Share this page!

Enter URL or ID to Unroll

You can paste full URL like: https://x.com/threadreaderapp/status/1644127596119195649
or just the ID like: 1644127596119195649

How to get URL link on X (Twitter) App

  1. On the Twitter thread, click on or icon on the bottom
  2. Click again on or Share Via icon
  3. Click on Copy Link to Tweet
  4. Paste it above and click "Unroll Thread"!
  5. More info at Twitter Help
Nick #RespiratorsFilterPathogens😷 Anderegg Profile picture
@NickAnderegg
Jul 7, 2024 • 28 tweets • 10 min read • Read on X
Scrolly
GUESS WHAT?! A new study has shown SARS-CoV-2 infection is DISTINCT from common respiratory viruses!

Unequivocally, COVID is NOT "just a cold."

These findings are HUGELY significant, for multiple reasons! Here's a breakdown of the study (written for a general audience)...
1/16 SARS-CoV-2 infections—both symptomatic and asymptomatic—produce distinct host immune responses compared to human rhinovirus infections (the common cold), influenza virus infections, and RSV infections. That is, SARS-CoV-2 induces a set of changes in gene expression with significantly higher magnitude of change compared to other common respiratory viruses. For each of the four viruses, the column on the left shows differential gene expression (relative to controls) for symptomatic infections, while the column on the right shows differential gene expression for asymptomatic infections. Note...
The paper is fairly complicated, so I'm going to start with the high-level takeaways before explaining everything in more detail.

Overall, they found a 3-gene signature that distinguishes SARS-CoV-2 infections from common viral infections—long before PCR test positivity!

2/ A T-Cell-Derived 3-Gene Signature Distinguishes SARS-CoV-2 from Common Respiratory Viruses Abstract: ..., we performed a multi-cohort analysis with integrated bioinformatics and machine learning. We collected 3730 blood samples from both asymptomatic and symptomatic individuals infected with SARS-CoV-2, seasonal human coronavirus (sHCoVs), influenza virus (IFV), respiratory syncytial virus (RSV), or human rhinovirus (HRV) across 15 cohorts. First, we identified an enhanced cellular immune response but limited interferon activities in SARS-CoV-2 infection, especially in asymptomatic cases. Se...
Because the signature:

1. is SPECIFIC to SARS-CoV-2,
2. is an EARLY indicator of infection,
3. is a DISTINCT pattern from other infections, and
4. even accurately identifies Omicron infections,

this discovery may be useful as a diagnostic tool AND a direction for treatment!

3/ "The 3-gene signature offered two major improvements to SARS-CoV-2 infection triage: specificity and early diagnostic power. ...showed superior diagnostic performance only in SARS-CoV-2 ... achieved excellent diagnostic performance in Omicron patients ... showed exceptional performance to identify SARS-CoV-2 infection before detectable viral RNA on RT-PCR testing.... ... The bioinformatics methods, including DEGs and WGCNA, provided biological insights into the stable SARS-CoV-2 specific candidate genes. The machine learning approaches on these candidates offered a better extrapolation po...
One of the major limitations of this study is that it's unknown how applicable this signature will be for immunocompromised individuals. Why?

Because T cells were the major source of this 3-gene signature being expressed! This is important, because...

4/ "Hence, we could not assess how the 3-gene signature would perform in patients with comorbidities, especially immune system-related disorders. Future studies validating the 3-gene signature should focus on addressing these limitations. In summary, our study aimed to uncover the unique pathogenesis of COVID-19 by investigating the differential host responses to prevalent viruses. We systematically identified a SARS-CoV-2-specific 3-gene signature that could independently distinguish asymptomatic and symptomatic individuals infected with SARS-CoV-2 from other respiratory viral infections. ...
This is YET ANOTHER study showing SARS-CoV-2 adversely impacts the immune system.

Monocyte abnormalities (decreases) were found in BOTH symptomatic and asymptomatic SARS-CoV-2 infections! Because monocytes INCREASE in normal immune response, this suggests monocyte infection!

5/ "In addition, the results of CIBERSORTx revealed a reduced level of monocytes in SARS-CoV2 infection, while other viruses introduced an elevated level of monocytes, especially in the symptomatic group (Figure 3A). SARS-CoV-2-related monocytic abnormalities have been observed in both symptomatic [53] and asymptomatic cases [17]. The possible mechanism might be that the monocytes could be directly infected with SARS-CoV-2, leading to pyroptosis [54]. Moreover, attention should be paid to the boosted levels of IFNG and TNF in COVID-19 (Figure 3B), as synergism of TNF-α and IFNG triggers i...
This study also found the same odd immune response patterns found by other studies: The immune system is STRONGLY activated (especially the inflammatory response), but the pathway responsible for signaling *targeted* attacks on infected cells is suppressed!

6/ "Host responses resulting in SARS-CoV-2 infection differed from several common respiratory viruses. These results were in line with previous in vitro studies [9] (Figure S5). Although part of ISGs (i.e., IFI27) were enhanced in SARS-CoV-2 infection (Figure 2A), moderate IFN responses have been a sign of COVID-19 (Figure 2C). The improved cellular immune response, such as strong T cell responses and high secretion of TNF, were observed, surprisingly in these asymptomatic subjects (Figures 2 and 3). It has been reported that asymptomatic SARS-CoV-2-infected individuals might develop an effi...
As shown in Figure 2C, BOTH symptomatic and asymptomatic SARS-CoV-2 activate identical cellular pathways, but with less inflammatory signaling for asymptomatic infections.

That is, even asymptomatic SARS-CoV-2 impacts processes usually unaffected by the other studied viruses!
7/ Figure 2C from the paper. This shows the pathways implicated by "differentially expressed genes" in symptomatic and asymptomatic cases of different viral infections. This shows that for both asymptomatic and symptomatic SARS-CoV-2 infections, there are many different cellular pathways that are strongly activated; there is usually much less activation of these pathways for HRV, IFV, and RSV in *symptomatic* infections than there is for SARS-CoV-2 in *asymptomatic* infections. This isn't good news. It suggests that the impacts of asymptomatic infections are likely similar to sympto...
This study strongly suggests that there are "distinct molecular mechanisms" at play during SARS-CoV-2 infections, relative to other common respiratory viruses.

It *unambiguously* shows, however, that even asymptomatic SARS-CoV-2 infections are NOT "just a cold."
8/ "Discovery and validation of SARS-CoV-2-specific host response genes have been calling [26]. To address this issue, an ideal dataset for biomarker discovery should include not only SARS-CoV-2 infections but also other respiratory infections (Figure 4). Therefore, we co-normalized datasets HRA000786 and GSE17156, which included both asymptomatic and symptomatic cases. With integrative bioinformatics and machine learning approaches, we identified that the combination of CLSPN, RBBP6, and CCDC91 was robustly associated with SARS-CoV-2 infection in both discovery and validation datasets. Col...
The authors validated their discovery with a longitudinal study that was able to detect even asymptomatic Omicron infections with high accuracy, long before a given patient is able to test positive with RT-PCR testing.

9/ "Research on the host responses to respiratory viruses could help develop effective interventions and therapies against the current and future pandemics from the host perspective. Here, we leveraged the substantial biological, clinical, and technical heterogeneity in publicly available respiratory virus datasets and identified a 3-gene (CLSPN, RBBP6, and CCDC91) host response signature for identifying the SARS-CoV-2 infection at either an asymptomatic or symptomatic stage. We validated this 3-gene signature in an independent longitudinal follow-up study and demonstrated that it performs ...
That's all the highlights! The study is Open Access and available at

The rest of this thread is going to be commentary/analysis of the details of the study...
10/16mdpi.com/1999-4915/16/7…
So what role do these genes play?

It seems to be a cascade that highjacks the innate and adaptive immune responses in a way that's advantageous for the SARS-CoV-2 virus itself. That's not to say that the virus *directly* increases expression of these genes...

11/ "We proposed that the upregulation of CLSPN, RBBP6, and CCDC91 by SARS-CoV-2 in T cells might create a cascade of effects that alter both the innate and adaptive immune responses. First, CLSPN plays a significant role in genomic stability during DNA replication [56]. ... CLSPN might help T cells manage the stress and damage induced by viral replication. Second, ... RBBP6 is involved in cell cycle regulation, apoptosis, and ubiquitination processes [58]. RBBP6 has been reported as a negative regulator of Ebola virus replication by mimicking the viral protein [59]. ... RBBP6 might preven...
Rather, these are the common product of the cascade of dysfunctional processes triggered by SARS-CoV-2 infection. This study identified a unique signature of *differentially expressed genes*, but there's not a 1:1 cause and effect for differential expression of a given gene!

12/ "Although there is limited specific information on the expression changes of CCDC91 in response to viral infections, CCDC50, a related gene to CCDC91, negatively regulated the type I IFN signaling pathway initiated by RIG-I-like receptors (RLRs), the sensors for RNA viruses [60]. Together, these genes may in concert with T cells not only respond to viral infections effectively through cellular immunity but also regulate the immune response to avoid excessive inflammation or autoimmunity. Further experimental validation and research would be essential to elucidate these proposed mechanisms...
The methods were thorough, in that they cross-validated all of their findings multiple ways to ensure they weren't picking up on some spurious signal in the data. Even if the genes turn out not to be meaningful for *pathogenesis*, they're VERY meaningful for *diagnosis*!

13/ Image
IMO, there's one big error. Figures 2A and 2B have slightly different Y-axes, likely because the graphs were generated separately, but it actually has the effect of shrinking a range that is *unexpectedly* larger.

I aligned the scales on Figures 2A and 2B here

14/ Image
When symptomatic and asymptomatic gene expression for each virus are put side by side, it's clear that SARS-CoV-2 has a wildly different pattern compared to the other viruses, and a vastly larger magnitude of effect.

Differential expression INCREASES in asymptomatic covid?!

15/ SARS-CoV-2 infections—both symptomatic and asymptomatic—produce distinct host immune responses compared to human rhinovirus infections (the common cold), influenza virus infections, and RSV infections. That is, SARS-CoV-2 induces a set of changes in gene expression with significantly higher magnitude of change compared to other common respiratory viruses. For each of the four viruses, the column on the left shows differential gene expression (relative to controls) for symptomatic infections, while the column on the right shows differential gene expression for asymptomatic infections. Note...
Most notably, T cells are the PRIMARY type of cell where the 3-gene signature is most differentially expressed... and it's specifically a pattern that will lead to T cell exhaustion through overactivation.

Say it with me: "COVID is airborne and exhausts T cells!"

16/end 3.4. T Cells Are the Primary Source of the 3-Gene Signature We used single-cell RNA sequencing (scRNA-seq) profiles of 15,639 cells from PBMC samples of 7 individuals (4 SARS-CoV-2 infections, 3 Controls) to identify the cell types that express the 3-gene signature. Visualization using UMAP illustrated the infection status (Figure 5A) followed by cell type (Figure 5B). T cells had the highest scores (Figure 5C), and 3-gene signature scores were significantly higher in T cells from patients with SARS-CoV-2 infection (Figure 5D), especially in activated CD4 T cells, mucosal-associated invarian...
Afterthought: The bit about “discovery should include not only SARS-CoV-2 infections but also other respiratory infections” is an echo of another paper about HCoV-OC43… from 1980! There, the author also complained about lack of dataset diversity



17/16
Discovery and validation of SARS-Co V-2-specific host response genes have been calling 26]. To address this issue, an ideal dataset for biomarker discovery should include not only SARS-CoV-2 infections but also other respiratory infections (Figure 4). Therefore, we co-normalized datasets HRA000786 and GSE17156, which included both asymptomatic and symptomatic cases. With integrative bioinformatics and machine learning approaches, we identified that the combination of CLSPN, RBBP6, and CCDC91 was robustly associated with SARS-CoV-2 infection in both discovery and validation datasets. Collect...
I’m not sure if it would, because at least one of the genes is involved in one type of cell entry, and there’s evidence that persistent infections may use *different* methods to move between cells that possibly wouldn’t engage that gene!

18/16
2. Lots of things can cause lymphopenia! () It's just usually *temporary* with most non-HIV causes.

1. Like the HIV patients on death's door in the 90s, who are alive today thanks to HAART, recovery may be possible

19/16
en.wikipedia.org/wiki/Lymphocyt…

The most common cause of temporary lymphocytopenia is a recent infection, such as the common cold.[citation needed] Lymphocytopenia, but not idiopathic CD4+ lymphocytopenia, is associated with corticosteroid use, infections with HIV and other viral, bacterial, and fungal agents, malnutrition, systemic lupus erythematosus,[3] severe stress,[4] intense or prolonged physical exercise (due to cortisol release),[5] rheumatoid arthritis, sarcoidosis,[6] multiple sclerosis,[7] and iatrogenic (caused by other medical treatments) conditions. Lymphocytopenia is a frequent, temporary result from man...
Simply put, if the cause of dysregulation is removed, the immune system can *likely* recover.

Time is the enemy, in this case! Cancer is a huge concern here, because without immune cells, cells with defective DNA will be ignored and grow into tumors
20/16
Opportunistic infections are the biggest concern with a compromised immune system (lack of defenses), but when an individual has effectively zero immune system, the body isn't able to perform basic janitorial tasks that clean up random defective processes!

21/16
Sure! Here's a meta-annotated version of the graph with simplified explanations of each element. The graph itself is fairly noisy, but the takeaways are simple!

tl;dr: larger graph = more intense response

[Quoted tweet was referring to the graph]
22/16

Image
Lack of symptoms may not even be because of immune system *destruction*! Symptoms of cold and flu are driven by interferon signaling, which SARS-CoV-2 suppresses.

But the end result is the same: lack of effective immune response!

23/16
The immune system has a vast range of functions spread across different systemic and cellular mechanisms.

It's likely that there are many people walking around with a compromised innate immune system, who don't realize it as leftover adaptive defenses fight infections

24/16
This discovery seems to have a clear path to commercialization, because this discovery is purely a new method of *analyzing* the results of existing types of Nucleic Acid Amplification Tests (NAAT), including RT-PCR and LAMP testing. It's software!

25/16
The advantage here is that, rather than requiring detection of a specific viral protein (which may be present in the body but not the swab location), it requires detection of elevated levels of HOST PROTEINS that indicate active viral infection!

26/16
Here's the entire thread about the article "A T-Cell-Derived 3-Gene Signature Distinguishes SARS-CoV-2 from Common Respiratory Viruses," on a single page for easier sharing:
readwise.io/reader/shared/…
[Caveat: This doesn’t apply to people trying supplements as *treatment*]

Supplements will have no effect. The deficiencies associated with severe covid/LC are likely a product of the infection itself, because the virus is dysregulating the production processes

27/16

• • •

Missing some Tweet in this thread? You can try to force a refresh
　

Keep Current with Nick #RespiratorsFilterPathogens😷 Anderegg

Nick #RespiratorsFilterPathogens😷 Anderegg Profile picture

Stay in touch and get notified when new unrolls are available from this author!

Read all threads

This Thread may be Removed Anytime!

PDF

Twitter may remove this content at anytime! Save it as PDF for later use!

Try unrolling a thread yourself!

how to unroll video
  1. Follow @ThreadReaderApp to mention us!

  2. From a Twitter thread mention us with a keyword "unroll"
@threadreaderapp unroll

Practice here first or read more on our help page!

More from @NickAnderegg

Nick #RespiratorsFilterPathogens😷 Anderegg Profile picture
Sep 7
Let’s talk about systemic risk from negligent public health: Catastrophe doesn’t require population-wide illness.

The worst case isn’t sickness. Worst case is infrastructure collapse due to overstressed resources.

You know power plants need stable power to operate?

1/many “8. Performance of Nuclear Power Plants Affected by the Blackout On August 14, 2003, nine U.S. nuclear power plants experienced rapid shutdowns (reactor trips) as a consequence of the power outage. Seven nuclear power plants in Canada operating at high power levels at the time of the event also experienced rapid shutdowns. […]. Many non-nuclear generating plants in both countries also tripped during the event. Numerous other nuclear plants observed disturbances on the electrical grid but continued to generate electrical power without interruption. […] - The severity of the grid transient...
If there is a widespread disruption in the service area of, e.g., a nuclear power plant, it shuts down for safety. Massive blackouts like in 2003 or in Spain this year are caused by safety systems!

If too much trips out at once, it has a ripple effect across the grid
2/ Source: https://www.insurancejournal.com/news/international/2025/04/29/821703.htm Why Restarting a Power Grid After Massive Collapse Is So Hard April 29, 2025 by Rachel Morison and William Mathis It’s a worst case scenario that grid operators plan for but hope never to encounter. After one of the worst blackouts in Europe in more than a decade, electricity grid operators in Spain and Portugal are trying to get networks back up and running from the ground up. The initial estimate from grid operator Red Electrica was that restoring all power supply in Spain may take between six and 10 hour...
Frequency Factor So far, the only information about what caused the crisis was a comment from grid operator Red Electrica that the blackout was a result of “oscillation,” which suggests a disruption in the grid’s frequency or voltage — both crucial factors for maintaining stability. The frequency, which normally stays pretty steady around 50 hertz, is the heartbeat of the grid. Frequency monitoring specialist Gridradar said it identified a rapid movement in frequency just after noon in Spain — right before the blackout hit. Such oscillations can cause chain reactions that ultimately lead ...
In 2003, it took 2 days to fully restore most power. The infrastructure is 20 years older than it was back then and higher demand creates risk of cascading failure.

As of 2003, recommendations from blackouts in 1965, 1977, 1982, 1996, and 1998 had not been implemented.
3/ “Recommendations to Prevent or Minimize the Scope of Future Blackouts As reported in previous chapters, the blackout on August 14, 2003, was preventable. It had several direct causes and contributing factors, including: • Failure to maintain adequate reactive power support • Failure to ensure operation within secure limits • Inadequate vegetation management • Inadequate operator training • Failure to identify emergency conditions and communicate that status to neighboring systems • Inadequate regional-scale visibility over the bulk power system.”
“Further, as discussed in Chapter 7, after each major blackout in North America since 1965, an expert team of investigators has probed the causes of the blackout, written detailed technical reports, and issued lists of recommendations to prevent or minimize the scope of future blackouts. Yet several of the causes of the August 14 blackout are strikingly similar to those of the earlier blackouts. Clearly, efforts to implement earlier recommendations have not been adequate. Accordingly, the recommendations presented below emphasize comprehensiveness, monitoring, training, and enforcement of r...
“1. Market mechanisms should be used where possible, but in circumstances where conflicts between reliability and commercial objectives cannot be reconciled, they must be resolved in favor of high reliability. 2. Regulators and consumers should recognize that reliability is not free, and that maintaining it requires ongoing investments and operational expenditures by many parties. Regulated companies will not make such outlays without assurances from regulators that the costs will be recoverable through approved electric rates, and unregulated companies will not make such outlays unless th...
“3. Recommendations have no value unless they are implemented. Accordingly, the Task Force emphasizes strongly that North American governments and industry should commit themselves to working together to put into effect the suite of improvements mapped out below. Success in this area will require particular attention to the mechanisms proposed for performance monitoring, accountability of senior manage-ment, and enforcement of compliance with standards. 4. The bulk power systems are among the most critical elements of our economic and social infrastructure. Although the August 14 blackout ...
Read 20 tweets
Nick #RespiratorsFilterPathogens😷 Anderegg Profile picture
Sep 4
If Florida drops vaccine mandates, society is probably officially over. I really, really, really don’t think most people get that herd immunity is the only thing keeping measles from ripping through the population, and a measles infection wipes out all pre-existing immunity

1/3
Measles specifically infects the cells that are responsible for “remembering” which pathogens your body has encountered before. So they ALL get wiped out, and all you’re left with is cells that remember your measles infection and nothing else.

2/3
Every infection, vaccination, and other pathogenic exposure you’ve ever had? Your body no longer knows how to detect them after a measles infection. The only immunity you’ll be left with is immunity to measles. That’s it. Open season for every other pathogen encountered.

3/3
Read 8 tweets
Nick #RespiratorsFilterPathogens😷 Anderegg Profile picture
Jun 30
Can I say something? I have a BA in psych, a BPhil in linguistics, and went to grad school for cognitive psych. My research, including an undergrad fellowship, was on the cognitive relationship between written and spoken language…

Audiobooks are NO DIFFERENT than reading print.
In the last hour, there have been a dozen replies from people nitpicking the first tweet

The topic of discussion is "do audiobooks 'count' as reading?," and the answer is "Audiobooks are NO DIFFERENT than reading print."

Maybe read the thread before arguing with it? lmfao
And for all those people with indignant responses who want to nitpick every detail, the fact that so many people hold THIS exact view—that audiobooks are somehow “cheating”—is the ENTIRE point. It leads to people who would benefit from audiobooks depriving themselves the medium
Read 4 tweets
Nick #RespiratorsFilterPathogens😷 Anderegg Profile picture
Feb 1
Many people are asking for recommendations about what storage media to buy, so here's a buying guide from an experienced data hoarder (me)

The MOST IMPORTANT thing to know is that SOLID-STATE MEDIA IS NOT DURABLE. Flash drives, SSDs, SD cards, etc. are NOT long-term storage.

1/
That's not to say that it's impossible to use solid-state media for long-term storage. It's just that anything with durability guarantees gets prohibitively expensive quickly. Spinning hard drives—as well as DVDs and Blu-ray discs!—are your friend.

2/
- The way data is stored in solid-state media makes it much more susceptible to bit rot than other media.
- In a spinning hard drive, the moving parts are the most common point of failure.
- When you burn a DVD, that shit is fairly permanent.

3/
Read 42 tweets
Nick #RespiratorsFilterPathogens😷 Anderegg Profile picture
Jan 9
I wish people would understand that insurance underwriters have armies of actuaries calculating risks, and if an insurance company drops you, it's because things have changed in such a way that insuring you will take more out of the financial pool than you're putting in

1/
It sucks, but it's a direct result of the fact that humans are widely inhabiting locations that are rapidly becoming impossible to inhabit safely. If you can't find insurance for your home, it means there's a high likelihood you'll need to move soon anyway.

2/
You get insurance so that you can replace all of your stuff in the event of a disaster. When the insurance company effectively says "the risk of disaster is so high that insuring you would almost certainly cause us to lose a lot of money," it ALSO means your life is in danger

3/
Read 7 tweets
Nick #RespiratorsFilterPathogens😷 Anderegg Profile picture
Jan 5
So here’s the thing about some of the subtle neuro damage related to SARS-CoV-2 infection that I think a lot of people miss: some of the known deficits are correlated with things like impulsiveness and poor emotional control, so we might expect to see deficits there are well

1/
Consider how impatient people seem to be on the road in the last couple years relative to the 2010s, and I think we have a perfect example of where this is LIKELY already manifesting.

2/
This impact is particularly insidious for the person experiencing it, because poor impulse control, by definition, doesn’t really come on gradually. My biggest concern is how interactions under these circumstances will play out if this impact continues to become more common

3/
Read 15 tweets

Did Thread Reader help you today?

Support us! We are indie developers!

This site is made by just two indie developers on a laptop doing marketing, support and development! Read more about the story.

Become a Premium Member ($3/month or $30/year) and get exclusive features!

Become Premium

Don't want to be a Premium member but still want to support us?

Make a small donation by buying us coffee ($5) or help with server cost ($10)

Donate via Paypal

Or Donate anonymously using crypto!

Ethereum

0xfe58350B80634f60Fa6Dc149a72b4DFbc17D341E copy

Bitcoin

3ATGMxNzCUFzxpMCHL5sWSt4DVtS8UqXpi copy

Thank you for your support!

Follow Us!

Send Email!

:(