that is a fatal vascular complication of severe COVID-19. Furthermore, we summarize clinical trials targeting the direct and indirect pathological pathways after SARS-CoV-2 infection to prevent or inhibit the virus induced endothelial disorders.

In silico analysis identifies neuropilin-1 as a potential therapeutic target for SARS-Cov-2 infected lung cancer patients.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), and is highly contagious and pathogenic. TMPRSS2 and Neuropilin-1, the key components that facilitate SARS-CoV-2 infection, are potential targets for treatment of COVID-19. Here we performed a comprehensive analysis on NRP1 and TMPRSS2 in lung to provide information for treating comorbidity of COVID-19 with lung cancer. NRP1 is widely expressed across all the human tissues while TMPRSS2 is expressed in a restricted pattern. High level of NRP1 associates with worse prognosis in multiple cancers, while high level of TMPRSS2 is associated with better survival of Lung Adenocarcinoma (LUAD). Moreover, NRP1 positively correlates with the oncogenic Cancer Associated Fibroblast (CAF), macrophage and endothelial cells infiltration, negatively correlates with infiltration of CD8+ T cell, the tumor killer cell in Lung Squamous cell carcinoma (LUSC). TMPRSS2 shows negative correlation with the oncogenic events in LUAD. RNA-seq data show that NRP1 level is slightly decreased in peripheral blood of ICU admitted COVID-19 patients, unaltered in lung, while TMPRSS2 level is significantly decreased in lung of COVID-19 patients. Our analysis suggests NRP1 as a potential therapeutic target, while sets an alert on targeting TMPRSS2 for treating comorbidity of COVID-19 and lung cancers.

SARS-CoV-2 Infection in the Central and Peripheral Nervous System-Associated Morbidities and Their Potential Mechanism.

The recent outbreak of SARS-CoV-2 infections that causes coronavirus-induced disease of 2019 (COVID-19) is the defining and unprecedented global health crisis of our time in both the scale and magnitude. Although the respiratory tract is the primary target of SARS-CoV-2, accumulating evidence suggests that the virus may also invade both the central nervous system (CNS) and the peripheral nervous system (PNS) leading to numerous neurological issues including some serious complications such as seizures, encephalitis, and loss of consciousness. Here, we present a comprehensive review of the currently known role of SARS-CoV-2 and identify all the neurological problems reported among the COVID-19 case reports throughout the world. The virus might gain entry into the CNS either through the trans-synaptic route via the olfactory neurons or through the damaged endothelium in the brain microvasculature using the ACE2 receptor potentiated by neuropilin-1 (NRP-1). The most critical of all symptoms appear to be the spontaneous loss of breathing in some COVID-19 patients. This might be indicative of a dysfunction within the cardiopulmonary regulatory centers in the brainstem. These pioneering studies, thus, lay a strong foundation for more in-depth basic and clinical research required to confirm the role of SARS-CoV-2 infection in neurodegeneration of critical brain regulatory centers.

More that ACE2? NRP1 may play a central role in the underlying pathophysiological mechanism of olfactory dysfunction in COVID-19 and its association with enhanced survival.

Three mechanisms have been proposed to account for COVID-19 associated olfactory dysfunction; obstruction of the olfactory cleft; epithelial injury and infection of the sustentacular supporting cells, which are known to express ACE2, or injury to the olfactory bulb due to axonal transport through olfactory sensory neurones. The absence of ACE2 expression by olfactory sensory neurones has led to the neurotropic potential of COVID-19 to be discounted. While an accumulating body of evidence supports olfactory epithelial injury as an important mechanism, this does not account for all the features of olfactory dysfunction seen in COVID-19; for example the duration of loss in some patients, evidence of changes within the olfactory bulb on MRI imaging, identification of viral particles within the olfactory bulb in post-mortem specimens and the inverse association between severity of COVID-19 and the prevalence of olfactory loss. The recent identification of a second route of viral entry mediated by NRP1 addresses many of these inconsistencies. Expression by the olfactory sensory neurones and their progenitor cells may facilitate direct injury and axonal transport to the olfactory bulb as well as a mechanism for delayed or absent recovery. Expression by regulatory T cells may play a central role in the cytokine storm. Variability in expression by age, race or gender may explain differing morbidity of infection and inverse association between anosmia and severity; in the case of higher expression there may be a higher risk of olfactory function but greater activation of regulatory T cells that may suppress the cytokine storm.

ACE2: Evidence of role as entry receptor for SARS-CoV-2 and implications in comorbidities.

Pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus 19 disease (COVID-19) which presents a large spectrum of manifestations with fatal outcomes in vulnerable people over 70-years-old and with hypertension, diabetes, obesity, cardiovascular disease, COPD, and smoking status. Knowledge of the entry receptor is key to understand SARS-CoV-2 tropism, transmission and pathogenesis. Early evidence pointed to angiotensin-converting enzyme 2 (ACE2) as SARS-CoV-2 entry receptor. Here, we provide a critical summary of the current knowledge highlighting the limitations and remaining gaps that need to be addressed to fully characterize ACE2 function in SARS-CoV-2 infection and associated pathogenesis. We also discuss ACE2 expression and potential role in the context of comorbidities associated with poor COVID-19 outcomes. Finally, we discuss the potential co-receptors/attachment factors such as neuropilins, heparan sulfate and sialic acids and the putative alternative receptors, such as CD147 and GRP78.