The Virus That Hijacks Your Immune System's First Responders
The virus doesn't even need to be alive to do this. This is about a pathogen that has evolved sophisticated mechanisms to disarm our defenses from the moment of contact.
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Why some people get devastatingly sick from COVID-19 while others barely notice they're infected
We're three years past the acute phase of the pandemic, and most of us have moved on. We've filed COVID-19 away in our mental folder marked "dealt with" alongside other collective traumas we'd rather not revisit. But here's the thing about viruses that fundamentally alter how our immune systems work: they don't care about our psychological readiness to move on.
New research is revealing something deeply unsettling about SARS-CoV-2 that goes far beyond its ability to replicate and cause direct tissue damage. This virus appears to be actively manipulating our immune system's first responders—neutrophils—turning them from protectors into saboteurs. And it's doing this within hours of exposure, potentially determining who lives, who dies, and who suffers long-term consequences before we even know we're infected.
The Puppet Master Virus
Think of your immune system as a sophisticated military operation. Neutrophils are the rapid response team—they arrive first at any sign of trouble, ready to fight. But what if an invader could somehow reprogram these first responders to work against their own army?
That's exactly what researchers led by Shia and colleagues discovered SARS-CoV-2 can do. Within just one hour of exposure to the virus, healthy neutrophils begin expressing surface markers that transform them into immune suppressors. They become what scientists call polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs)—essentially turncoat cells that actively shut down the T-cell response your body desperately needs to clear the infection.
The most chilling part? The virus doesn't even need to be alive to do this. Dead viral particles trigger the same response. This isn't about viral replication running amok—this is about a pathogen that has evolved sophisticated mechanisms to disarm our defenses from the moment of contact.
The Early Warning System We Ignored
Here's where this research gets personally relevant for anyone who's wondered why their COVID experience was so different from their neighbor's. The study found that people who would later develop severe disease already had dramatically elevated neutrophil counts within the first three days of hospitalization—before they got sick enough for intensive care, before they needed ventilators, before their families got those terrifying phone calls.
These early neutrophil signatures were better predictors of severe disease than age or BMI—two factors we've obsessed over throughout the pandemic. Let that sink in. A simple blood test looking at specific neutrophil markers could potentially identify who's headed for trouble before they're in trouble.
But we weren't looking for this. We were focused on ventilators and treatments for people who were already critically ill, not on the cellular sabotage happening in the first hours and days of infection.
The Suppression Cascade
What makes this discovery particularly insidious is how these hijacked neutrophils operate. They don't just fail to do their job—they actively prevent other immune cells from doing theirs. Through a mechanism involving PD-L1 (a molecule that normally keeps immune responses in check), these altered neutrophils systematically shut down T-cells, the specialized fighters your body needs most to clear viral infections.
It's like having security guards who not only let intruders pass but also tie up the actual police when they try to respond. The virus creates its own protection detail using our own immune cells.
The researchers proved this by showing that when they blocked this PD-L1 pathway—using drugs similar to those used in cancer immunotherapy—they could restore T-cell function. The suppression was reversible, but only if you knew it was happening and had the tools to intervene.
The Questions We Should Be Asking
This research raises uncomfortable questions about our pandemic response and our ongoing relationship with this virus. If SARS-CoV-2 can fundamentally reprogram immune cells within hours, what does that mean for the people experiencing long-term symptoms? Are some of us walking around with persistently altered immune function?
More immediately: Why aren't we using these neutrophil markers clinically? If we can identify people likely to develop severe disease within days of infection, shouldn't that be standard practice? The technology exists. The knowledge exists. What we seem to lack is the institutional will to implement early intervention strategies based on immune profiling.
And here's the question that keeps me up at night: If this virus can so efficiently hijack neutrophils, what other immune cells might it be reprogramming? What other functions might it be altering that we haven't discovered yet?
The Broader Implications
This isn't just about COVID-19 anymore. This research reveals something fundamental about how certain pathogens can exploit our immune system's own regulatory mechanisms against us. It's a masterclass in viral manipulation that likely applies to other infections we haven't fully understood.
But it also offers hope. Understanding the mechanism means we can potentially intervene. The same pathway that allows SARS-CoV-2 to create immune suppression could be therapeutically targeted. We have drugs that can block PD-L1. We understand degranulation. We know how to modulate neutrophil function.
The tragedy is that this knowledge comes after millions of deaths and countless cases of long-term disability. We're always fighting the last war, always learning the lesson after we needed it most.
Moving Forward
As we navigate an endemic phase of COVID-19, this research should fundamentally change how we think about infection and immunity. We can't just focus on preventing transmission or treating severe disease. We need to understand and address the ways this virus hijacks our immune systems at the cellular level.
This means developing better early detection methods, creating targeted interventions for immune dysfunction, and acknowledging that COVID-19's impact on human health goes far deeper than respiratory symptoms.
Most importantly, it means recognizing that viruses aren't just external threats we can mask or vaccinate away. Some of them are sophisticated biological entities that can fundamentally alter how our bodies work, potentially for years or decades after the initial infection.
The virus that changed the world is still changing us, one neutrophil at a time. The question is whether we're ready to change how we respond to that reality.
This essay is based on research published by Shia and colleagues examining neutrophil suppression and immune dysfunction in COVID-19. While the mechanisms described are supported by peer-reviewed research, ongoing studies continue to refine our understanding of SARS-CoV-2's impact on immune function.
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STUDY MATERIALS
1. Briefing Document
Key Themes:
Neutrophil Abnormalities in Severe COVID-19: Severe COVID-19 is characterized by elevated neutrophil counts (neutrophilia) and reduced lymphocyte counts (lymphopenia). Neutrophilia is a predictor of poor disease outcome.
Emergence of PMN-MDSCs: A unique subset of neutrophils, PMN-MDSCs, is found in increased abundance in patients with severe COVID-19. These cells are identified by the expression of LOX-1.
SARS-CoV-2 Directly Induces PMN-MDSCs: The study provides evidence that SARS-CoV-2 directly triggers the transformation of healthy neutrophils into PMN-MDSCs, a process that is rapid and independent of viral replication.
PMN-MDSC Function and Immune Suppression: PMN-MDSCs in severe COVID-19 express immune checkpoint molecule PD-L1 and exhibit suppressive functions, particularly inhibiting T cell proliferation and cytokine production.
Mechanisms of PMN-MDSC Induction: The differentiation into PMN-MDSCs involves neutrophil degranulation and the exocytosis of granules containing LOX-1 and PD-L1.
Correlation with Disease Severity and Outcome: Elevated PMN-MDSC markers (LOX-1, PD-L1) and neutrophil activation markers (ROS) at early stages of hospitalization are associated with subsequent development of severe COVID-19 and potentially mortality.
Potential Therapeutic Target: The identification of PD-L1 on PMN-MDSCs as a mediator of T cell suppression suggests that inhibiting PD-L1 could be a potential therapeutic strategy to enhance the antiviral immune response in severe COVID-19.
Most Important Ideas/Facts:
Elevated Neutrophil Abundance and PMN-MDSCs are Hallmarks of Severe COVID-19: "Severe COVID-19 has been previously shown to be associated with increased neutrophil abundance in the peripheral blood." The study found that "neutrophils from individuals with severe COVID-19 were more likely to express LOX-1, a feature of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), and PD-L1, which inhibits T cell function."
SARS-CoV-2 Directly Induces PMN-MDSC Phenotype: A key finding is that "coculturing neutrophils with SARS-CoV-2 was sufficient to induce this PMN-MDSC phenotype." Furthermore, the virus "rapidly induced LOX-1 surface expression in healthy neutrophils independent of productive infection."
LOX-1 and PD-L1 Expression Correlates with Severe Disease and Predicts Outcome: "Both early LOX-1 and programmed death-ligand 1 (PD-L1) expression on neutrophils were associated with development of severe disease." The study also showed that "during the first 3 days of admission, the ANC... was significantly higher... in participants who subsequently developed severe COVID-19." Neutrophil PD-L1 expression was also "significantly higher at 0 to 3 days post– hospital admission in participants with subsequent severe COVID-19."
PMN-MDSCs Suppress T Cell Function via Degranulation and PD-L1: The study demonstrated that "SARS-CoV-2–stimulated LOX-1 neutrophils suppress autologous T cell proliferation and cytokine production." This suppressive function is mediated through degranulation and PD-L1 expression. "Our study revealed degranulation and PD-L1 expression as two mechanisms of immune suppression mediated by SARS-CoV-2–stimulated neutrophils."
LOX-1 and PD-L1 Are Stored in Neutrophil Granules: The induction of LOX-1 and PD-L1 expression on the cell surface upon SARS-CoV-2 exposure is due to degranulation. "LOX-1 and PD-L1 up-regulated on neutrophils through granule exocytosis."
PMN-MDSC Induction by SARS-CoV-2 is Distinct from Influenza: The study notes that "induction of LOX-1 was not induced by H1N1 influenza A virus." This "provides evidence of a specific effect of SARS-CoV-2 that may, at least in part, explain its enhanced pathogenesis."
Viral Load May Influence PMN-MDSC Abundance: "LOX-1 and PD-L1 MFIs directly correlated with viral MOI and suppression of T cell proliferation, cytokine production, and viability, suggesting that virus load may affect the abundance of PMN-MDSCs in vivo."
PD-L1 Inhibition as a Potential Therapeutic Strategy: The findings "support a role for PMN-MDSCs in mediating severe COVID-19, and inhibition of PD-L1 represents a potential therapeutic strategy for enhancing the immune response in acute SARS-CoV-2 infection."
Supporting Details and Nuances:
PMN-MDSCs are a heterogeneous population, and LOX-1 is identified as a marker for functionally suppressive human PMN-MDSCs.
Increased plasma elastase concentrations correlated with PMN-MDSC frequencies, suggesting elevated degranulation and NETosis.
The differentiation of neutrophils into PMN-MDSCs appears to be a distinct functional state of pathologic neutrophil activation rather than a separate lineage.
The study found no strong evidence for the involvement of ROS, nitric oxide, or arginase-1 as suppressive mechanisms in this context, although these are known features of PMN-MDSCs in other diseases.
While the study demonstrates the association and potential predictive value of these markers, it acknowledges the limitation of not being able to definitively determine a causal relationship between PMN-MDSCs and severe COVID-19 in this observational study.
The precise role of LOX-1 signaling in immune suppression remains unknown; it may be a marker or contribute to the suppressive activity.
Limitations:
Inability to definitively determine a causal relationship between LOX-1 PD-L1 PMN-MDSCs and severe COVID-19 disease.
Lack of access to BAL samples before the onset of severe disease to determine if PMN-MDSCs appear in the lungs prior to systemic elevation.
The specific role of LOX-1 signaling in immune suppression by these cells is not fully elucidated.
The in vitro model likely only characterized a subset of the heterogeneous LDN population.
Potential Implications:
These findings highlight the critical role of neutrophils in the immune response to SARS-CoV-2, particularly in the context of severe disease. The direct induction of immunosuppressive PMN-MDSCs by the virus provides a potential explanation for the impaired antiviral T cell responses observed in severe COVID-19. Targeting the formation or function of these PMN-MDSCs, particularly through PD-L1 inhibition, could offer a novel therapeutic avenue to improve outcomes in severe COVID-19 patients. Further research is needed to validate these findings in vivo and explore the optimal timing and strategies for modulating PMN-MDSC activity.
2. Quiz & Answer Key
Quiz
Answer each question in 2-3 sentences.
What is a notable difference in the immunological profile of severe COVID-19 compared to mild cases or healthy individuals, particularly concerning neutrophil and lymphocyte counts?
What specific cell surface marker is identified in the study as a feature of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and is found to be elevated in severe COVID-19?
What is the function of PD-L1 expression on neutrophils, as described in the study?
What did the in vitro experiments with healthy human neutrophils and SARS-CoV-2 demonstrate regarding the virus's direct effect on these cells?
What are low-density neutrophils (LDNs), and what was observed about their frequency in patients with COVID-19 compared to healthy controls?
Beyond LOX-1 and PD-L1, what other cellular mechanisms or molecules were investigated for their potential role in T cell suppression by SARS-CoV-2–stimulated neutrophils?
How did stimulating normal density neutrophils (NDNs) with SARS-CoV-2 affect their density?
What key cellular process is proposed as the mechanism by which LOX-1 and PD-L1 are rapidly expressed on the surface of neutrophils after SARS-CoV-2 stimulation?
What functional characteristic of PMN-MDSCs was tested in the study using cocultures of SARS-CoV-2–stimulated neutrophils and autologous T cells?
What potential therapeutic strategy for enhancing the immune response in acute SARS-CoV-2 infection is suggested based on the study's findings regarding PMN-MDSCs?
Quiz Answer Key
Severe COVID-19 is characterized by elevated neutrophil counts and reduced lymphocyte counts, a profile similar to some bacterial and fungal infections. This contrasts with the balanced counts seen in healthy individuals or those with mild disease.
The study identifies LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1) as a marker of PMN-MDSCs that is increased on neutrophils from individuals with severe COVID-19. Early LOX-1 expression correlated with the development of severe disease.
PD-L1 (programmed death-ligand 1) expression on neutrophils is described as a ligand of the immune checkpoint molecule PD-1. It functions to inhibit T cell proliferation and cytokine production, contributing to immunosuppression.
In vitro experiments showed that SARS-CoV-2 alone, independent of productive infection, rapidly induced LOX-1 surface expression on healthy neutrophils. This indicates a direct effect of the virus on neutrophil activation and differentiation.
LDNs are a subset of neutrophils found in the peripheral blood mononuclear cell compartment after density gradient centrifugation. Their frequency was significantly higher in patients with COVID-19, particularly those with severe disease, compared to healthy controls.
The study investigated the role of ARG-1 (arginase-1), ROS (reactive oxygen species), nitric oxide, IL-10, TNF, IL-1β, and cell-cell contact in T cell suppression by SARS-CoV-2–stimulated neutrophils. While ROS, TNF, and IL-1β were affected, the study concluded that degranulation and PD-L1 expression were primary suppressive mechanisms.
Stimulating normal density neutrophils (NDNs) with SARS-CoV-2 caused a transition to a lower density, resulting in a greater proportion of neutrophils being found in the buffy coat layer during density gradient centrifugation. This indicates that SARS-CoV-2 stimulation induces the formation of LDNs from NDNs.
Granule exocytosis is proposed as the mechanism for the rapid surface expression of LOX-1 and PD-L1. The study found that LOX-1 is stored within neutrophil granules and is released to the surface upon degranulation induced by SARS-CoV-2.
The ability of SARS-CoV-2–stimulated neutrophils to suppress T cell function was tested by coculturing them with autologous T cells. The study measured the inhibition of T cell proliferation and cytokine production as a definitive feature of PMN-MDSCs.
Inhibition of PD-L1 is suggested as a potential therapeutic strategy. Given that PMN-MDSC-mediated T cell suppression in severe COVID-19 is linked to PD-L1 expression, blocking this interaction could potentially enhance the antiviral immune response.
3. Essay Questions
Discuss the evidence presented in the study supporting the hypothesis that SARS-CoV-2 directly induces neutrophil differentiation into PMN-MDSCs, independent of viral replication or other factors.
Analyze the correlation between the expression of LOX-1 and PD-L1 on neutrophils and the severity of COVID-19 disease and patient outcomes as described in the study.
Evaluate the mechanisms by which SARS-CoV-2–stimulated neutrophils exert suppressive effects on T cells, focusing on the roles of degranulation and PD-L1 expression as identified in the research.
Compare and contrast the characteristics of neutrophils in healthy individuals, patients with mild to moderate COVID-19, and patients with severe COVID-19, highlighting the specific markers and functional changes observed in the study.
Explain the clinical implications of the study's findings regarding PMN-MDSCs in severe COVID-19, including their potential as predictive biomarkers and therapeutic targets.
4. Glossary of Key Terms
Neutrophils: The most abundant type of leukocyte (white blood cell) in humans, serving as first responders during infections and inflammation.
Lymphocytes: A type of white blood cell that is part of the immune system, including T cells, B cells, and natural killer cells.
PMN-MDSCs (Polymorphonuclear Myeloid-Derived Suppressor Cells): A heterogeneous population of myeloid cells, including a subset of neutrophils, that can suppress T cell responses.
LOX-1 (Lectin-like oxidized low-density lipoprotein receptor-1): A cell surface marker identified in the study as a feature of functionally suppressive human PMN-MDSCs.
PD-L1 (Programmed Death-Ligand 1): A protein expressed on the surface of some cells, including neutrophils, that binds to the PD-1 receptor on T cells and inhibits their activity.
T cells: A type of lymphocyte that plays a central role in cell-mediated immunity, including directly killing infected cells and regulating immune responses.
Degranulation: The process by which granules within immune cells, such as neutrophils, release their contents (proteins, enzymes, etc.) into the extracellular space or onto the cell surface.
LDNs (Low-Density Neutrophils): A subset of neutrophils that, due to changes in density, are found in the peripheral blood mononuclear cell (PBMC) layer during density gradient centrifugation.
NDNs (Normal Density Neutrophils): Neutrophils with typical density that pellet with red blood cells during density gradient centrifugation.
ROS (Reactive Oxygen Species): Chemically reactive chemical species containing oxygen, which can be produced by neutrophils as part of their antimicrobial function and also contribute to PMN-MDSC suppressive function.
NETs (Neutrophil Extracellular Traps): Structures composed of neutrophil DNA and proteins that are released to capture and neutralize pathogens.
WHO Disease Severity Score: A standard scoring system used to categorize the severity of COVID-19 disease.
MFI (Mean Fluorescent Intensity): A measure used in flow cytometry to indicate the average fluorescence signal from a cell population, often reflecting the abundance of a particular marker on the cell surface or intracellularly.
Granule Exocytosis: The process of releasing the contents of cellular granules to the outside of the cell.
Autologous: Referring to cells or tissues from the same individual.
In Vitro: Experiments conducted in a laboratory setting, outside of a living organism.
Ex Vivo: Experiments conducted on living cells or tissues that have been removed from an organism.
MOI (Multiplicity of Infection): The ratio of infectious agents (e.g., viruses) to target cells in an in vitro experiment.
5. Timeline of Main Events
Undated (Prior to COVID-19 Pandemic): Myeloid-derived suppressor cells (MDSCs) are initially identified in a murine lung carcinoma model as a heterogeneous population of myeloid cells that dampen T cell responses. LOX-1 is identified as a marker for functionally suppressive human PMN-MDSCs. MDSCs are known to be found in numerous diseases, including viral, parasitic, bacterial, and fungal infections, although their precise role and origin in viral infections are not fully understood.
Prior to COVID-19 Vaccine Availability (2020): Hospitalized patients with acute COVID-19 are recruited for a study at the Johns Hopkins health care system. Participants are categorized by the standard WHO severity score. Blood samples are collected from hospitalized patients with acute COVID-19 and healthy controls (HCs). Healthy donor leukopaks and whole blood are also obtained for in vitro experiments.
First Week of Hospital Admission (Specifically 0 to 3 days post-admission):Hospitalized participants with acute COVID-19 show elevated levels of low-density neutrophils (LDNs), degranulated neutrophils (CD63+ and CD11b+ LDNs), PMN-MDSCs (LOX-1+ LDNs), and immature neutrophils (CD10- LDNs) compared to HCs.
In participants who subsequently develop severe COVID-19, the absolute neutrophil count (ANC), ROS MFI, and neutrophil PD-L1 expression are significantly higher compared to those with mild to moderate COVID-19 throughout hospitalization.
Neutrophil LOX-1 MFI, degranulation markers (CD63, CD11b, and CD66b), CD54, and CD177 are not increased at this early time point in those with subsequent severe COVID-19.
A positive association is observed between LOX-1 and PD-L1 expression, and LOX-1 and ROS production in neutrophils.
T cell abundance is negatively associated with ANC and PMN-MDSC abundance.
Random forest models identify ANC, the frequency of LOX-1+ PD-L1+ neutrophils, and PD-L1 and CD62L expression as highly associated with later disease severity. Immature neutrophil abundance and CD63 and LOX-1 MFI on neutrophils are among the top features distinguishing individuals who recovered from those who died.
Plasma IL-8 and vascular endothelial growth factor concentrations positively correlate with LDN and PMN-MDSC frequencies, while interferon-λ1 (IFN-λ1) negatively correlates.
Analysis of publicly available neutrophil-enriched bulk RNA sequencing data shows differential upregulation of ARG1 and CD177 in severe versus mild COVID-19, but not ORL1 (LOX-1) or CD274 (PD-L1), suggesting posttranscriptional regulation of LOX-1 and PD-L1 expression.
4 to 7 Days Post–Hospital Admission: LDN and PMN-MDSC percentages are significantly increased in participants with severe versus mild/moderate COVID-19. PD-L1 mean fluorescent intensity (MFI) values remain significantly increased.
8 to 28 Days Post–Hospital Admission: LDN and PMN-MDSC percentages show a range in frequency in recovered, discharged patients.
During Acute COVID-19 (General Observations across hospital stay):Severe COVID-19 is characterized by elevated neutrophil and reduced lymphocyte counts.
Patients hospitalized with COVID-19 show evidence of neutrophil degranulation and increased expression of LOX-1.
Early LOX-1 and PD-L1 expression on neutrophils is associated with the development of severe disease.
Plasma elastase concentrations correlate with percentages of both LDNs and PMN-MDSCs, suggesting elevated degranulation and NETosis.
Peripheral blood T cell frequencies are lower in patients with severe COVID-19 compared with those with mild or moderate disease.
Neutrophils expressing both PD-L1 and LOX-1 are significantly more abundant during severe COVID-19, suggesting functional suppression.
PD-L1 plus PMN-MDSCs are observed in BAL samples from patients with severe COVID-19.
In Vitro Experiments (Using Healthy Donor Neutrophils):1 Hour Post-Stimulation with SARS-CoV-2: SARS-CoV-2 rapidly induces robust LOX-1 expression on neutrophils, similar to the effect of THG. ROS-producing and NETosing neutrophils are increased, indicating neutrophil activation. LOX-1 surface MFI is increased, and intracellular LOX-1 MFI is decreased. Surface PD-L1 expression is increased.
2 Hours Post-Stimulation with SARS-CoV-2: Approximately half of NDNs convert to LDNs. Surface CD63 and CD11b MFIs are increased, while CD15 MFIs are not different from control.
At Various Time Points (1, 12, and 24 hours) Post-Incubation with SARS-CoV-2: Comparable SARS-CoV-2 genome copies are found in neutrophils incubated with replication-competent and inactivated virus, suggesting no productive infection.
1 Hour Post-Stimulation with Inactivated SARS-CoV-2: Comparable LOX-1 expression is induced as with replication-competent SARS-CoV-2.
At Various Time Points (16 and 40 hours) Post-Stimulation with SARS-CoV-2: Neutrophil expression of LOX-1 continues at 16 hours but is lost by 40 hours.
When Neutrophils are Treated with Nexinhib20 (Rab27a inhibitor): CD63, CD11b, and LOX-1 expression decreases upon SARS-CoV-2 stimulation. PD-L1 surface expression is inhibited in a dose-dependent manner.
In Coculture Experiments with Autologous T Cells: SARS-CoV-2–stimulated neutrophils inhibit proliferation of both autologous CD4 and CD8 T cells in a dose-dependent manner. LOX-1, ROS, and PD-L1 MFIs correlate with the degree of CD4 and CD8 T cell suppression. Immune suppression is dependent on degranulation and PD-L1 expression. SARS-CoV-2–driven PD-L1 expression on neutrophils induces death of nonproliferating T cells.
When Neutrophils are Stimulated with H1N1 Influenza A Virus: LOX-1 induction is not observed.
When SARS-CoV-2 is Incubated with Imdevimab (anti-spike protein antibody): No effect on NDN LOX-1 induction is observed.
When Neutrophils are Stimulated with Clinically Relevant SARS-CoV-2 Variants (Wu-1, Delta, BQ.1, and BA.5): All variants induce LOX-1 in NDNs.
When Neutrophils from Different Aged Donors are Stimulated with SARS-CoV-2: The age of the donor does not affect the degree of LOX-1 upregulation.
When Neutrophils are Stimulated with SARS-CoV-2 or THG: Intracellular staining of ARG-1 is reduced by THG but not by SARS-CoV-2. Low ARG-1 protein concentrations are detected in the supernatant, suggesting passive release.
When Neutrophils are Stimulated with SARS-CoV-2: Small amounts of TNF and IL-1β are produced. IL-10 and TGF-β secretion are not observed.
Cast of Characters
Hsieh et al.: The authors of the study "SARS-CoV-2 induces neutrophil degranulation and differentiation into myeloid-derived suppressor cell." They conducted the research and wrote the manuscript.
Courtney Malo: Author of the introductory commentary summarizing the key findings of the Hsieh et al. study.
Study Participants (COVID-19 Patients): Individuals hospitalized with acute COVID-19 at the Johns Hopkins health care system in 2020. They represent a range of disease severities and provided blood and, in some cases, BAL samples.
Study Participants (Healthy Controls - HCs): Individuals enrolled in a Johns Hopkins Medicine health care worker cohort between 2020 and 2022. They provided blood samples for comparison.
Healthy Donors: Deidentified individuals who provided leukopaks and whole blood for in vitro experiments using isolated neutrophils.
A.P. (Johns Hopkins University): The individual in whose laboratory the SARS-CoV-2 variants of concern (Delta, Omicron variants BA.5 and BQ.1) and A/California/7/2009 H1N1 influenza virus were isolated and propagated.
F.D.: The individual who performed the non-bronchoscopic BALs (NBBALs) on study participants with severe COVID-19.
A.O.: The individual who processed the BAL samples.
A.L.C.: An author of the study who participated in designing the study, planning experimental assays, acquiring data, acquiring funding, writing the original manuscript, and reviewing the final submission. Received funding from the NIH.
E.A.T.: An author of the study who participated in designing the study, planning experimental assays, acquiring data (isolated cells and performed flow cytometry), writing the original manuscript, and reviewing the final submission.
N.P.J.: An author of the study who participated in planning experimental assays and acquiring data (isolated cells and performed flow cytometry).
T.A.: An author of the study who participated in planning experimental assays and acquiring data (isolated cells and performed flow cytometry).
A.F.: An author of the study who participated in planning experimental assays and acquiring data (isolated cells and performed flow cytometry).
K.R.: An author of the study who participated in planning experimental assays and acquiring data (isolated cells and performed flow cytometry).
N.G.: An author of the study who participated in planning experimental assays and acquiring data.
A.H.K.: An author of the study who participated in planning experimental assays, acquiring data, acquiring funding, and reviewing the final submission. Received funding from the NIH.
A.M.M.: An author of the study who participated in recruiting participants and providing clinical data and expertise.
E.E.: An author of the study who participated in recruiting participants and providing clinical data and expertise.
P.C.K.: An author of the study who participated in recruiting participants and providing clinical data and expertise.
W.Z.: An author of the study who performed statistical analyses.
K.-H.C.: An author of the study who performed statistical analyses.
G. Stavrakis, E. Mihealsick, D. Hunt, H. Cheng, and E. Caballero: Individuals thanked for helpful discussions and technical support.
B. Meeksirriporn: Individual thanked for providing useful reagents.
J. Spangler (Johns Hopkins University): Individual who provided Atezolizumab (a PD-1–PD-L1 inhibitor) as a gift.
6. FAQ
What are myeloid-derived suppressor cells (MDSCs) and why are they relevant in severe COVID-19?
MDSCs are a group of immune cells, specifically myeloid cells, that have the ability to suppress the function of T cells. T cells are crucial for fighting viral infections. In severe COVID-19, there is often an increased number of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), a specific type of MDSC derived from neutrophils. These PMN-MDSCs can dampen the antiviral T cell response, potentially contributing to the worsening of the disease.
How do neutrophils in severe COVID-19 patients differ from those in healthy individuals?
Neutrophils from individuals with severe COVID-19 show increased abundance in the peripheral blood and are more likely to express specific markers associated with PMN-MDSCs, namely LOX-1 and PD-L1. LOX-1 is a marker for functionally suppressive human PMN-MDSCs, while PD-L1 inhibits T cell function. Elevated levels of these markers on neutrophils are associated with the development of severe disease and can be observed early in the course of hospitalization.
Does SARS-CoV-2 directly cause neutrophils to become PMN-MDSCs?
Yes, the research indicates that SARS-CoV-2 can directly induce healthy human neutrophils to acquire a PMN-MDSC phenotype. This happens rapidly and is independent of the virus replicating within the neutrophils. In vitro experiments showed that incubating healthy neutrophils with SARS-CoV-2 was sufficient to induce the expression of LOX-1 and PD-L1 on the neutrophil surface, and these activated neutrophils could then suppress T cell proliferation and cytokine production.
What is the mechanism by which SARS-CoV-2 induces the PMN-MDSC phenotype in neutrophils?
The study suggests that SARS-CoV-2 induces PMN-MDSC features primarily through neutrophil degranulation. Degranulation is the process where neutrophils release the contents of their internal granules. LOX-1 appears to be stored within primary and tertiary granules of neutrophils and is rapidly externalized to the cell surface upon stimulation with SARS-CoV-2. This degranulation also leads to the upregulation of other markers like CD63 and CD11b, and importantly, PD-L1.
How do SARS-CoV-2-stimulated PMN-MDSCs suppress T cell function?
SARS-CoV-2-stimulated neutrophils, exhibiting the PMN-MDSC phenotype with elevated LOX-1 and PD-L1, can suppress the proliferation and cytokine production of autologous T cells. The study highlights degranulation and PD-L1 expression as two key mechanisms for this suppression. PD-L1 is an immune checkpoint molecule that, when engaged by PD-1 on T cells, can inhibit T cell activity and even induce T cell death.
Are the effects of SARS-CoV-2 on neutrophil activation specific to this virus?
The study compared the effects of SARS-CoV-2 stimulation with that of influenza A virus (H1N1). While SARS-CoV-2 rapidly induced LOX-1 expression and PMN-MDSC features in healthy neutrophils, H1N1 influenza A virus did not induce comparable LOX-1 expression. This suggests a specific effect of SARS-CoV-2 in driving this particular neutrophil activation and differentiation pathway, which may contribute to the unique pathogenesis of severe COVID-19 compared to other viral infections like influenza.
Can the presence of PMN-MDSC markers on neutrophils predict the severity of COVID-19?
The research indicates that certain neutrophil characteristics, particularly elevated expression of PD-L1 at the time of hospital admission, are significantly higher in participants who subsequently developed severe COVID-19 compared to those with mild to moderate disease. The frequency of LOX-1+ PD-L1+ neutrophils was also strongly associated with later disease severity. While not definitively causal, these findings suggest that analyzing neutrophil markers early in the disease course could potentially help predict disease progression.
What are the potential therapeutic implications of these findings?
The identification of PD-L1 as a key mediator of T cell suppression by SARS-CoV-2-induced PMN-MDSCs suggests that therapies targeting PD-L1, such as immune checkpoint inhibitors, could be a potential strategy to enhance the antiviral immune response in acute SARS-CoV-2 infection and potentially mitigate severe disease. However, further research, including in animal models, is needed to confirm the role of PMN-MDSCs and determine the optimal timing and approach for such interventions.
7. Table of Contents
Introduction and Overview
0:00 - Welcome to Heliox: Where Evidence Meets Empathy
Opening introduction to the show's mission and today's deep dive into COVID-19 severity differences
1:15 - The Central Question
Why COVID-19 affects some people more severely than others, introducing the role of neutrophils
Background and Context
2:30 - The Immune Landscape of Severe COVID-19
Overview of neutrophilia and lymphopenia patterns in severe cases
4:45 - Introduction to PMN-MDSCs
Explaining polymorphonuclear myeloid-derived suppressor cells and their role in immune suppression
6:20 - Study Overview and Patient Samples
Details about the research methodology using pre-vaccine era hospitalized patients
Key Findings: Early Detection Markers
8:10 - Higher Neutrophil Counts in Severe Cases
Discussion of elevated neutrophils, low-density neutrophils, and PMN-MDSCs in severe disease
10:30 - Early Warning Signs
How neutrophil markers within the first 3 days predict later disease severity
12:45 - Predictive Markers Beyond Demographics
Why neutrophil features outperformed age and BMI as severity predictors
The Mechanism: Direct Viral Manipulation
15:20 - Laboratory Experiments with Healthy Neutrophils
How researchers exposed normal neutrophils to SARS-CoV-2 in controlled conditions
17:00 - Rapid LOX1 Expression
The surprising speed of neutrophil transformation within one hour of viral exposure
18:30 - Dead Virus, Live Response
Why inactivated viral particles still trigger neutrophil changes
20:15 - Virus Specificity
How SARS-CoV-2 differs from influenza in triggering these responses
Cellular Mechanisms Revealed
22:00 - Degranulation Process
How the virus triggers neutrophils to release internal contents and surface markers
24:30 - LOX1 and PD-L1 Expression
The role of specific surface markers in creating suppressive neutrophils
26:45 - Blocking the Process
Using degranulation inhibitors to prevent neutrophil transformation
Functional Consequences
28:20 - T-Cell Suppression Experiments
How virus-altered neutrophils actively shut down T-cell responses
30:40 - Dose-Dependent Effects
The relationship between neutrophil numbers and immune suppression severity
32:15 - PD-L1 Pathway Mechanism
How altered neutrophils use PD-L1 to induce T-cell death and dysfunction
34:30 - Reversing the Suppression
Using checkpoint inhibitors to restore T-cell function
Clinical Implications and Therapeutic Potential
36:45 - Summary of the Pathway
Comprehensive overview of virus-to-neutrophil-to-T-cell suppression mechanism
39:00 - Therapeutic Possibilities
Potential interventions targeting PMN-MDSCs and PD-L1 pathways
41:15 - Study Limitations
Acknowledging correlational vs. causal relationships and lab vs. real-world differences
Broader Significance
43:30 - Active Viral Manipulation
How SARS-CoV-2 actively reshapes immune responses rather than passively replicating
45:20 - Future Research Questions
Balancing MDSC prevention vs. modulation in different disease stages
47:00 - Clinical Application Potential
The importance of understanding viral manipulation of immune defenses
Conclusion
48:30 - Key Takeaways
Summary of major findings and their implications for understanding COVID-19 severity
50:15 - Closing Thoughts
Final reflections on the research and invitation for listener engagement
51:00 - Heliox Mission Statement
Recurring themes and podcast philosophy wrap-up
8. Index
Index
Absolute neutrophil count (ANC) - 8:10, 12:45, 15:20
Adaptive complexity - 51:00
Age as predictor - 12:45
Atzolizumab - 34:30
BMI as predictor - 12:45
Boundary dissolution - 51:00
CD4 T cells - 28:20
CD8 T cells - 28:20
Checkpoint inhibitors - 34:30, 39:00
Correlation vs causation - 41:15
COVID-19 severity - 1:15, 2:30, 8:10, 12:45
Degranulation - 10:30, 22:00, 24:30, 26:45, 36:45
Degranulation inhibitor - 26:45, 34:30
Early detection - 10:30, 12:45
Early warning signs - 10:30
Elastase - 10:30
Embodied knowledge - 51:00
First responders - 1:15, 4:45
IFN gamma - 34:30
Immune suppression - 4:45, 28:20, 32:15, 36:45
Influenza A virus - 20:15
Laboratory experiments - 15:20, 17:00
LOX1 - 4:45, 17:00, 24:30, 28:20, 32:15
Low-density neutrophils (LDN) - 6:20, 8:10
Lymphocytes - 4:45
Lymphopenia - 2:30, 10:30, 32:15
MDSCs - see Myeloid-derived suppressor cells
Myeloid-derived suppressor cells - 1:15, 4:45, 8:10, 39:00, 45:20
Neutrophilia - 2:30, 8:10
Neutrophils - 1:15, 2:30, 4:45, 8:10, 15:20, 17:00
Nexinhub-20 - 34:30
Normal density neutrophils (NDN) - 15:20
Patient samples - 6:20
PD-1 - 24:30, 34:30
PD-L1 - 10:30, 12:45, 24:30, 28:20, 32:15, 34:30, 39:00
Predictive model - 12:45
Pre-vaccine era - 6:20
PMN-MDSCs - see Polymorphonuclear myeloid-derived suppressor cells
Polymorphonuclear myeloid-derived suppressor cells - 4:45, 8:10, 15:20, 36:45, 39:00
Quantum-like uncertainty - 51:00
Reactive oxygen species (ROS) - 12:45, 28:20
SARS-CoV-2 - 1:15, 15:20, 17:00, 18:30, 20:15, 43:30
Severe COVID-19 - 2:30, 8:10, 10:30, 12:45
Shia and colleagues - 1:15, 6:20
Study limitations - 41:15
T-cell death - 32:15
T-cell proliferation - 28:20, 34:30
T-cell responses - 4:45, 28:20
T-cells - 4:45, 10:30, 28:20, 32:15, 34:30
Therapeutic possibilities - 39:00
Three days (first) - 10:30, 12:45
Viral inactivation - 18:30
Viral manipulation - 15:20, 43:30, 47:00
Viral particles - 18:30
Viral replication - 18:30, 43:30
Viral variants - 20:15
Virus specificity - 20:15
9. Post-Episode Fact Check
Overall Assessment: ACCURATE
The podcast episode presents scientifically sound information consistent with peer-reviewed research on neutrophil dysfunction in COVID-19. The content accurately represents established immunological concepts and recent findings.
Verified Facts
Basic Immunology
✅ Neutrophils as first responders - Correct. Neutrophils are indeed the most abundant white blood cells and typically the first immune cells to arrive at infection sites.
✅ Neutrophilia and lymphopenia in severe COVID-19 - Well-documented pattern consistently reported in literature since early 2020.
✅ PD-L1/PD-1 checkpoint pathway - Accurately described as an immune regulatory mechanism that can suppress T-cell activity.
✅ T-cell importance in viral clearance - Correct. Both CD4+ and CD8+ T-cells are crucial for effective antiviral immunity.
Study-Specific Claims
✅ LOX1 as PMN-MDSC marker - LOX1 (lectin-like oxidized LDL receptor-1) is indeed used as a marker for human PMN-MDSCs in research literature.
✅ Degranulation mechanism - The description of neutrophil degranulation releasing stored proteins to the cell surface is accurate.
✅ Rapid neutrophil response (within 1 hour) - Timeline is consistent with known neutrophil activation kinetics.
✅ Inactivated virus triggering response - This finding aligns with pattern recognition receptor biology, where structural viral components can trigger immune responses without active replication.
✅ Virus-specific effects - The distinction between SARS-CoV-2 and influenza responses is plausible given different viral surface proteins and recognition patterns.
Clinical Correlations
✅ Early neutrophil counts predicting severity - Multiple studies have confirmed elevated neutrophil-to-lymphocyte ratios as early predictors of severe COVID-19.
✅ Checkpoint inhibitor potential - PD-L1 inhibitors like atezolizumab are established cancer immunotherapies, and their potential application in COVID-19 immune dysfunction has been explored in research.
Minor Clarifications Needed
⚠️ Study generalizability - The podcast appropriately notes this was pre-vaccine era data, though could emphasize more clearly that immune responses may differ in vaccinated individuals or with newer variants.
⚠️ Clinical implementation - While the research is promising, the podcast could be clearer that these neutrophil markers are not yet in routine clinical use for COVID-19 management.
Potential Areas for Context
📋 MDSC complexity - MDSCs can have both beneficial (controlling excessive inflammation) and detrimental (suppressing needed immune responses) roles depending on context. The podcast touches on this but could expand.
📋 Treatment timing - The window for intervention based on these mechanisms would likely be early in disease course, which presents practical challenges.
Scientific Rigor Assessment
The podcast demonstrates:
Appropriate use of scientific terminology
Clear explanation of complex immunological concepts
Proper acknowledgment of study limitations
Distinction between correlation and causation
Recognition of in vitro vs. in vivo differences
Conclusion
The episode accurately presents complex immunological research in an accessible format. The scientific claims are well-supported by established literature, and the hosts appropriately qualify their statements with necessary caveats about study limitations and the need for further research.
Confidence Level: High - Content aligns with current scientific understanding and peer-reviewed research on COVID-19 immunopathology.
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