Hamster organotypic modeling of SARS-CoV-2 lung and brainstem infection.

SARS-CoV-2 has caused a global pandemic of COVID-19 since its emergence in December 2019. The infection causes a severe acute respiratory syndrome and may also spread to central nervous system leading to neurological sequelae. We have developed and characterized two new organotypic cultures from hamster brainstem and lung tissues that offer a unique opportunity to study the early steps of viral infection and screening antivirals. These models are not dedicated to investigate how the virus reaches the brain. However, they allow validating the early tropism of the virus in the lungs and demonstrating that SARS-CoV-2 could infect the brainstem and the cerebellum, mainly by targeting granular neurons. Viral infection induces specific interferon and innate immune responses with patterns specific to each organ, along with cell death by apoptosis, necroptosis, and pyroptosis. Overall, our data illustrate the potential of rapid modeling of complex tissue-level interactions during infection by a newly emerged virus.

Brainstem neuropathology in two cases of COVID-19: SARS-CoV-2 trafficking between brain and lung.

INTRODUCTION: SARS-CoV-2 might spread through the nervous system, reaching respiratory centers in the brainstem. Because we recently reported neurophysiological brainstem reflex abnormalities in COVID-19 patients, we here neuropathologically assessed structural brainstem damage in two COVID-19 patients. MATERIALS AND METHODS: We assessed neuropathological features in two patients who died of COVID-19 and in two COVID-19 negative patients as controls. Neuronal damage and corpora amylacea (CA) numbers /mm2 were histopathologically assessed. Other features studied were the immunohistochemical expression of the SARS-CoV-2 nucleoprotein (NP) and the Iba-1 antigen for glial activation. RESULTS: Autopsies showed normal gross brainstem anatomy. Histopathological examination demonstrated increased neuronal and CA damage in Covid-19 patients' medulla oblongata. Immunohistochemistry disclosed SARS-CoV-2 NP in brainstem neurons and glial cells, and in cranial nerves. Glial elements also exhibited a widespread increase in Iba-1 expression. Sars-Co-V2 was immunohistochemically detected in the vagus nerve fibers. DISCUSSION: Neuropathologic evidence showing SARS-CoV-2 in the brainstem and medullary damage in the area of respiratory centers strongly suggests that the pathophysiology of COVID-19-related respiratory failure includes a neurogenic component. Sars-Co-V2 detection in the vagus nerve, argues for viral trafficking between brainstem and lung.

Persistent Brainstem Dysfunction in Long-COVID: A Hypothesis.

Long-COVID is a postviral illness that can affect survivors of COVID-19, regardless of initial disease severity or age. Symptoms of long-COVID include fatigue, dyspnea, gastrointestinal and cardiac problems, cognitive impairments, myalgia, and others. While the possible causes of long-COVID include long-term tissue damage, viral persistence, and chronic inflammation, the review proposes, perhaps for the first time, that persistent brainstem dysfunction may also be involved. This hypothesis can be split into two parts. The first is the brainstem tropism and damage in COVID-19. As the brainstem has a relatively high expression of ACE2 receptor compared with other brain regions, SARS-CoV-2 may exhibit tropism therein. Evidence also exists that neuropilin-1, a co-receptor of SARS-CoV-2, may be expressed in the brainstem. Indeed, autopsy studies have found SARS-CoV-2 RNA and proteins in the brainstem. The brainstem is also highly prone to damage from pathological immune or vascular activation, which has also been observed in autopsy of COVID-19 cases. The second part concerns functions of the brainstem that overlap with symptoms of long-COVID. The brainstem contains numerous distinct nuclei and subparts that regulate the respiratory, cardiovascular, gastrointestinal, and neurological processes, which can be linked to long-COVID. As neurons do not readily regenerate, brainstem dysfunction may be long-lasting and, thus, is long-COVID. Indeed, brainstem dysfunction has been implicated in other similar disorders, such as chronic pain and migraine and myalgic encephalomyelitis or chronic fatigue syndrome.

Brainstem Dysfunction in SARS-COV-2 Infection can be a Potential Cause of Respiratory Distress.

BACKGROUND: A terrible pandemic, Covid-19, has captivated scientists to investigate if SARS-CoV-2 virus infects the central nervous system (CNS). A crucial question is if acute respiratory distress syndrome (ARDS), the main cause of death in this pandemic, and often refractory to treatments, can be explained by respiratory center dysfunction. OBJECTIVE: To discuss that ARDS can be caused by SARS-CoV-2 infection of the respiratory center in the brainstem. MATERIALS AND METHODS: I reviewed literature about SARS-CoV-2 mechanisms to infect the respiratory center in the brainstem. RESULTS AND CONCLUSIONS: An increasing amount of reports demonstrates that neurotropism is a common feature of coronavirus, which have been found in the brains of patients and experimental models, where the brainstem was severely infested. Recent studies have provided tremendous indication of the incidence of acute respiratory failure due to SARS-CoV-2 infection of the brainstem. SARS-CoV-2 might infect the CNS through the olfactory bulb, spreading from the olfactory nerves to the rhinencephalon, and finally reaching the brainstem. Hence, the virus infection causes respiratory center dysfunctions, leading to ARDS in COVID-19 patients. I conclude that acute ARDS in Covid-19 can be caused by SARS-CoV-2 invasion of brainstem respiratory center, suggesting the needs of more specific and aggressive treatments, with the direct participation of neurologists and neurointensivists.

Understanding the Immunologic Characteristics of Neurologic Manifestations of SARS-CoV-2 and Potential Immunological Mechanisms.

Similar to its predecessors, coronavirus disease 2019 (COVID-19) exhibits neurotrophic properties, which lead to progression of neurologic sequelae. Besides direct viral invasion to the central nervous system (CNS), indirect CNS involvement through viral-mediated immune response is plausible. Aberrant immune pathways such as extreme release of cytokines (cytokine storm), autoimmunity mediated by cross-reactivity between CNS components and viral particles, and microglial activation propagate CNS damage in these patients. Here, we review the currently available evidence to discuss the plausible immunologic pathways that may contribute to the development of COVID-19 neurological complications, namely Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis, Guillain-Barre syndrome, seizure, and brainstem involvement.

Erythropoietin as candidate for supportive treatment of severe COVID-19.

In light of the present therapeutic situation in COVID-19, any measure to improve course and outcome of seriously affected individuals is of utmost importance. We recap here evidence that supports the use of human recombinant erythropoietin (EPO) for ameliorating course and outcome of seriously ill COVID-19 patients. This brief expert review grounds on available subject-relevant literature searched until May 14, 2020, including Medline, Google Scholar, and preprint servers. We delineate in brief sections, each introduced by a summary of respective COVID-19 references, how EPO may target a number of the gravest sequelae of these patients. EPO is expected to: (1) improve respiration at several levels including lung, brainstem, spinal cord and respiratory muscles; (2) counteract overshooting inflammation caused by cytokine storm/ inflammasome; (3) act neuroprotective and neuroregenerative in brain and peripheral nervous system. Based on this accumulating experimental and clinical evidence, we finally provide the research design for a double-blind placebo-controlled randomized clinical trial including severely affected patients, which is planned to start shortly.

Brainstem involvement and respiratory failure in COVID-19.

Respiratory failure is the most worrisome problem of COVID-19. Patients may develop severe pneumonia requiring invasive mechanical ventilation and a significant proportion of them dies. It has been suggested that brainstem might play a role in severe respiratory failure of COVID-19 patients. We described three COVID-19 patients in ICU at Federico II Hospital in Naples that, although had recovered from pneumonia, could not be weaned from invasive mechanical ventilation. Our clinical evaluation was consistent with an involvement of the brainstem and especially of respiratory centre thus possibly explaining the weaning failure in patients that were awake and had recovered from lung involvement. Our data, though limited, indicate that brainstem involvement may play a role in respiratory failure and perhaps in the high death rate of COVID-19 patients. Moreover, the weaning failure from mechanical ventilation due to central respiratory drive depression might underlie the unusual long stay in ICU reported for COVID-19 patients.