Rose continues to grow. She has gone from 12 pounds to 23 pounds in 3 weeks! She sits, lays, down, comes to me when I call, and can shake. She has largely quit biting so I am healing up now. Overall, a big enjoyment in my life, a great companion.
MAPS
KP.3.1.1 continues its dominance, making up roughly 53% of the infections. KP.2.3 and LB.1 continue to hang around. XEC and LF.7 have not appeared in the estimates, expect XEC to appear in the next analysis.
This is the latest MAPS forecast. This is better than the last forecast in terms of the minimum. The average of the ensemble, shown in purple, bottoms out around Thanksgiving at roughly 300,000 New Daily Infections. I have included both XEC and LF.7 in this forecast, with XEC starting October 10th and LF.7 on October 20th. They make up most of the rise after Thanksgiving, although KP.3.1.1 still contributes.
Remember when 300,000 a day was considered a huge number? Yes, that was back in 2020. Here is our estimation of New Daily Infections starting from the beginning of the pandemic and ending on 9-15-2024. This has been an incredible summer surge and is approaching the 3rd largest ever. It looks like we will be getting our usual January peak, but currently the spread is quite large between the ensemble members. I would not be surprised if it was larger than last January.
In California, this was the largest wave ever! There are other concerns when it comes to California. They just reported 7 new dairy herds have tested positive for H5N1. They also have positive tests for Dengue Fever reported in L.A. county. If a resident there gets a co-infection of Covid and Dengue the outcome will likely be miserable. You can read more about this in this thread: EMERGENCE of some SARS-CoV-2 VARIANTS Are INDUCED by CO-INFECTIONS With DENGUE 😨😨😨
This could be one of the most significant ticking time bomb 💣💣💣
Here are a few more from around the country. Notice they exhibit a significant recent double peak.
It looks like we will be getting our usual January peak, but currently the spread is quite large between the ensemble members. I would not be surprised if it was larger than last January.
I need to show the masking study from the last forecast. I will present the current forecast masking study in a couple of days. In this set of runs, I used the 9-12 forecast as the template for these integrations. The only difference was the masking compliance. It varied from none to 2.5, 5, 15, 25, 35, 45, 55, 65, 75, 85, 95% compliance. The mask was an N95 with 78% effectiveness. Folks, it is clear that if we could get to a mere 15% the results would be dramatic. What the hell is the matter with people? Similar results have been seen in my previous posts examining this.
Daily Feed of Brain Damage Part III
Here is the study we will examine today, titled “SARS-CoV-2 Rapidly Infects Peripheral Sensory and Autonomic Neurons, Contributing to Central Nervous System Neuroinvasion before Viremia”.
First, what is the Peripheral Nervous System (PNS)? Here is a graphic to give you an idea. The majority of the studies focus on the Central Nervous System (CNS).
Your peripheral nervous system (PNS) is that part of your nervous system that lies outside your brain and spinal cord. It plays key role in both sending information from different areas of your body back to your brain, as well as carrying out commands from your brain to various parts of your body.
Some of those signals, like the ones to your heart and gut, are automatic. Others, like the ones that control movement, are under your control.
From the paper’s Abstract:
Although studies have shown olfactory and hematogenous invasion into the CNS, coinciding with neuroinflammation, little attention has been paid to susceptibility of the PNS to infection or to its contribution to CNS invasion. Here we show that sensory and autonomic neurons in the PNS are susceptible to productive infection with SARS-CoV-2 and outline physiological and molecular mechanisms mediating neuroinvasion.
…
Additionally, we demonstrate, in vitro, that neuropilin-1 facilitates SARS-CoV-2 neuronal entry. SARS-CoV-2 rapidly invades the PNS prior to viremia, establishes a productive infection in peripheral neurons, and results in sensory symptoms often reported by COVID-19 patients.
Viremia is the presence of viruses in the bloodstream, so let that last statement sink. It is an important part of this discussion. Also remember in our previous installments that 60-80% of those infected with SARS-CoV-2 experience some neurological symptoms and for many this will persist for months or longer after the acute phase of the infection.
As anosmia is a primary symptom of COVID-19, early studies assessed CNS invasion via olfactory sensory neurons (OSNs) using transgenic mice expressing human angiotensin converting enzyme 2 (hACE2), the receptor for SARS-CoV-2 [14–16]. Virus detection in OSNs and sustentacular cells confirmed these cells as viable routes into the CNS. However, the oronasal mucosa and target organs of SARS-CoV-2 (lungs, gut) are heavily innervated by sensory and autonomic neurons of the PNS, providing an alternative route of entry directly into peripheral neurons from the mucosa rapidly upon infection, which could facilitate invasion into functionally connected CNS tissues … Since PNS symptoms are often reported among non-hospitalized COVID-19 patients, who constitute the majority of those infected, and up to one-third of those with post-COVID-19 syndrome, understanding the susceptibility of the PNS to SARS-CoV-2 infection and the functional consequences thereof is essential [17,18].
This is a pretty cool component of the study. They determine whether the PNS infection preceded that of the CNS.
To determine if infection of the PNS preceded and contributed to CNS infection, we assessed early neuroinvasion of CNS tissues functionally connected to peripheral neurons innervating oronasal and gut mucosa (lumbosacral spinal cord and specific brain regions [olfactory bulb, cortex, hippocampus, brainstem, cerebellum]). We also characterized viral growth kinetics in primary PNS neuronal cultures and investigated the contribution of neuropilin-1 (NRP-1) to entry into PNS neurons.
They move on to discuss the odds ratio for an ancestral infection (4.0) and Omicron (.18). This surprised me at first. One of the first parts of the results Focuses on the PNS Sensory Trigeminal Ganglia (TG) and Sympathetic Superior Cervical Ganglia (SCG). Even a layman can see the constrasts between the uninfected and infected TG and SCG. This substack would be too long if I included all the results Figures, my intention is to give you an idea of how they go about the different components of the PNS/CNS.
(d) Immunofluorescence for SARS-CoV-2 nucleocapsid (SARS-N, grey)- and NeuN (red)-labeled neurons in TG and SCG sections at 6 dpi in 105 PFU-inoculated mice. SARS-N was more prevalent in hACE2 than in WT but observable in both. No SARS-N was detected in ganglia from uninfected animals. Neurons in SCG were particularly sensitive to infection; in the magnified single z-plane of the area shown in the yellow box on hACE2-infected SCGs, significant vacuolization can be observed in infected hACE2 SCG cells. Contrast for NeuN was increased in the z-plane to better illustrate residual NeuN immunoreactivity inside SARS-N-negative vacuoles in the SCGs. This cytopathology was common across numerous SCGs in hACE2 mice. (e) Immunofluorescence for SARS-CoV-2 spike (SARS-S, grey)- and NeuN (red)-labeled neurons in TG and SCG sections at 6 dpi in 105 PFU-inoculated mice. Immunostaining was similar to that for SARS-N, with greater SARS-S in hACE2 neurons, but present in both. Vacuolization was again observed in SCG neurons. SARS-S was absent in uninfected neurons. (f) Immunofluorescence for double stranded RNA (dsRNA, grey)- and NeuN (red)-labeled neurons
The subsequent sections focus on the PNS Sensory Lumbosacral Dorsal Root Ganglia (LS-DRG) and CNS Lumbosacral Spinal Cord (LS-SC) Neurons Are Susceptible to Infection, Individual Brain Regions Support Varying Levels of Viral Invasion and Reproduction, Neuroinvasion of the PNS and CNS Occurs before Viremia, and Neuronal Entry in the PNS Involves Neuropilin-1 (NRP-1). I urge you to go through the paper and examine the Figures for these sections. The depth of this study is amazing! It only took me 2.5 hours to read it. I do want you to see this part on the varying levels of invasion in the brain. The bold typeface is mine.
We detected viral RNA in all brain regions at 3 dpi, which increased by 6 dpi, in both hACE2 and WT mice (Figure 3a–e). Higher viral RNA concentrations were found in hACE2 mice compared to WT mice in all regions, with the highest in the brainstem and hippocampus at 6 dpi. In WT mice, all regions contained similar quantities of SARS-CoV-2 RNA, suggesting that ACE2-independent spread or replication through the nervous system may differ from hACE2 mice. Infectious virus was recovered from the hippocampus and brainstem (3 log PFU/mg homogenate) as early as 3 dpi in hACE2 mice, supporting viral spread into the CNS from the PNS (Figure 3f). Unexpectedly, infectious virus was also recovered from the hippocampus (103 group: 2 PFU/mg homogenate; 105 group: 5 PFU/mg homogenate) and brainstem (105 group: 3 PFU/mg homogenate) from WT mice at 6 dpi. These results indicate that viral invasion and replication in the brain is not uniform, that the highest concentrations of virus are found in areas connected to the trigeminal and limbic systems, and that neuroinvasion is not solely dependent on hACE2 since the WT mice do not express this receptor.
The discussion is extremely long and technical, here are the highlights.
Neurotropic viruses can enter the nervous system hematogenously or through neural pathways. From the blood, they can infect vascular endothelial cells to access underlying tissues, transport across barriers inside extravasating leukocytes, or invade through cytokine-induced disruptions of the blood–brain barrier integrity. Viruses can enter neural pathways through peripheral sensory, autonomic, and/or motor axon terminals and reach the CNS by retrograde transport, often moving trans-synaptically along functionally connected pathways. SARS-CoV-2 likely uses both mechanisms. SARS-CoV-2 CNS invasion has been proposed via infection of OSNs in the nasal neuroepithelium, the olfactory bulb, and its cortical projections [14–16,24,26–28]. Organoid, stem cell, microfluidic, and mouse models, correlating with human autopsy findings, demonstrate disruption of endothelial barriers and choroid plexus integrity, as well as transcytosis of SARS-CoV-2, supporting hematogenous CNS entry as infection progresses to severe disease that results in death of the human host [5,24,33–37]. While OSNs are a key constituent of the nasal neuroepithelium, the oronasopharynx is innervated by other PNS sensory and autonomic pathways through which SARS-CoV-2 may enter the nervous system. Utilizing hACE2 mice, WT mice, golden Syrian hamsters, and primary PNS neuronal cultures, we show susceptibility of PNS neurons to SARS-CoV-2 infection very early following infection within 18 h of exposure, demonstrating differential replication kinetics and cytopathic outcomes following infection of sensory, autonomic, and central neurons. We also show evidence supporting axonal transport of SARS-CoV-2 from the PNS to the CNS, preceding viremia, through functionally connected neural pathways. Furthermore, we show that NRP-1 is an entry factor for PNS neuronal entry in the absence of hACE2. As COVID-19 neurological symptoms are often related to peripheral neuron dysfunction, focusing solely on CNS neuroinvasion overlooks the potential impacts of SARS-CoV-2 in the PNS. …
Our results complement findings from post-mortem studies of COVID-19 patients, which have found viral RNA in the TGs of 14% of patients assessed with axonal damage and neuron loss in the TGs of some patients [37,38]. Our use of in vivo and ex vivo infections demonstrates that sensory trigeminal neurons are both susceptible and permissive to productive infection with SARS-CoV-2, culminating in the release of infectious virus, suggesting the TG can serve as an alternative route for CNS invasion …
Entry into TGs and SCGs following intranasal inoculation was expected, but detection of SARS-CoV-2 in LS-DRGs was unanticipated. Viral RNA in LS-DRGs at levels comparable to TGs in both animal models demonstrates that distal sensory neurons, regardless of their location, are equally susceptible to infection. …
Spinal cord involvement is becoming increasingly associated with COVID-19, and a recent review of spinal cord disorders in COVID-19 posited that direct invasion of the cord by SARS-CoV-2 could cause these pathologies [45]. Our results indicate that neurons in the LS-DRG and in the spinal cord are susceptible to SARS-CoV-2 infection, which results in allodynia, providing a rationale for a deeper investigation of the LS-DRG as a site of productive viral infection in COVID-19 and the possibility of directional axonal transport …
Notably, SARS-CoV-2 was detected in the PNS and CNS of WT mice and hamsters, indicating that hACE2 expression is not a strict requirement for neuronal infection. While NRP-1 has been shown to facilitate entry of SARS-CoV-2 in various non-neuronal tissues, we have shown, using cultured primary adult sensory neurons in vitro, that NRP-1 facilitates viral entry in the PNS, thus providing a molecular mechanism for direct neuronal invasion.
One of the most incredible and thorough studies I have read. Thank you, Dr. Joffe!
Stay safe and help those who need it most.
take care,
Joe
FYI’s:
SARS-CoV-2 is a vascular virus, not just a respiratory virus. To make it simpler for folks call it a whole-body virus. No organ is spared. It infects our entire body and creates reservoirs throughout and should be thought of as a Long Covid virus and will exploit pre-existing risk factors.
Interviews Dr. Michael Hoerger, Dr. David Joffe, and Dr. Yaneer Bar-Yam.
Check out this article. I love this article, an easy read but it stimulates the brain in many ways.
Viruses Finally Reveal Their Complex Social Life - Quanta Magazine
Where do viruses hide in the human body? | The BMJ
Understanding immunity and viruses through the John Snow Project
Variant tracking at the CDC
Infections at WHN (updated!)
The neuroinvasiveness, neurotropism, and neurovirulence of SARS-CoV-2: Trends in Neurosciences (cell.com)