New SARS-CoV-2 Variants Possibly Linked to Persistent Low Grade HMGB1-Mediated Inflammation
Nikhil Prasad Fact checked by:Thailand Medical News Team May 31, 2025 1 day, 15 hours, 44 minutes ago
Thailand Medical News: Emerging Variants and a Persistent Alarm Signal
Scientists are closely monitoring new SARS-CoV-2 Omicron subvariants – notably NB.1.8.1, LF.7.7.2, XFG.2, Lp.8.1.1 – which appear to cause unusually persistent low-grade inflammation. A key finding is that infections by these variants are associated with upregulated levels of High Mobility Group Box 1 (HMGB1), a nuclear protein that doubles as a potent damage-associated molecular pattern (DAMP) when released extracellularly. HMGB1 is normally involved in DNA organization, but upon cell stress or death it is unleashed as an “alarmin,” triggering immune responses. It can leak out passively from necrotic cells or be actively secreted by immune cells (e.g. macrophages, NK cells, dendritic cells) during inflammation. High levels of elevated HMGB1 in the bloodstream has been strongly linked to severe COVID-19; critically ill patients in hyperinflammatory phases show significantly higher HMGB1 levels, and an HMGB1 serum concentration above ~125 ng/mL correlates with increased risk of death.
New SARS-CoV-2 Variants Possibly Linked to Persistent Low Grade HMGB1-Mediated Inflammation
Already, as covered in a previous
Thailand Medical News report, it has been confirmed by many doctors in various geolocations that individuals infected with the new variants especially NB.1.8.1 are experiencing a unique form persistence low grade hyperthermia which is also a sign of persistent inflammation triggered by HMGB1.
The persistence of elevated HMGB1 in patients infected with NB.1.8.1, LF.7.7.2 and similar new lineages suggests these new variants may be triggering more sustained cell damage or immune dysregulation than earlier strains.
What might make these variants prone to sustained HMGB1 release? Researchers are investigating several mechanisms. Enhanced viral replication and tissue tropism could lead to ongoing cell injury and HMGB1 leakage. At the same time, improved evasion of innate immunity – a hallmark of recent Omicron-lineage evolution – allows the virus to spread “silently,” delaying clearance while inflammation smolders. Specific mutations in the spike protein and in non-structural/accessory proteins are under the microscope for their roles in amplifying these effects. Below, we explore how these factors intertwine to keep HMGB1 – the cellular fire alarm – ringing at high volume in NB.1.8.1 and LP.7.7.2 infections.
HMGB1: An Inflammatory Alarm Bell in COVID-19
HMGB1 has emerged as a pivotal mediator of inflammation in COVID-19. Once outside the cell, HMGB1 binds pattern recognition receptors such as Toll-like receptor 4 and the RAGE receptor on immune cells, potently driving the release of cytokines and chemokines that contribute to the “cytokine storm” and tissue damage in severe disease. In SARS-CoV-2 infection, HMGB1 is both a marker and a mediator of damage: it is released in large amounts when infected cells undergo lytic forms of cell death (necrosis or pyroptosis), and in turn it activates immune cells to sustain a
nd amplify inflammation. Studies have indeed found that higher HMGB1 levels correlate with greater disease severity and poor outcomes in COVID-19. This makes HMGB1 not only a biomarker of an ongoing intense immune response, but also a participant in driving lung injury, vascular leak, and multi-organ involvement.
Importantly, HMGB1 release in COVID-19 can become self-perpetuating. For example, SARS-CoV-2’s accessory protein ORF3a is known to activate the NF-κB pathway and the NLRP3 inflammasome in infected cells, leading to the maturation of IL-1β and a form of inflammatory cell death (pyroptosis). Pyroptotic cells release HMGB1 as well as IL-1β. HMGB1 then binds to RAGE/TLR receptors on other cells, which can further amplify NF-κB signaling and inflammasome activation, creating a feed-forward loop of inflammation. In essence, once SARS-CoV-2 infection sets off the HMGB1 alarm, the signal can sustain itself – unless the virus is cleared and the immune reaction is brought under control. This background sets the stage for why a variant that causes more HMGB1 to be released, or fails to shut it off, would be especially concerning.
Viral Replication and Cell Damage: Fueling the HMGB1 Release
One straightforward explanation for persistently elevated HMGB1 in NB.1.8.1 and LF.7.7.2 infections is that these variants may simply damage more cells due to heightened infectivity or replicative fitness. NB.1.8.1, for instance, carries several notable mutations in its spike protein (in addition to the constellation of Omicron-defining mutations). Compared to the currently dominant LP.8.1 lineage, NB.1.8.1’s spike has acquired changes such as V445H and T478I, among others. The mutation at position 445 is known to enhance binding affinity to ACE2, potentially increasing the variant’s ability to infect host cells. T478I is a mutation in the receptor-binding domain that has been associated with evading certain neutralizing antibodies, which might allow the virus to spread even in previously immune individuals. More efficient ACE2 binding and immune escape translate to more cells infected and higher viral loads. As a result, the virus can cause more widespread tissue infection (e.g. in the lungs and other organs), leading to more cell death over time. Each dying cell can passively release HMGB1 into the extracellular space, adding to systemic HMGB1 levels.
Beyond the spike, these variants likely owe some of their success to mutations in non-spike proteins that can increase replication or cell damage. Scientists have pointed out a mutation in the viral endoribonuclease Nsp15 in some new SARS-CoV-2 isolates that could boost replication stealth. Nsp15’s normal function is to destroy the virus’s own RNA remnants that would otherwise alert the host’s RNA sensors. A recent study identified an Nsp15 mutation (E266Q in its catalytic domain) that made the enzyme more active and stable, enabling the virus to cut up RNA “warning signs” more efficiently and thereby hide longer from immune detection. Variants carrying such a mutation could replicate extensively before the immune system realizes an intruder is present. While not yet confirmed in NB.1.8.1 or LF.7.7.2 specifically, this finding exemplifies how a single amino acid change in a non-structural protein can lead to more undetected replication, ultimately resulting in greater cumulative cell damage. The more cells that succumb (through virus-induced apoptosis, necrosis, or pyroptosis), the more HMGB1 is dumped into circulation to propagate inflammation.
Another factor is the fusogenicity of the virus – how readily the spike causes infected cells to fuse into syncytia, which often then die. Earlier Omicron subvariants were noted to be less fusogenic than the Delta variant, correlating with somewhat less lower-airway damage. If NB.1.8.1 or LP.7.7.2 have changes that restore some fusogenic behavior (for example, mutations near the S1/S2 cleavage site or in S2 that affect cell–cell fusion), that could increase lung cell death and HMGB1 release. While data is still emerging, the overall trend is that greater infective spread and direct cytopathic effect of these variants would provide a larger continuous source of HMGB1 from injured cells.
Innate Immune Evasion: Letting the Fire Smolder Unchecked
A critical piece of the puzzle is how these new variants interact with the innate immune system – the body’s early warning and response network. Normally, when a cell is infected, innate sensors detect viral components and trigger interferons and other antiviral defenses which not only fight the virus but also limit excessive tissue damage by clearing infection. However, SARS-CoV-2 encodes multiple innate immune antagonists (like Nsp1, Nsp3, Nsp14, ORF6, ORF9b, etc.) that blunt these responses. Over the course of the pandemic, variants of concern have repeatedly evolved improvements in innate immune evasion. The Omicron lineage is no exception – even as it dramatically mutated spike to escape antibodies, it also accrued changes in other genes to fine-tune immune suppression.
Studies comparing Omicron sublineages found that later subvariants (such as BA.4/BA.5 and descendant recombinant lineages) regained a stronger ability to shut down innate immune signals compared to the early BA.1/BA.2 Omicron strains. In particular, recent subvariants show higher expression of ORF6 and nucleocapsid (N) proteins, which are key interferon antagonists, akin to the levels seen in the more pathogenic Alpha–Delta variants. ORF6 is a short viral protein that localizes to the nuclear pore and blocks the activation of interferon regulatory factors (like IRF3) and STAT1, thereby suppressing interferon production and signaling. N (nucleocapsid) can also contribute to immune evasion; for example, a mutation (D3L in N) in Alpha was known to enhance N’s stability and increase ORF9b production, both aiding interferon suppression. By convergent evolution, Omicron subvariants like XBB and others seem to be boosting these antagonistic functions again.
For variants like NB.1.8.1, which descends from a recombinant lineage (XDV.1.5.1) and shares ancestry with XBB, it is very plausible that it carries such optimizations for innate evasion. In practical terms, evasion of innate immunity means the virus does not trigger alarm signals early, delaying the recruitment of immune cells that would normally contain the infection. This stealthy approach has two consequences relevant to HMGB1 levels:
-Prolonged viral presence: With interferons and antiviral defenses dampened, the virus can replicate unabated for longer, causing continuous waves of cell infection and death. Instead of a rapid clearance in a few days, the infection might smolder, giving HMGB1 a longer window to be released from successive rounds of cell injury. Essentially, the fire burns longer because the sprinkler system failed to activate early.
-Delayed but low-grade persistent inflammation: Paradoxically, when the innate system eventually does detect the virus (often through massive cell damage or delayed second-line sensors), it may react in an overcompensating burst – leading to high levels of HMGB1 and cytokines at later stages. Researchers have characterized a phenomenon called PANoptosis in SARS-CoV-2 infection, a mixed cell-death program (pyroptosis, apoptosis, and necroptosis) that can occur when innate defenses are finally triggered; this leads to release of HMGB1 and other DAMPs en masse. Thus, immune evasion can ironically set the stage for more tissue damage and DAMP release by preventing the infection from being nipped in the bud.
In summary, NB.1.8.1 and LF.7.7.2 likely possess a suite of mutations that tip the balance toward immune evasion. For example, if a variant acquired the Nsp15 E266Q mutation discussed earlier, it would hide its RNA more effectively from sensors. Combine that with high ORF6 expression (blocking interferon) and any tweaks in other antagonistic proteins, and you have a virus that can silently ravage tissues for a time. By the time the immune system mounts a full response, there is a lot of cellular carnage – with HMGB1 serving as a beacon of the destruction. This could explain clinical reports of patients with these new subvariant infections experiencing persistent inflammation (fever, high CRP, etc.) even as viral loads slowly wane, reflecting that the body is dealing with the aftermath of unchecked early spread.
Mutation Spotlight: Viral Proteins Driving HMGB1 Upregulation
While spike protein mutations grab headlines (for their role in transmission and antibody escape), scientists are increasingly shining a light on non-spike mutations in NB.1.8.1, LF.7.7.2, and similar variants that could specifically influence HMGB1-related inflammatory pathways:
-ORF3a: This accessory protein is conserved in Omicron lineages and, as mentioned, is a known instigator of NLRP3 inflammasome activation and pyroptotic cell death. If new variants carry amino-acid changes in ORF3a, they might alter its propensity to form ion channels or interact with host proteins. Even without new mutations, the continued presence of ORF3a in these variants means they retain the ability to induce IL-1β release and HMGB1-driven inflammation. Some researchers speculate that differences in ORF3a function could partially explain why certain Omicron subvariants (despite causing “milder” illness on average) can still lead to severe outcomes in a subset of patients – essentially, ORF3a might be a wildcard that, if hyperactive, keeps the inflammatory fire burning.
-Nucleocapsid (N) and RAGE interaction: A recent study (yet to be peer-reviewed) highlighted an intriguing mechanism: the SARS-CoV-2 N protein can bind to the receptor RAGE on cell surfaces and mediate acute lung injury. RAGE is one of the main receptors for HMGB1 as well, and its engagement is known to amplify inflammatory signaling cascades in the lungs. If the N protein of a new variant has mutations that strengthen its binding to RAGE or prolong its retention on cell surfaces, it could act as an agonist to the RAGE pathway, mimicking and magnifying HMGB1’s effects. In essence, the virus might directly trigger the same receptor that HMGB1 uses to promote inflammation. This synergy between a viral protein and a DAMP receptor could be another reason for persistent inflammation. It is noteworthy that Omicron variants like XBB (from which NB.1.8.1 is derived) have accumulated multiple mutations in N; whether these affect RAGE binding is an active area of investigation.
-Nsp6 and other autophagy modulators: Nsp6 is an autophagy-related protein that SARS-CoV-2 uses to remodel cellular membranes for replication. Certain deletions in Nsp6 (seen in early Omicron isolates) were thought to affect how the virus interacts with cellular stress pathways. A mutation that makes Nsp6 more adept at blocking autophagosome formation could prevent the cell from degrading viral components, inadvertently leading to more cell stress and death – another potential source of HMGB1. There has been at least one report of a novel Nsp6 mutation in a circulating variant that “hijacks” host cell signaling and weakens immune defenses, underlining that we should not ignore these less-glamorous proteins.
-Other innate antagonists (ORF9b, NSP1, etc.): ORF9b suppresses mitochondrial antiviral signaling (MAVS) and interferon production; NSP1 shuts off host protein translation (including immune signals). Mutations that enhance ORF9b’s binding to host factors or NSP1’s ribosome blocking could further dampen early immunity, indirectly contributing to the HMGB1 problem as discussed. The cumulative effect of multiple small mutations across the genome may be what sets these new variants apart, creating a virus that is both stealthier and yet more inflammatory once unmasked.
Implications and Ongoing Research
The convergence of enhanced replication, immune evasion, and pro-inflammatory mutations in variants like NB.1.8.1 and LF.7.7.2 paints a concerning picture: these viruses can spread more efficiently within the host and prolong the inflammatory damage. Persistent HMGB1 elevation is not just a laboratory number – it can translate to prolonged low grade fever, coagulopathy, tissue fibrosis, and even autoimmune sequelae, given HMGB1’s role in sustaining cytokine production and recruiting immune cells. Clinicians have noted that some patients infected with recent Omicron subvariants experience longer durations of illness and inflammation than what was typical for earlier Omicron waves, though comprehensive clinical data are still being collected.
On a positive note, understanding these mechanisms opens up new avenues for therapy. If HMGB1 is a central mediator in this prolonged inflammation, it becomes a potential therapeutic target. In fact, drugs that neutralize HMGB1 or block its receptors (such as RAGE antagonists or TLR4 inhibitors) could dampen the harmful inflammation. One candidate, glycyrrhizin (a compound from licorice), is an HMGB1 inhibitor that has been shown to mitigate SARS-CoV-2 ORF3a-induced cell death and inflammation in cell studies.
Thailand Medical News was one of the entities that brought up the attention of licorice to combat SARS-CoV-2 effects as early as January 2020.
Many new findings hint that adjunct therapies targeting the HMGB1 pathway might reduce tissue damage in patients infected with these a new variants. Additionally, interventions that restore interferon responses (for example, lambda interferon therapy or small molecules that block viral antagonists) might curtail the virus before HMGB1 release spirals out of control.
Researchers are now racing to keep up with the virus’s evolution. The World Health Organization has designated NB.1.8.1 as a Variant Under Monitoring (VUM) as of May 2025, and global efforts are ongoing to characterize its virological properties. Preliminary assessments indicate that, despite increased transmissibility, NB.1.8.1 does not cause higher acute mortality during initial acute infection stages than other variants – a reassuring sign. However, the immunopathology it triggers (i.e. the way it orchestrates the immune response) could differ, as suggested by the HMGB1 connection. These new varianst could be causing more dame and health issues over time. Large cohort studies and lab experiments are underway to measure DAMP and cytokine profiles in NB.1.8.1/LF.7.7.2 infections versus earlier strains. Genomic analyses are also probing whether these lineages share common mutations in ORF6, N, Nsp15 or other regions that could mechanistically explain the HMGB1 surge.
In conclusion, the emergence of NB.1.8.1, LF.7.7.2, and similar variants illustrates the virus’s continued adaptation not just to escape antibodies, but to modulate the host’s innate immune reaction. By permitting robust viral replication and by tweaking the molecular triggers of inflammation, these variants create a perfect storm for sustained HMGB1 release and prolonged inflammation. Unraveling these mechanisms is crucial – it will help clinicians anticipate which patients might need anti-inflammatory or DAMP-targeted interventions and inform the next generation of treatments or vaccines. As we learn more, one message is clear: in the tug-of-war between SARS-CoV-2 and the human immune system, variants that can quietly start a bigger fire (and keep feeding it) pose a distinct challenge, even if they don’t appear more “severe” in traditional epidemiologic terms.
Keeping an eye on markers like HMGB1 may thus become an important part of assessing the true impact of new COVID-19 variants. For now, health experts urge vigilance as these molecular underpinnings come to light – a reminder that the story of COVID-19’s evolution is still unfolding, with HMGB1 now part of the plot.
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