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Nick #RespiratorsFilterPathogens😷 Anderegg Profile picture
@NickAnderegg
Jul 7, 2024 • 28 tweets • 10 min read • Read on X
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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

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More from @NickAnderegg

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/
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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/
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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

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Read 15 tweets
Nick #RespiratorsFilterPathogens😷 Anderegg Profile picture
Jan 3
Let's review some major points in the Nukit controversy, since some people are unclear:

- Someone criticized someone's use of Nukit lanterns.
- Nukit attacked the critic because, as noted, this is how they market
- Nukit now demands "mediation" with the community (how??)

1/ @marigoldglitter: "these tools should be used for people who must be in public despite the dangers, not for white men who want to eat in restaurants and maintain the status quo. if this is what you're gonna use these for, give them to a disabled person who can't go to the doctor b/c of risk." Nukit: ""White man" in this case is buying those products from non-white small businesses who are focused on providing the community with effective, tested mitigations at far, far lower costs than anyone else." OP: "Like why are you coming at me with this aggressive...
Nukit: "If you are in the US, and would like to purchase Far-UVC products, we cannot help you at this time. We tried to resolve the issues there, but the US COVID-Aware community was uninterested in mediation or intercession. As a result of that disinterest, a great deal of harm was done. When stock is finished, we will not be selling our products to the Us anymore. If you are in the US and want Nukit products, would like 333 million Americans, many disabled or immune compromised, to be able to access the most affordable Far-UVC on the market, kindly address the people who made it unsa...
So let's look at this a bit more critically. Here is the "evidence" Nukit provided that the didn't say anything racist. First of all, these aren't the comments in question, but it's worth a look anyway.

2/ Ok, I get that "evidence," "citations," and "personal accountability" are going to be called racist, but since people insist on just spewing lie after lie without any pushback- here's what actually happened. @marigoldglitter- a white woman attacked a Nukit customer who was supporting us by showing our products. This is something we rely on to fund research and donations. If our customers do not do this, that money goes to paid advertising. So yes, attacking our customers is attacking our company and directly harming marginalized folks who receive our products. ...
Seems to be framed this way because Nukit knows it's not an adequate explanation, so they're acting like anyone who criticizes them is in the wrong. --- A bigoted comment is a bigoted comment, even if it's not directed at someone who might be personally offended. Of course, Nukit didn't include the comments people actually call racist! --- Nukit is explicitly saying here that they view any criticism as an "attack," because criticisms can potentially hurt their business goals. Fundamentally, Nukit is angry that this usage of their products are being criticized. --- After Nuki...
Let's be clear about what happened here: Someone lamented the unequal access to protective measures and criticized someone who seems to be using a certain device to *maintain the status quo*, and the manufacturer of the device found it unacceptable.

3/
Read 16 tweets
Nick #RespiratorsFilterPathogens😷 Anderegg Profile picture
Oct 9, 2024
NEW STUDY! This exploratory study identifies a SPECIFIC PHENOTYPE OF LONG COVID that appears related to NEUROMUSCULAR DISTURBANCE rather than lung damage—and they've termed it Complex Ventilatory Dysfunction!

Breakdown of the paper (thread written for a general audience!)...

1/ Published Oct 7, 2024: "A new phenotype of patients with post-COVID-19 condition is characterised by a pattern of complex ventilatory dysfunction, neuromuscular disturbance and fatigue symptoms" Abstract: Background Patients with post-COVID-19 condition frequently suffer from chronic dyspnoea. The causes and mechanism for dyspnoea in these patients without evidence of structural lung disease are unclear. ... Results ... A pattern of reduced forced vital capacity (FVC), but normal total lung capacity (TLC), termed complex ventilatory dysfunction ... was observed and occurred mo...
Broadly speaking, there are two groups of acute covid outcomes involving dyspnea (shortness of breath) as a long-term symptom:

- Severe cases that may have physical lung damage
- "Mild" cases that now have ME/CFS-like features, but who have no evidence of lung damage!

2/ "Current evidence suggests that cellular damage, a robust innate immune response with inflammatory cytokine production and a procoagulant state induced by SARS-CoV-2 infection are factors potentially contributing to post-COVID-19 sequelae such as dyspnoea, fatigue, and cognitive and mental disturbances... Dyspnoea has been well characterised as a major clinical symptom of post-COVID condition after severe and critical COVID-19 and is correlated with impaired lung function in terms of pulmonary restriction, and with reduced diffusion capacity as a possible consequence of pulmonary remod...
In this study, they explored this distinction further and identified a distinct subset of patients with a pattern of breathing abnormality that they have termed complex ventilatory dysfunction (CVD).

So how did they arrive at this conclusion? Let's dig in!

3/16 "We hypothesise that patients suffering from post-COVID-19 condition who have fatigue and exertional intolerance also have a reduction in respiratory muscle strength, causing a dysfunctional breathing pattern which is distinct from typical pulmonary sequelae after COVID-19 such as obstruction, restriction or impaired diffusion capacity. Based on clinical observations, we describe a new breathing abnormality termed complex ventilatory dysfunction (CVD), defined as total lung capacity (TLC) - forced vital capacity (FVC) >10% predicted value and absence of restriction (TLC ≥ lower limit o...
Read 16 tweets
Nick #RespiratorsFilterPathogens😷 Anderegg Profile picture
Sep 22, 2024
NEW STUDY! It VERY thoroughly supports the hypothesis that SARS-CoV-2 emerged as a zoonotic spillover event in the Huanan Seafood Wholesale Market—using multiple methods!

Breakdown of the paper (written for a general audience!)...

1/many (but it's worth it, I promise!) Published Sep 19, 2024 in Cell: "Genetic tracing of market wildlife and viruses at the epicenter of the COVID-19 pandemic" Highlights: - Common ancestor of SARS-CoV-2 linked to Huanan market matches the global common ancestor - Wildlife mitochondrial DNA identified in samples from stalls positive for SARS-CoV-2 Abstract: "... We demonstrate that market-linked severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genetic diversity is consistent with market emergence and find increased SARS-CoV-2 positivity near and within a wildlife stall. We identify wildlife DNA in...
This paper reanalyzes the same data from the April 2023 paper in Nature that cast doubt on the Huanan Market hypothesis (pictured).

In the new paper published in Cell this week, another group conducted far more detailed (and statistically sound) analyses!

2/
Original paper that analyzed this same data: "Surveillance ofSARS-CoV-2 at the Huanan Seafood Market" "Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019, emerged in December 2019. Its origins remain uncertain. It has been reported that a number of the early human cases of coronavirus disease 2019 had a history of contact with the Huanan Seafood Market...."
"...It should be noted that the selection of shops for sampling was biased because shops selling wildlife as well as shops linked to early cases were prioritized for sampling. The origin of the virus cannot be determined from the analyses available so far. Although gene barcode analysis of animal species in the study suggested that Myotis, Nyctereutes and Melogale-species that have been recognized as potential host species of sarbecoviruses-were present at the market, these barcodes were mostly detected within the SARS-CoV-2 RT-qPCR-negative samples from the environment. It remains pos...
This new paper starts by reviewing the evidence supporting the Huanan Market hypothesis, and some of the details are FASCINATING!

To begin with, of the 174 COVID cases identified with an onset of December 2019, 32% had a link to the Huanan Market.

In a city of 12 million.

3/ "INTRODUCTION Many of the earliest known cases of COVID-19 worked at or visited the Huanan Seafood Wholesale Market ("Huanan market") in the city of Wuhan, a link first made by clinicians at different hospitals throughout the city. Retrospective review of early COVID-19 cases identified 174 patients with onset in December 2019, 32% of whom had an ascertained link to this location, within a city of over 12 million."
Read 24 tweets

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