MECHANISMS OF SARS-COV-2 PATHOGENESIS: FOCUS ON ACUTE AND LONG COVID-19
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and its associated disease Coronavirus Disease 2019 (COVID-19) were first recognized in December 2019. The World Health Organization (WHO) declared a pandemic on March 11, 2020. More than 118 million cases have been reported a year later, with 2.6 million related deaths. COVID-19 typically presents fever, dry cough, shortness of breath, myalgia, and headache. However, neurological manifestations in SARS-CoV-2 infection are being increasingly described. The projected prevalence of these complications is expected to outweigh the neurological burden seen with other related viruses, SARS-CoV and MERS-CoV, already considered neurotropic, suggesting a different mechanism of action. However, the mechanisms by which SARS-CoV-2 results in brain compromise are mostly unknown.
Currently, most publications in NeuroCOVID-19 are “scattered” into five proposed mechanisms: first, retrograde viral transport by neuronal axons into the brain; second, direct infection of neurons and endothelial cells due to the expression of angiotensin-converting enzyme 2 (ACE-2) receptors; third, an accelerated trombo-hypoxic related mechanism resulting in a compromised blood-brain barrier and blood supply to specific brain areas; fourth, the transmigration of leukocytes/platelets containing the virus into the neuronal parenchyma and lastly, an unspecific neuronal/blood-brain barrier compromise due to hypoxia and systemic cytokine storm. In the current proposal, we will focus on how SARS-CoV-2 compromises the human BBB in vitro and in vivo.
Our published and preliminary data indicate that acute SARS-CoV-2 infection resulted in lung tissue compromise, systemic inflammation, leukocyte activation (or infection), hypercoagulation, and platelet activation (or infection). We detected several of these components at the BBB and proposed to be the source of micro-strokes or hemorrhagic events described in individuals with NeuroCOVID. We determine that at least one-third of COVID-19 patients in ICU developed perivascular lesions within the brain that last for months to years, again suggesting a breach of the BBB. We also determined that leukocytes and platelets are infected with SARS-CoV-2 and could predict long-term complications or demise. Furthermore, new data in macaques infected with SARS-CoV-2 confirmed that brain infection is localized at the BBB, and no infection in neurons was detected, suggesting that NeuroCOVID corresponds to an endothelial disease. In this proposal, we will focus on the contribution of the BBB to NeuroCOVID.
The blood-brain barrier (BBB) is a structural and functional multicellular barrier comprised of specialized endothelial cells, astrocytes end feet, pericytes, other accessory cells, and the basal membrane. A healthy BBB excludes most immune cells, microorganisms, and other harmful proteins from the nervous system, maintaining an immune privilege site. However, our in vitro and in vivo data indicates that SARS-CoV-2 compromises BBB function and permeability. Our hypothesis is that “SARS-CoV-2 disrupts the BBB resulting in local hemorrhagic events that compromise perfusion and neuronal function.” We truly believe that will develop alternative therapeutic interventions to reduce communicational ' devastating consequences of NeuroCOVID.