CV19: Mechanisms of COVID-19 in Brain

The Covid-19 pandemic. caused by the virus SARS-Cov2. is the gravest public health crisis in a century. causing over 2.5 million global deaths and enormous human suffering. Along with its signature infection of the respiratory system. are widely seen serious deleterious effects on the brain. Cognitive manifestations of brain infection include delirium. a state characterized by confusion and disorientation. which is prevalent in 70% of Covid-19 patients with severe symptoms and memory deficits. Critically. delirium is often associated with long-term cognitive decline and neurodegeneration. At present. however. the mechanisms through which SARs-COV-2 affects the brain remain largely unknown. Here. we will test the novel hypothesis that the viral spike protein itself causes neuronal damage using cognitive behavioral models. tracking of in vivo neuronal alterations. and evaluation of epithelial and neuronal damage in vivo and in vitro.Specifically. we will test whether cognitive alterations result from: 1) The spike protein affecting the cerebral endothelial cells. causing breakdown of the blood-brain-barrier (BBB). micro-strokes and a maladaptive inflammatory response. or 2) Direct infection of neurons. through binding of the spike protein to angiotensin-converting enzyme 2 (ACE2) receptors present in epithelia and neurons. To test these hypotheses. we will use purified spike protein obtained from transfected tissue-culture cells. wild-type mice and transgenic mice expressing the human ACE2 (hACE2). and test neuronal alterations in vivo to assess dysfunction in real time and in vitro assay to determine neuroinflammation and neuronal death. We will use tasks to assess spatial disorientation. attentional processing. and memory and evaluate changes in hippocampal representations through in vivo visualization of calcium activity using miniendoscopes or recording single units and local field potential activity using tetrodes. These measures will be recorded immediately and several weeks after the infection. The brains from the studied animals will then be evaluated using in vitro assays of blood brain barrier (BBB) breakdown. neuronal death and microstrokes. as well as assays of microgliosis typical of damaging inflammatory responses. We anticipate that our discoveries will yield insight into the effects of spike proteins. which will be fundamental to develop novel preventative and ameliorative therapies against neurological damage from Covid-19. This project brings together two leading San Antonio neuroscientists with complementary expertise that should lead to major national funding.