COVID Virus May Tunnel through Nanotubes from Nose to Brain【SCIENTIFIC AMERICAN:Stephanie Pappas 2022年7月20日】

Nanotubes may provide a cunning answer to the mystery of how the virus that causes COVID infects neurons and produces long-lasting neurological symptoms

As familiar to everyone as the COVID-causing coronavirus SARS-CoV-2 has become over the past two years, feverish research is still trying to parse a lingering puzzle. How, in fact, does the pandemic virus that has so changed the world cross over into the brain after entering the respiratory system? An answer is important because neurological complaints are some of the most common in the constellation of symptoms called long COVID. The mystery centers around the fact that brain cells don’t display the receptors, or docking sites, that the virus uses to get into nasal and lung cells.

SARS-CoV-2, though, may have come up with an ingenious work-around. It may completely do away with the molecular maneuverings needed to attach to and unlock a cell membrane. Instead it wields a blunt instrument in the form of nanotube “bridges”—cylinders constructed of the common protein actin that are no more than a few tens of nanometers in diameter. These tunneling nanotubes extend across cell-to-cell gaps to penetrate a neighbor and give viral particles a direct route into COVID-impervious tissue. Researchers at the Pasteur Institute in Paris demonstrated the prospects for a nanotube-mediated cell crossing in a study in a lab dish that now needs to be confirmed in infected human patients. Given further proof, the findings could explain why some people who get COVID-19 experience brain fog and other neurological symptoms. Also, if the intercellular conduits could be severed, that might prevent some of these debilitating aftereffects of infection.

The nanotube route “is a shortcut that propagates infection fast and between different organs, permissive or not permissive, to the infection,” says Chiara Zurzolo, a cell biologist at the Pasteur Institute, who conducted the study. “And it might be also a way for the virus to hide and escape the immune response.”

The virus may be capable of commandeering a cell’s own nanotubes, diverting them away from other routine tasks, such as transferring lipids and proteins between cells. Early research on SARS-CoV-2 suggested that it might be able to hijack similar cell projections. A 2020 paper published in the journal Cell found that cells infected with the novel coronavirus extended out antennalike feelers called filopodia with viral particles onboard.

SARS-CoV-2 typically gets into cells in the respiratory tract and elsewhere by latching its protruding “spike” protein to ACE2 receptors on their surface. Zurzolo and her team wondered if the coronavirus was using tunneling nanotubes to sneak into cells that were not studded with these receptors. To find out what was going on, the researchers took cells from monkey kidneys, infected them with SARS-CoV-2 and cultured them alongside human neurons in a lab dish.

Monkey kidneys cells are commonly used to model the human respiratory tract in studies of COVID-19 because the cells display ACE2 receptors. The neurons came from a cell line that was originally cultured from a cancer called neuroblastoma. These cells lack ACE2 receptors, but after 48 hours side-by-side with coronavirus-infected kidney cells, 62.5 percent of them were infected with SARS-CoV-2.

The team then used cutting-edge microscopy techniques to image how this viral transfer occurred. By tagging viral proteins with antibodies and fluorescent compounds so that they stood out, the researchers captured high-resolution images of the virus within the tunneling nanotubes that connected the cells. They could see both viral particles and little sacs called vesicles in which the virus copies itself. They also detected proteins that are part of the cellular machinery the virus uses to replicate. The imaging was so detailed that even the spike proteins that give the virus its prickly appearance were visible, the researchers reported in the journal Science Advances. Once nestled in the neuronal cells, the coronavirus was able to continue replicating.

The experiments also showed that cells infected with the coronavirus grew far more tunneling nanotubes than uninfected cells, suggesting that the virus itself spurs a cell to put out these connectors. SARS-CoV-2 isn’t the only pathogen that controls cells in this way. HIV also takes advantage of tunneling nanotubes to move between cells, and the Marburg virus triggers the growth of filopodia.

“The virus is so sinister,” says Nevan Krogan, a molecular biologist at the University of California, San Francisco, who was not involved in the new research but conducted the 2020 study that found the increase in filopodia after coronavirus infection. “It’s manipulating all of our processes with a very limited genetic [repertoire].”

The cellular bridges may play a role in how the virus sometimes triggers long COVID, Krogan says. Zurzolo and her team suspect that the virus enters through the nose and travels along to one of the brain’s two olfactory bulbs, which contain tissue that processes smells. The nanotubes may help the virus avoid antibodies, allowing it to linger longer in the body. “If you can manipulate enzymes that are responsible for this filopodia or nanotube formation, this could be a way to maybe have an effect on long COVID,” Krogan says.

His work showed that the coronavirus increases production of the enzyme casein kinase II, which in turn helps build the protein backbone of filopodia and nanotubes. Senhwa Biosciences, a Taiwan–based drug development company, is currently conducting clinical trials of a drug called silmitasertib that inhibits casein kinase II to probe whether it has an impact on COVID-19 recovery.

Meanwhile Zurzolo and her colleagues are now working to prove that their hypothesis about how SARS-CoV-2 reaches the brain occurs in actual infections. If they can do so, they may be a step closer to figuring out why, for some people, COVID-19 triggers a lingering health debacle.

Peripheral Neuropathy Evaluations of Patients With Prolonged Long COVID【Neurology Neuroimmunology & Neuroinflammation 2022年3月1日】


Background and Objectives Recovery from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection appears exponential, leaving a tail of patients reporting various long COVID symptoms including unexplained fatigue/exertional intolerance and dysautonomic and sensory concerns. Indirect evidence links long COVID to incident polyneuropathy affecting the small-fiber (sensory/autonomic) axons.

Methods We analyzed cross-sectional and longitudinal data from patients with World Health Organization (WHO)-defined long COVID without prior neuropathy history or risks who were referred for peripheral neuropathy evaluations. We captured standardized symptoms, examinations, objective neurodiagnostic test results, and outcomes, tracking participants for 1.4 years on average.

Results Among 17 patients (mean age 43.3 years, 69% female, 94% Caucasian, and 19% Latino), 59% had ≥1 test interpretation confirming neuropathy. These included 63% (10/16) of skin biopsies, 17% (2/12) of electrodiagnostic tests and 50% (4/8) of autonomic function tests. One patient was diagnosed with critical illness axonal neuropathy and another with multifocal demyelinating neuropathy 3 weeks after mild COVID, and ≥10 received small-fiber neuropathy diagnoses. Longitudinal improvement averaged 52%, although none reported complete resolution. For treatment, 65% (11/17) received immunotherapies (corticosteroids and/or IV immunoglobulins).

Discussion Among evaluated patients with long COVID, prolonged, often disabling, small-fiber neuropathy after mild SARS-CoV-2 was most common, beginning within 1 month of COVID-19 onset. Various evidence suggested infection-triggered immune dysregulation as a common mechanism.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause long-term disability (long COVID) with new neurologic manifestations after even mild infections. Reports of peripheral neuropathy include Guillain-Barré syndrome, mononeuritis multiplex, brachial plexitis, cranial neuropathies, and orthostatic intolerance, although some studies included patients with potentially contributory conditions. Various long COVID symptoms overlap with those of small-fiber polyneuropathy (SFN). Hence, we prospectively analyzed a cross-section of patients with long COVID evaluated for incident neuropathy.

Acute-Onset Psychosis Following Prolonged Hospitalization for COVID-19 Pneumonia【American Journal of Case Reports 2022年3月4日】


BACKGROUND: SARS-CoV-2 infection presents with a variety of clinical manifestations, from asymptomatic courses to prolonged hospitalizations with severe systemic inflammatory responses and multiorgan failure. One particular sequela of the disease that has gained wider attention over the past year is the sudden onset of neuropsychiatric symptoms in the weeks following recovery from COVID-19 pneumonia. While the pathophysiology for the development of this condition is uncertain, symptoms ranging from mild confusion and anxiety to florid psychosis with manic delusions and auditory and visual hallucinations have been rarely, but increasingly, reported in the literature. The acute development of such symptoms in the post-recovery period can be devastating for patients, their caregivers, and clinicians who may be unaware of effective management options.

CASE REPORT: In this case report, we present a 23-year old man who developed psychotic symptoms, including acute mania, delusions of grandeur, and auditory and visual hallucinations, 1 week following an extended hospitalization for COVID-19 pneumonia. The patient was admitted to our psychiatric unit and treated with a combination of antipsychotic and mood stabilizer medications. After 2 weeks of treatment, the patient’s psychotic and mood-related symptoms resolved, with normal mental status maintained at last follow-up 1 month following discharge from our unit.

CONCLUSIONS: The acute development of neuropsychiatric symptoms is a rare but increasingly recognized sequela of COVID-19. Despite the severity of initial presentation, patients can be successfully treated with short courses of typical antipsychotic medications with complete return to baseline, unimpaired functioning, and no lingering psychiatric sequela.

Brain functional connectivity alterations associated with neuropsychological post-COVID syndrome【Research Square 2022年3月14日】


Neuropsychological deficits and brain damage following SARS-CoV-2 infection are not well understood. 110 patients, with either severe, moderate or mild disease in the acute phase underwent neuropsychological and olfactory tests, as well as completed psychiatric and respiratory questionnaires at 223 ± 42 days post-infection. Additionally, a subgroup of 50 patients underwent functional magnetic resonance imaging. Patients in the severe group displayed poorer verbal episodic memory performances, and moderate patients had reduced mental flexibility. Neuroimaging revealed patterns of hypo and hyper functional connectivity in severe patients, while only hyperconnectivity patterns were observed for moderate. The default mode, somatosensory, dorsal attention and cerebellar networks were implicated. Partial least squares correlations analysis confirmed specific association between memory performances and brain functional connectivity. The severity of the infection in the acute phase is a predictor of neuropsychological post-COVID syndrome. SARS-CoV-2 infection causes long-term memory and executive dysfunctions, related to largescale functional brain connectivity alterations.

Tracking SARS-CoV-2 Omicron diverse spike gene mutations identifies multiple inter-variant recombination events【bioRxiv 2022年3月14日】


The current pandemic of COVID-19 is fueled by more infectious emergent Omicron variants. Ongoing concerns of emergent variants include possible recombinants, as genome recombination is an important evolutionary mechanism for the emergence and re-emergence of human viral pathogens. Although recombination events among SARS-CoV-1 and MERS-CoV were well-documented, it has been difficult to detect the recombination signatures in SARS-CoV-2 variants due to their high degree of sequence similarity. In this study, we identified diverse recombination events between two Omicron major subvariants (BA.1 and BA.2) and other variants of concern (VOCs) and variants of interest (VOIs), suggesting that co-infection and subsequent genome recombination play important roles in the ongoing evolution of SARS-CoV-2. Through scanning high-quality completed Omicron spike gene sequences, eighteen core mutations of BA.1 variants (frequency >99%) were identified (eight in NTD, five near the S1/S2 cleavage site, and five in S2). BA.2 variants share three additional amino acid deletions with the Alpha variants. BA.1 subvariants share nine common amino acid mutations (three more than BA.2) in the spike protein with most VOCs, suggesting a possible recombination origin of Omicron from these VOCs. There are three more Alpha-related mutations (del69-70, del144) in BA.1 than BA.2, and therefore BA.1 may be phylogenetically closer to the Alpha variant. Revertant mutations are found in some dominant mutations (frequency >95%) in the BA.1 subvariant. Most notably, multiple additional amino acid mutations in the Delta spike protein were also identified in the recently emerged Omicron isolates, which implied possible recombination events occurred between the Omicron and Delta variants during the on-going pandemic. Monitoring the evolving SARS-CoV-2 genomes especially for recombination is critically important for recognition of abrupt changes to viral attributes including its epitopes which may call for vaccine modifications.