Brain pathophysiology in SARS-CoV-2 disease

OBJECTIVES/GOALS: The SARS-CoV-2 (Severe Acute Respiratory Syndrome CoronaVirus-2), which underlies the current COVID-19 pandemic, among other tissues, also targets the central nervous system (CNS). The goal of this study is to investigate mechanisms of neuroinflammation in Lipopolysaccharides (LPS)-treated mouse model and SARS-CoV-2-infected hamsters. METHODS/STUDY POPULATION: In this research I will assay vascular reactivity of cerebral vessels to assess vascular dysfunction within the microcirculation. I will determine expression of proinflammatory cytokines, coagulation factors and AT1 receptors (AT1R) in isolated microvessels from the circle of Willis to assess inflammation, thrombosis and RAS activity in the microvasculature. LPS and SARS-CoV-2, are both associated with coagulopathies and because of that I will measure concentration of PAI-1, von Willebrand Factor, thrombin and D-dimer to assess the thrombotic pathway in the circulation. Histology and immunohistochemistry will assess immune cell type infiltration into the brain parenchyma, microglia activation and severity of neuroinflammation and neural injury. RESULTS/ANTICIPATED RESULTS: We hypothesize that under conditions of reduced ACE2 (e.g., SARS-CoV-2 infection), AT1R activity is upregulated in the microvasculature. In the presence of an inflammatory insult, these AT1Rs promote endothelialitis and immunothrombosis through pro-thrombotic pathways and pro-inflammatory cytokine production leading to endothelial dysfunction in the microvasculature, blood brain barrier (BBB) injury, deficits in cognition and increased anxiety. We will test this hypothesis through 2 aims: Aim 1: Determine the role of the pro-injury arm of the RAS in the pathophysiology of the brain in animal models of neuroinflammation and COVID-19. Aim 1: Determine the role of the protective arm of the RAS in the pathophysiology of the brain in animal models of neuroinflammation and COVID-19. DISCUSSION/SIGNIFICANCE: This study will provide insights that will complement on-going clinical trials on angiotensin type 1 receptor (AT1R) blockers (ARBs) in COVID-19. This research is a necessary first step in understanding mechanisms of brain pathogenesis that can set the groundwork for future studies of more complex models of disease.

SARS-CoV-2 Infection and Racial Disparities in Children: Protective Mechanisms and Severe Complications Related to MIS-C.

A novel coronavirus has resulted in a pandemic with over 176 million confirmed cases and over 3.8 million recorded deaths. In the USA, SARS-CoV-2 infection has a significant burden on minority communities, especially Hispanic and Black communities, which are overrepresented in cases compared to their percentage in the population. SARS-CoV-2 infection can manifest differently in children and adults, with children tending to have less severe disease. A review of current literature was performed to identify the hypothesized protective immune mechanisms in children, and to describe the rare complication of multisystem inflammatory syndrome in children (MIS-C) that has been documented in children post-SARS-CoV-2 infection. Epidemiologic data and case studies have indicated that children are less susceptible to more severe clinical features of SARS-CoV-2 infection, a finding that may be due to differences in the cytokine response generated by the innate immune system, high amounts of ACE-2 which maintain homeostatic functions by preventing inflammation, and trained immunity acquired from regular vaccinations. Despite these protective mechanisms, children are still susceptible to severe complications, such as MIS-C. The racial disparities seen in MIS-C are extremely apparent, and certain populations are more affected. Most specifically, 33% of MIS-C patients are Hispanic/Latino, and 30% Black. Current studies published on MIS-C do not detail whether certain symptoms are more present in certain racial/ethnic groups. Knowledge of these disparities could assist health care professionals with devising appropriate strategies for post-acute SARS-CoV-2 infection follow-up in children as well as vaccine distribution in specific communities to help slow the spread of SARS-CoV-2 infection, and ultimately reduce the potential for complications such as MIS-C.

Chloroquine to fight COVID-19: A consideration of mechanisms and adverse effects?

The COVID-19 outbreak emerged in December 2019 and has rapidly become a global pandemic. A great deal of effort has been made to find effective drugs against this disease. Chloroquine (CQ) and hydroxychloroquine (HCQ) were widely adopted in treating COVID-19, but the results were contradictive. CQ/HCQ have been used to prevent and treat malaria and are efficacious anti-inflammatory agents in rheumatoid arthritis and systemic lupus erythematosus. These drugs have potential broad-spectrum antiviral properties, but the underlying mechanisms are speculative. In this review, we re-evaluated the treatment outcomes and current hypothesis for the working mechanisms of CQ/HCQ as COVID-19 therapy with a special focus on disruption of Ca2+ signaling. In so doing, we attempt to show how the different hypotheses for CQ/HCQ action on coronavirus may interact and reinforce each other. The potential toxicity is also noted due to its action on Ca2+ and hyperpolarization-activated cyclic nucleotide-gated channels in cardiac myocytes and neuronal cells. We propose that intracellular calcium homeostasis is an alternative mechanism for CQ/HCQ pharmacology, which should be considered when evaluating the risks and benefits of therapy in these patients and other perspective applications.