SARS-CoV-2, the third major coronavirus of the 21st century, causing COVID-19 disease, profoundly impacts public health and workforces worldwide. Identifying individuals at heightened risk of SARS-CoV-2 infection is crucial for targeted interventions and preparedness. This study investigated 35 SNVs within viral infection-associated genes in SARS-CoV-2 patients and uninfected controls from the Basque Country (March 2020-July 2021). Its primary aim was to uncover genetic markers indicative of SARS-CoV-2 susceptibility and explore genetic predispositions to infection. Association analyses revealed previously unreported associations between SNVs and susceptibility. Haplotype analyses uncovered novel links between haplotypes and susceptibility, surpassing individual SNV associations. Descriptive modelling identified key susceptibility factors, with rs11246068-CC (IFITM3), rs5742933-GG (ORMDL1), rs35337543-CG (IFIH1), and GGGCT (rs2070788, rs2298659, rs17854725, rs12329760, rs3787950) variation in TMPRSS2 emerging as main infection-susceptibility indicators for a COVID-19 pandemic situation. These findings underscore the importance of integrated SNV and haplotype analyses in delineating susceptibility to SARS-CoV-2 and informing proactive prevention strategies. The genetic markers profiled in this study offer valuable insights for future pandemic preparedness.

Human body constitutes unique biological system containing specific fluid mechanics and biomechanics. Traditional cell culture techniques of 2D and 3D do not recapitulate these specific natures of the human system. In addition, they lack the spatiotemporal conditions of representing the cells. Moreover, they do not enable the study of cell-cell interactions in multiple cell culture platforms. Therefore, establishing biological system of dynamic cell culture was of great interest. Organs on chips systems were fabricated proving their concept to mimic specific organs functions. Therefore, it paves the way for validating new drugs and establishes mechanisms of emerging diseases. It has played a key role in validating suitable vaccines for Coronavirus disease (COVID-19). Herein, the concept of organs on chips, fabrication methodology and their applications are discussed.

The COVID-19 pandemic has highlighted the need for a Sustainable Pandemic Response Strategy (SPRS), driven by scientific research and engineering principles. This study focuses on Environmental and Climatic Determinants (ECDs) that may influence the occurrence pattern of infectious diseases. The objective of SPRS is to develop a climate-resilient framework for infectious diseases using Earth Observation (EO) data. ECDs were derived from EO data during the COVID-19 study period in India, spanning 1094 days (January 3, 2020, to December 31, 2022). A Convergent Search - Add or Eliminate (CS-AE) algorithm was developed for the investigation of complex association between ECDs and disease occurrence patterns. This algorithm identifies the most influential ECDs in the spread of COVID-19 in India, categorizing them as Determinants of Concern (DOC) or Determinants of Interest (DOI). Shortwave Downward Radiation (SDR) was identified as a DOC, showing a strong correlation (r = 0.9525) with COVID-19 spread. Granger causality analysis was conducted to support the classification of SDR as a Determinant of Concern (DOC). The results confirmed a temporal causal relationship between SDR and disease spread. During the first pandemic wave, significant causality was observed at lags of 2 to 7 days, with the strongest effect at lag 6 (p = 0.001), while in subsequent waves, significance was found across lags of 1 to 6 days. The seasonal effect of SDR and the three pandemic waves in India were observed through a radar chart, illustrating the temporal causal relationship between SDR and COVID-19 spread. The algorithm shows the note of a significant role by SDR in surface and air temperature (r = 0.9525; r = 0.9942) and influences other ECDs which are categorized as DOI. Hence, the proposed CS-AE algorithm provides a robust tool for identifying the most influential ECDs in the spread of infectious diseases, provided the datasets are time-series based.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced impaired antiviral immunity and excessive inflammatory responses cause lethal pneumonia. However, the in vivo roles of key pattern recognition receptors that elicit protective antiviral and fatal inflammatory responses, specifically in the lungs, are not well described. Coronaviruses possess single-stranded RNA genome that activates TLR7/8 to induce an antiviral interferon (IFN) and robust inflammatory cytokine response. Here, using wild-type and TLR7-deficient (TLR7-/-) mice infected with mouse-adapted SARS-CoV-2 (MA-CoV-2), we examined the role of TLR7 in the lung antiviral and inflammatory response and severe pneumonia. We showed that TLR7 deficiency significantly increased lung virus loads and morbidity/mortality, which correlated with reduced levels of type I IFNs (Ifna/b), type III IFNs (Ifnl), and IFN-stimulated genes (ISGs) in the lungs. A detailed evaluation of MA-CoV-2-infected lungs revealed increased neutrophil accumulation and lung pathology in TLR7-/- mice. We further showed that blocking type I IFN receptor (IFNAR) signaling enhanced SARS-CoV-2 replication in the lungs and caused severe lung pathology, leading to 100% mortality compared to infected control mice. Moreover, immunohistochemical assessment of the lungs revealed increased numbers of SARS-CoV-2 antigen-positive macrophages, pneumocytes, and bronchial epithelial cells in TLR7-/- and IFNAR-deficient mice compared to control mice. In summary, we conclusively demonstrated that despite TLR7-induced robust lung inflammation, TLR7-induced IFN/ISG responses suppress lung virus replication and pathology and provide protection against SARS-CoV-2-induced fatal pneumonia. Additionally, given the similar disease outcomes in control, TLR7-/-, and IFNAR-deficient MA-CoV-2-infected mice and coronavirus disease 2019 (COVID-19) patients, we propose that MA-CoV-2-infected mice constitute an excellent model for studying COVID-19.IMPORTANCESevere coronavirus disease 2019 (COVID-19) is caused by a delicate balance between a strong antiviral and an exuberant inflammatory response. A robust antiviral immunity and regulated inflammation are protective, while a weak antiviral response and excessive inflammation are detrimental. However, the key host immune sensors that elicit protective antiviral and inflammatory responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenge are poorly defined. Here, we examined the role of viral RNA-mediated TLR7 activation in the lung antiviral and inflammatory responses in SARS-CoV-2-infected mice. We demonstrate that TLR7 deficiency led to a high rate of morbidity and mortality, which correlated with an impaired antiviral interferon (IFN)-I/III response, enhanced lung virus replication, and severe lung pathology. Furthermore, we show that blocking IFN-I signaling using anti-IFN receptor antibody promoted SARS-CoV-2 replication in the lungs and caused severe disease. These results provide conclusive evidence that TLR7 and IFN-I receptor deficiencies lead to severe disease in mice, replicating clinical features observed in COVID-19 patients.

Viruses modulate various aspects of host physiology, including carbon metabolism, redox balance, and mitochondrial bioenergetics to acquire the building blocks for replication and regulation of the immune response. Understanding how SARS-CoV-2 alters the host metabolism may lead to treatments for COVID-19. We report that a ubiquitous gaseous molecule, hydrogen sulfide (H2S), regulates redox, metabolism, and mitochondrial bioenergetics to control SARS-CoV-2. Virus replication is associated with down-regulation of the H2S-producing enzymes cystathionine-β-synthase (CBS), cystathionine-γ-lyase (CTH), and 3-mercaptopyruvate sulfurtransferase (3-MST) in multiple cell lines and nasopharyngeal swabs of symptomatic COVID-19 patients. Consequently, SARS-CoV-2-infected cells showed diminished endogenous H2S levels and a protein modification (S-sulfhydration) caused by H2S. Genetic silencing or chemical inhibition of CTH resulted in SARS-CoV-2 proliferation. Chemical supplementation of H2S using a slow-releasing H2S donor, GYY4137, diminished virus replication. Using a redox biosensor, metabolomics, transcriptomics, and XF-flux analyzer, we showed that GYY4137 blocked SARS-CoV-2 replication by inducing the Nrf2/Keap1 pathway, restoring redox balance and carbon metabolites and potentiating mitochondrial oxidative phosphorylation. Treatment of SARS-CoV-2-infected mice or hamsters with GYY4137 suppressed viral replication and ameliorated lung pathology. GYY4137 treatment reduced the expression of inflammatory cytokines and re-established the expression of Nrf2-dependent antioxidant genes in the lungs of SARS-CoV-2-infected mice. Notably, non-invasive measurement of respiratory functions using unrestrained whole-body plethysmography (uWBP) of SARS-CoV-2-infected mice showed improved pulmonary function variables, including pulmonary obstruction (Penh), end-expiratory pause (EEP), and relaxation time (RT) upon GYY4137 treatment. Together, our findings significantly extend our understanding of H2S-mediated regulation of viral infections and open new avenues for investigating the pathogenic mechanisms and therapeutic opportunities for coronavirus-associated disorders.

Neurodegenerative diseases are chronic progressive disorders that impair memory, cognition, and motor functions, leading to conditions such as dementia, muscle weakness, and speech difficulties. Aging disrupts the stringent balance between pro- and anti-inflammatory cytokines, increasing neuroinflammation, which contributes to neurodegenerative diseases. The aging brain is particularly vulnerable to infections due to a weakened and compromised immune response and impaired integrity of the blood-brain barrier, allowing pathogens like viruses to trigger neurodegeneration. Coronaviruses have been linked to both acute and long-term neurological complications, including cognitive impairments, psychiatric disorders, and neuroinflammation. The virus can induce a cytokine storm, damaging the central nervous system (CNS) and worsening existing neurological conditions. Though its exact mechanism of neuroinvasion remains elusive, evidence suggests it disrupts the blood-brain barrier and triggers immune dysregulation, leading to persistent neurological sequelae in elderly individuals. This review aims to understand the interaction between the peripheral immune system and CNS glial cells in aged individuals, which is imperative in addressing coronavirus-induced neuroinflammation and concomitant neurodegeneration.

Females demonstrate elevated type-I interferon production and a stronger antiviral immune response; however, the mechanisms underlying sex-based differences in antiviral immunity are incompletely understood. We previously reported that low adenosine deaminase (ADA) activity perturbs the methylation-based transcriptional silencing of endogenous retroviral elements (hERV), which stimulates IFN-Stimulated Genes (ISG) and primes antiviral immunity. Here we demonstrate lower ADA activity in females compared to their male counterparts, which correlated with higher hERV and ISG expression in female lungs. Sex differences in ADA2 were linked to the number and expression profiles of blood and lung-derived monocyte populations. Single-cell RNA sequencing of respiratory cells from patients with COVID-19 showed a significant female bias in hERV-ISG signatures, and implicated IL-18 as a driver of sex-specific ADA2 expression. Observations in healthy and COVID-19 cohorts indicate that higher ADA activity is associated with suppressed antiviral innate immunity in the male respiratory tract, which may drive adverse COVID-19 outcomes.

The COVID-19 pandemic highlighted the need for new therapeutic strategies to counter emerging pathogenic viruses. Herein, we introduce a novel fusion protein platform that enables antiviral targeting of distinct viral species based on host receptor specificity. Proof-of-concept studies focused on the human coronavirus NL63, which shares specificity for the ACE2 host receptor with the pandemic SARS-CoV and SARS-CoV-2 species. This antiviral fusion protein combines IFN-β with the soluble extracellular domain of ACE2 (IFNβ-ACE2). Both domains retained predicted bioactivities in that the IFN-β domain exhibited potent antiproliferative activity and the ACE2 domain exhibited full binding to the transmembrane SARS-CoV-2 Spike protein. In virus-washed (virus-targeted) and non-washed in vitro infection systems, we showed that the pool of IFNβ-ACE2 targeted to the virion surface had superior antiviral activity against NL63 compared to soluble ACE2, IFN-β, or the unlinked combination of ACE2 and IFN-β. The pool of IFNβ-ACE2 on the virion surface exhibited robust antiviral efficacy based on the preemptive targeting of antiviral IFN-β activity to the proximal site of viral infection. In conclusion, virus-targeted IFN-β places interferon optimally and antecedent to viral infection to constitute a new antiviral strategy.

SARS-CoV-2 hijacks multiple organelles for virion assembly, of which the mechanisms have not been fully understood. Here, we identified a SARS-CoV-2-driven membrane structure named the 3a dense body (3DB). 3DBs are unusual electron-dense and dynamic structures driven by the accessory protein ORF3a via remodeling a specific subset of the trans-Golgi network (TGN) and early endosomal membrane. 3DB formation is conserved in related bat and pangolin coronaviruses but was lost during the evolution to SARS-CoV. During SARS-CoV-2 infection, 3DB recruits the viral structural proteins spike (S) and membrane (M) and undergoes dynamic fusion/fission to maintain the optimal unprocessed-to-processed ratio of S on assembled virions. Disruption of 3DB formation resulted in virions assembled with an abnormal S processing rate, leading to a dramatic reduction in viral entry efficiency. Our study uncovers the crucial role of 3DB in maintaining maximal SARS-CoV-2 infectivity and highlights its potential as a target for COVID-19 prophylactics and therapeutics.

SARS-CoV-2 can cause severe lung damage due to uncontrolled viral replication or/and excessive inflammation. New variants of concern (VOCs) have raised additional concerns due to disparate pathogenicity and possible enhanced virulence. Herein, using RNA sequencing, we performed a comparative transcriptomic analysis following infection with major VOCs. We evaluated the transcriptional changes induced in the lungs of K18-hACE2 mice following infection with the ancestral B.1 lineage (Wuhan), B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.2 (Delta), B.1.1.529 (Omicron) variants or mouse-adapted SARS-CoV-2 (MA10). Our work reveals the molecular basis of pathological hallmarks in the lungs associated with SARS-CoV-2 infection. We report that infection with B.1, pre-Omicron VOCs, and MA10 induce similar molecular fingerprints of excessive lung inflammation and immune activation in K18-hACE2 mice. Analysis of differentially expressed genes revealed both shared and variant-specific responses, with key immune markers such as Cxcl10, Zbp1, Ifit3, Isg15, Rsad2, and Irf7 consistently upregulated across variants. Clustering of highly variable genes across samples revealed two variant groups distinguished by upregulation of antigen presentation and immune-related genes (e.g. Retnla, Saa3, Plac8, Ly6c2, H2-D1, and H2-K1). Delta, Beta, Alpha, and MA10 showed elevated expression, whereas Wuhan and Omicron exhibited attenuated responses. In addition, we show that Z-DNA-binding protein 1 (ZBP1) plays a role in viral clearance in the lungs after SARS-CoV-2 infection. ZBP1 deficiency resulted in reduced expression of cell death-associated markers and virus-induced cell death in the lungs following MA10 infection. Furthermore, the knockout of ZBP1 resulted in an attenuated inflammatory response with reduced production of proinflammatory cytokines and chemokines and decreased macrophage infiltration in the lungs. These results suggest that ZBP1 plays a role in viral clearance and in enhancing the inflammatory response and virus-induced cell death during SARS-CoV-2 infection. Altogether, our study provides insights into the pathogenesis of SARS-CoV-2 infection in mice, facilitating the identification of biomarkers and the development of potential therapeutic targets.

Developing vaccines that promote CD8+ T cell memory is a challenge for infectious disease and cancer immunotherapy. TCF-1+ stem cell-like memory CD8+ T (TSCM) cells are important determinants of long-lived memory. Yet, the developmental requirements for TSCM cell formation are unclear. Here, we identify the temporal window for type I interferon receptor (IFNAR) blockade to drive TSCM cell generation following viral infection and mRNA-lipid nanoparticle vaccination. We reveal a reversible developmental trajectory where transcriptionally distinct TSCM cells emerged from a transitional precursor of exhausted T cellular state concomitant with viral clearance. TSCM cell differentiation correlated with T cell retention within the lymph node paracortex due to disrupted CXCR3 chemokine gradient formation. These effects were linked to increased antigen load and a counterintuitive increase in IFNγ, which controlled cell location. Vaccination with the IFNAR blockade promoted TSCM cell differentiation and enhanced protection against chronic infection. These findings propose an approach to vaccine design whereby modulation of inflammation promotes memory formation and function.

Despite the growing clinical need, the therapeutic efficacy of drugs for acute lung injury (ALI) remains inadequate. Traditional Chinese Medicine (TCM) holds potential in managing ALI due to its unique therapeutic properties. However, the intricate nature of TCM formulations hinders global adoption. Component-based Chinese medicine (CCM) offers a promising pathway for TCM's internationalization. Phillyrin-Emodin-Baicalin-Liquiritin (PEBL), a CCM with significant anti-inflammatory activity, is derived from the well-established TCM formula Liang-Ge-San. Whether PEBL effectively addresses viral ALI, however, remains unclear.

This study aims to investigate the therapeutic effects and underlying mechanisms of PEBL on viral ALI.

The efficacy of PEBL against Poly(I:C)-induced ALI was assessed by analyzing cytokine production, macrophage infiltration, pulmonary damage, and mortality. Bioinformatics and network pharmacology were employed to identify key targets and signaling pathways. The molecular mechanisms were further validated using Poly(I:C)-treated RAW264.7 cells, Tg(coro1α: GFP) zebrafish, BALB/c mice, and models of Influenza A/Puerto Rico/8/1934 (H1N1) virus strain (PR8)-induced ALI in BALB/c mice and SARS-CoV-2 Omicron XBB.1.16 subvariant (XBB)-induced ALI in hACE2-transgenic C57BL/6 mice.

PEBL mitigated Poly(I:C)-induced ALI, as evidenced by reduced cytokine levels, diminished macrophage infiltration, alleviated lung damage, and decreased mortality. Virtual screening identified the farnesyl X receptor (FXR) and angiotensin-converting enzyme 2 (ACE2) as key therapeutic targets for viral pneumonia. Mechanistically, PEBL downregulated FXR expression, inhibiting FXR binding to ACE2 promoters, which subsequently suppressed NF-κB-p65 nuclear translocation and cytokine production. In vivo, PEBL attenuated cytokine production by inhibiting ACE2 transcription through FXR downregulation, leading to alleviation of Poly(I:C)-induced ALI in both zebrafish and mice. Additionally, PEBL significantly improved symptoms of ALI caused by PR8 and XBB infections, by disrupting the FXR/ACE2 signaling axis, resulting in reduced weight loss, lower lung indices, diminished viral load and titer, fewer pulmonary lesions, and suppressed NF-κB-p65 nuclear translocation, along with decreased cytokine storm.

This study provides the first evidence that PEBL offers protective effects against ALI induced by acute respiratory viruses. PEBL prevents FXR from binding to ACE2 by inhibiting FXR transcription, which reduces macrophage infiltration, cytokine storm formation, and inflammatory injury, thereby ameliorating viral ALI. These findings underscore the potential of PEBL as a candidate for further exploration in the treatment of viral ALI.

The rapid onset of innate immune defenses is critical for early control of viral replication in an infected host and yet it can also lead to irreversible tissue damage, especially in the respiratory tract. Sensitive regulators must exist that modulate inflammation, while controlling the infection. In the present study, we identified acetylcholine (ACh)-producing B cells as such early regulators. B cells are the most prevalent ACh-producing leukocyte population in the respiratory tract demonstrated with choline acetyltransferase (ChAT)-green fluorescent protein (GFP) reporter mice, both before and after infection with influenza A virus. Mice lacking ChAT in B cells, disabling their ability to generate ACh (ChatBKO), but not those lacking ChAT in T cells, significantly, selectively and directly suppressed α7-nicotinic-ACh receptor-expressing interstitial, but not alveolar, macrophage activation and their ability to secrete tumor necrosis factor (TNF), while better controlling virus replication at 1 d postinfection. Conversely, TNF blockade via monoclonal antibody treatment increased viral loads at that time. By day 10 of infection, ChatBKO mice showed increased local and systemic inflammation and reduced signs of lung epithelial repair despite similar viral loads and viral clearance. Thus, B cells are key participants of an immediate early regulatory cascade that controls lung tissue damage after viral infection, shifting the balance toward reduced inflammation at the cost of enhanced early viral replication.

Investigating the infection mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the airway epithelium and developing effective defense strategies against infection are important. To achieve this, establishing appropriate infection models is crucial. Therefore, various in vitro models, such as cell lines and primary cultures, and in vivo models involving animals that exhibit SARS-CoV-2 infection and genetically humanized animals have been used as animal models. However, no animal model has been established that allows infection experiments with human cells under the physiological environment of airway epithelia. Therefore, we aimed to establish a novel animal model that enables infection experiments using human cells. Human induced pluripotent stem cell-derived airway epithelial cell-transplanted nude rats (hiPSC-AEC rats) were used, and infection studies were performed by spraying lentiviral pseudoviruses containing SARS-CoV-2 spike protein and the GFP gene on the tracheae. After infection, immunohistochemical analyses revealed the existence of GFP-positive-infected transplanted cells in the epithelial and submucosal layers. In this study, a SARS-CoV-2 infection animal model including human cells was established mimicking infection through respiration, and we demonstrated that the hiPSC-AEC rat could be used as an animal model for basic research and the development of therapeutic methods for human-specific respiratory infectious diseases.

Traditional Chinese medicine has been recognized for its significant role in treating acute lung injury (ALI) due to its distinct therapeutic advantages. Liang-Ge-San (LGS), a formulation from the ancient "Taiping Huimin Hejiju Fang", is believed to possess beneficial effects for treating ALI. However, LGS's precise mechanisms and efficacy in addressing viral ALI remain inadequately explored.

To evaluate LGS's therapeutic effects and underlying mechanisms in treating viral-induced ALI.

The protective effects of LGS were examined in a Polyinosinic-polycytidylic acid [Poly(I:C)]-induced ALI model using real-time quantitative PCR, enzyme-linked immunosorbent assay, and histopathological analysis. A bioinformatics approach combined with network pharmacology was utilized to ascertain the key targets of LGS in viral pneumonia. The pharmacodynamic mechanisms of LGS in viral ALI were further validated through immunofluorescence, overexpression, short hairpin RNA, chromatin immunoprecipitation, and target agonist assays.

LGS administration resulted in a reduction of IL-1β, IL-6, and TNF-α levels, along with a decrease in macrophage infiltration, pulmonary damage, and pneumonedema following the Poly(I:C) challenge. Bioinformatics and network pharmacology analyses suggested that Farnesyl X receptor (FXR) and angiotensin converting enzyme 2 (ACE2) are potential therapeutic targets for LGS in viral pneumonia. Further experiments revealed that LGS suppressed the expression of FXR, ACE2, and NF-κB-p65 in Poly(I:C)-infected cells. Notably, overexpression of FXR counteracted the repressive effects of LGS, while ACE2 expression remained unchanged in FXR-knockdown RAW264.7 cells upon treatment with Poly(I:C) or LGS. Additionally, LGS inhibited the interaction between FXR and ACE2 transcriptional promoters. In vivo, LGS attenuated the Poly(I:C)-induced upregulation of FXR, ACE2, IL-1β, IL-6, and TNF-α in ALI zebrafish and mice models, effects that could be reversed by chenodeoxycholic acid (CDCA), an FXR agonist. Moreover, LGS markedly alleviated weight loss, improved survival rates, reduced lung index, diminished viral load, and inhibited lung pathological changes in H1N1-PR8-induced ALI mice. IL-1β, IL-6, TNF-α, INF-γ, FXR, ACE2, small heterodimer partner, and NF-κB-p65 levels were markedly reduced by LGS, with these effects being reversed by CDCA.

This investigation provides the first evidence that FXR/ACE2 signaling is pivotal in acute respiratory viral infections, while LGS demonstrates antiviral activity against viral-induced ALI. LGS inhibits ACE2 expression induced by viral infection via FXR inhibition and modulates the cytokine storm, thus alleviating viral ALI. These findings suggest that LGS may be a promising treatment strategy for treating viral ALI.

The nucleocapsid protein (N protein) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is elevated in bodily fluids at the onset of infection and has recently been found to have a direct role in lung damage. However, the exact mode of action of the N protein in acute lung injury is still unknown.

Recombinant N protein was used to treat mice and A549 cells in vivo and in vitro. Enzyme-linked immunosorbent assay and hematoxylin and eosin staining were used to detect the levels of inflammatory factors and lung damage in lung tissue. The total iron and Fe2+ contents and the expression of ferroptosis markers in mouse lung tissues and cells were detected. Co-immunoprecipitation detects the binding of N protein and solute carrier family 7 member 11 (SLC7A11). Replenishment experiments were conducted by activating SLC7A11 to study the effect of SLC7A11 on N protein-induced lung injury.

Recombinant N protein caused acute lung injury and lung inflammation, increased total iron and Fe2+ contents in vivo and in vitro, promoted the expression of ACSL4, inhibited the expression of GPX4 and FTH1, and triggered ferroptosis. Recombinant N protein can interact with SLC7A11, and activating SLC7A11 can reverse N protein-induced ferroptosis and acute lung injury.

SARS-CoV-2 N protein can directly interact with SLC7A11 to cause ferroptosis, which produces a lot of inflammatory factors and results in lung injury in mice.

Porcine respiratory coronavirus (PRCV) is a naturally occurring pneumotropic coronavirus in the pig, providing a valuable large animal model to study acute respiratory disease. PRCV pathogenesis and the resulting immune response were investigated in pigs, the natural large animal host. We compared 2 strains, ISU-1 and 135, which induced differing levels of pathology in the respiratory tract to elucidate the mechanisms leading to mild or severe disease. The 135 strain induced greater pathology which was associated with higher viral load and stronger spike-specific antibody and T-cell responses. In contrast, the ISU-1 strain triggered mild pathology with a more balanced immune response and greater abundance of T regulatory cells. A higher frequency of putative T follicular helper cells was observed in animals infected with strain 135 at 11 days postinfection. Single-cell RNA-sequencing of bronchoalveolar lavage revealed differential gene expression in B and T cells between animals infected with 135 and ISU-1 at 1 day postinfection. These genes were associated with cell adhesion, migration, and immune regulation. Along with increased IL-6 and IL-12 production, these data indicate that heightened inflammatory responses to the 135 strain may contribute to pronounced pneumonia. Among bronchoalveolar lavage (BAL) immune cell populations, B cells and plasma cells exhibited the most gene expression divergence between pigs infected with different PRCV strains, highlighting their role in maintaining immune homeostasis in the respiratory tract. These findings indicate the potential of the PRCV model for studying coronavirus-induced respiratory disease and identifying mechanisms that determine infection outcomes.

RNA-DNA differences (RDDs) challenge the traditional view of RNA as a faithful copy of DNA, arising through RNA editing, transcriptional errors, and oxidative damage. Reactive oxygen species (ROS) play a central role, inducing lesions like 8-oxo-guanine that compromise transcription and translation, leading to dysfunctional proteins. This review explores the biochemical basis of RDDs, their exacerbation under oxidative stress, and their dual roles in cellular adaptation and disease. RDDs contribute to genomic instability and are implicated in cancers, neurodegenerative disorders, and autoimmune diseases, while also driving phenotypic diversity. Drawing on terrestrial and spaceflight studies, we highlight the intersection of oxidative stress, RDD formation, and cellular dysfunction, proposing innovative mitigation approaches. Advancements in RDD detection and quantification, along with ROS management therapies, offer new avenues to restore cellular homeostasis and promote resilience. By positioning RDDs as a hallmark of genomic entropy, this review underscores the limits of biological adaptation. Furthermore, the prevalence of guanine-rich codons in antioxidant genes increases their susceptibility to ROS-induced oxidative lesions, linking redox stress, genomic instability, and constrained adaptation. These insights have profound implications for understanding aging, disease progression, and adaptive mechanisms in both terrestrial and space environments.

Post-infection sequela of several viruses have been linked with Parkinson's disease (PD). Here, we investigated whether mice infected with SARS-CoV-2 alone or in combination with two putative Parkinsonian toxins, MPTP and paraquat, increased the susceptibility to develop Parkinsonian pathology. We also examined if G2019S LRRK2 mice had any change in sensitivity to SARS-CoV-2 as well as if vaccination against this virus altered any neuropathology. Infection with WA-1/2020 or Omicron B1.1.529 strains sensitized both WT and G2019S LRRK2 mice to the neuropathological effects of a subtoxic exposure to MPTP, but not paraquat. These neuropathologies were rescued in WT mice vaccinated with mRNA- or protein-based SARS-CoV-2 vaccines. However, G2019S LRRK2 mutant mice were only protected with the protein-based vaccine. These results highlight the role of both environmental exposures and familial background on the development of Parkinsonian pathology secondary to viral infection and the benefit of vaccines in reducing these risks.

The outcome of the immune response depends on the content and magnitude of inflammatory mediators, the right time to start, and the duration of inflammatory responses. Patients with coronavirus disease 2019 (COVID-19) represent diverse disease severity. Understanding differences in immune responses in individuals with different disease severity levels can help elucidate disease mechanisms. Here, we serially analyzed the cytokine profiles of 809 patients with mild to critical COVID-19. The cytokine profile revealed an overall increase in IL-1β, IL-1Ra, TNF-α, IL-6, IL-2, IL-8, and IL-18 and impaired production of IFN-α and -β. Only an early rise in IL-1Ra, IL-6, and IL-2 levels was linked to worse disease outcomes. On the other hand, long-term rises in IL-1β, IL-1Ra, TNF-α, IL-6, IL-2, IL-8, and IL-18 levels were linked to worse disease outcomes. Principal component analysis identified a component, including IL-1β, TNF-α, IFN-α, and IL-12, that was associated with disease severity. Spearman analysis revealed that the correlation of IL-1β and IFN-α was entirely different between mild and critical patients. Therefore, the ratio of IL-1β to IFN-α seemed to be a suitable criterion for distinguishing critical patients from mild ones. The higher levels of the IL-1β to IFN-α ratio correlated with improved outcomes. These data point to an imbalance of IL-1β/IFNα, contributing to hyperinflammation in COVID-19.

Since 2022, mpox has emerged as a global health threat, with two clades (I and II) causing outbreaks of international public health concern. The third generation smallpox vaccine modified vaccinia Ankara, manufactured by Bavarian Nordic (MVA-BN), has emerged as a key component of mpox prevention. To date, the immunogenicity of this vaccine, including determinants of response, has been incompletely described, especially when MVA-BN has been administered intradermally at a fifth of the registered dose (so-called fractionated dosing), as recommended as a dose-sparing strategy. The aim of this study was to explore the immunogenicity of MVA-BN and baseline determinants of vaccine response in an observational public-health response setting.

We conducted a prospective cohort study and immunological analysis of responses to MVA-BN in patients attending a sexual health vaccination clinic in Oxford, UK. Blood samples were taken at baseline, day 14, and day 28 after first vaccine, and 28 and 90 days following a second vaccine. A subcohort had additional blood samples collected day 1 following their first vaccine (optional timepoint). We assessed IgG responses to mpox and vaccinia antigens using Luminex assay (MpoxPlex) using generalised linear mixed modelling, and T-cell responses using IFN-γ enzyme-linked immunospot and activation-induced marker assay. Associations between blood transcriptomic signatures (baseline, day 1) and immunogenicity were assessed using differential expression analysis and gene set enrichment methods.

We recruited 34 participants between Dec 1, 2022 and May 3, 2023 of whom 33 received fractionated dosing. Of the 30 without previous smallpox vaccination, 14 (47%) seroconverted by day 28, increasing to 25 (89%) 90 days after second vaccination. However, individuals seronegative on day 28 had persistently lower responses compared with individuals seropositive on day 28 (numerically lower antibody responses to six of seven dynamic antigens in the MPoxPlex assay, p<0·05). Serological response on day 28 was positively associated with type I and II interferon signatures 1 day after vaccination (n=18; median module score 0·13 vs 0·06; p=1·1 × 10-⁶), but negatively associated with these signatures at baseline (normalised enrichment score -2·81 and -2·86, respectively).

Baseline inflammatory states might inhibit MVA-BN serological immunogenicity by inhibiting the upregulation of MVA-induced innate immune signalling. If confirmed mechanistically, these insights could inform improved vaccination strategies against mpox in diverse geographic and demographic settings. Given the likelihood of vaccine supply limitations presently and in future outbreak settings, the utility of dose-sparing vaccine strategies as a general approach to maximising population benefit warrants further study.

UKRI via the UK Monkeypox Research Consortium, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, the Kennedy Trust for Rheumatology Research, the John Climax Donation, the Medical Research Council (UK), the Wellcome Trust, the Center for Cooperative Human Immunology (National Institutes of Health), and the National Institute for Health and Care Research Oxford Biomedical Research Centre.

Cytokine storm (CS) is a severe systemic inflammatory syndrome characterized by the excessive activation of immune cells and a significant increase in circulating levels of cytokines. This pathological process is implicated in the development of life-threatening conditions such as fulminant myocarditis (FM), acute respiratory distress syndrome (ARDS), primary or secondary hemophagocytic lymphohistiocytosis (HLH), cytokine release syndrome (CRS) associated with chimeric antigen receptor-modified T (CAR-T) therapy, and grade III to IV acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation. The significant involvement of the JAK-STAT pathway, Toll-like receptors, neutrophil extracellular traps, NLRP3 inflammasome, and other signaling pathways has been recognized in the pathogenesis of CS. Therapies targeting these pathways have been developed or are currently being investigated. While novel drugs have demonstrated promising therapeutic efficacy in mitigating CS, the overall mortality rate of CS resulting from underlying diseases remains high. In the clinical setting, the management of CS typically necessitates a multidisciplinary team strategy encompassing the removal of abnormal inflammatory or immune system activation, the preservation of vital organ function, the treatment of the underlying disease, and the provision of life supportive therapy. This review provides a comprehensive overview of the key signaling pathways and associated cytokines implicated in CS, elucidates the impact of dysregulated immune cell activation, and delineates the resultant organ injury associated with CS. In addition, we offer insights and current literature on the management of CS in cases of FM, ARDS, systemic inflammatory response syndrome, treatment-induced CRS, HLH, and other related conditions.

This perspective examines the potential oncogenic mechanisms of SARS-CoV-2 through comparative analysis with established cancer-causing viruses, integrating classical virological approaches with artificial intelligence (AI)-driven analysis. The paper explores four key themes: shared oncogenic mechanisms between classical viruses and SARS-CoV-2 (including cell cycle dysregulation, inflammatory signaling, immune evasion, and metabolic reprogramming); the application of AI in understanding viral oncogenesis; the integration of neuroimaging evidence; and future research directions. The author presents novel hypotheses regarding SARS-CoV-2's potential oncogenic mechanisms, supported by recent PET/FDG imaging studies showing persistent metabolic alterations. The manuscript emphasizes the transformative potential of combining traditional virological methods with advanced AI technologies for better understanding and preventing virus-induced cancers, while highlighting the importance of long-term monitoring of COVID-19 survivors for potential oncogenic developments.

Long noncoding RNAs (lncRNAs) are a newer class of noncoding transcripts identified as key regulators of biological processes. Here, we aimed to identify novel lncRNA targets that play critical roles in major human respiratory viral infections by systematically mining large-scale transcriptomic data sets. Using bulk RNA-sequencing (RNA-seq) analysis, we identified a previously uncharacterized lncRNA, named virus-inducible lncRNA modulator of interferon response (VILMIR), that was consistently upregulated after in vitro influenza infection across multiple human epithelial cell lines and influenza A virus subtypes. VILMIR was also upregulated after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and respiratory syncytial virus (RSV) infections in vitro. We experimentally confirmed the response of VILMIR to influenza infection and interferon-beta (IFN-β) treatment in the A549 human epithelial cell line and found the expression of VILMIR was robustly induced by IFN-β treatment in a dose- and time-specific manner. Single-cell RNA-seq analysis of bronchoalveolar lavage fluid samples from coronavirus disease 2019 (COVID-19) patients uncovered that VILMIR was upregulated across various cell types, including at least five immune cells. The upregulation of VILMIR in immune cells was further confirmed in the human T cell and monocyte cell lines, SUP-T1 and THP-1, after IFN-β treatment. Finally, we found that knockdown of VILMIR expression reduced the magnitude of host transcriptional responses to both IFN-β treatment and influenza A virus infection in A549 cells. Together, our results show that VILMIR is a novel interferon-stimulated gene (ISG) that regulates the host interferon response and may be a potential therapeutic target for human respiratory viral infections upon further mechanistic investigation.IMPORTANCEIdentifying host factors that regulate the immune response to human respiratory viral infection is critical to developing new therapeutics. Human long noncoding RNAs (lncRNAs) have been found to play key regulatory roles during biological processes; however, the majority of lncRNA functions within the host antiviral response remain unknown. In this study, we identified that a previously uncharacterized lncRNA, virus-inducible lncRNA modulator of interferon response (VILMIR), is upregulated after major respiratory viral infections including influenza, severe acute respiratory syndrome coronavirus 2, and respiratory syncytial virus. We demonstrated that VILMIR is an interferon-stimulated gene that is upregulated after interferon-beta (IFN-β) in several human cell types. We also found that knockdown of VILMIR reduced the magnitude of host transcriptional responses to IFN-β treatment and influenza A infection in human epithelial cells. Our results reveal that VILMIR regulates the host interferon response and may present a new therapeutic target during human respiratory viral infections.

Respiratory viral infections trigger immune and inflammatory responses that can be associated with excessive oxidative stress, glutathione (GSH) depletion, and a cytokine storm that drives virus-induced cell/tissue damage and severe disease. Erdosteine is a thiol-based drug with proven mucolytic, anti-inflammatory, antioxidant, and antibacterial properties, but less is known about its antiviral effects. We performed in vitro studies to investigate the antiviral and anti-inflammatory activity of erdosteine in A549-hACE2 human lung epithelial cells infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or respiratory syncytial virus (RSV) and in Caco-2 human colon carcinoma cells infected with influenza A virus (H1N1). The cells were treated with different concentrations of erdosteine or its active metabolite 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MET-1) before and after viral infection. The viral replication/load in the cell culture supernatants was measured by real-time quantitative polymerase chain reaction (RT-qPCR) assay and digital droplet PCR. The gene expression of innate immune response signaling pathways and oxidative stress was analyzed by reverse transcription PCR custom-array. The results showed that erdosteine and its active metabolite, at concentrations consistent with an approved therapeutic human dosage, were not directly cytotoxic and had significant antiviral effects in cells pre-infected with SARS-CoV-2, RSV, and H1N1. The transcriptome analysis showed that erdosteine activated innate immune responses by stimulating overexpression of type I interferon and inflammasome pathways and modulated oxidative stress by inducing the modulation of oxidative stress and GSH pathways. These findings suggest that erdosteine may be a useful treatment for respiratory viral infections.

Extracellular vesicles (EVs) are produced by virtually all types of cells and can be detected in nearly all extracellular places. These particles mediate intercellular communication and transfer their cargo to the recipient cells, inducing a variety of processes in these cells through transmission of several biomolecules such as miRNAs, lncRNAs, other transcripts and a variety of proteins. It has been documented that size, quantity, and expression of biomolecules in the EVs are influenced by the level of oxygen. In fact, hypoxia can affect several cellular processes through modulation of the cargo of these vesicles. Hypoxic exosomes derived from tumor cells have several protumoral effects on the recipient cells, including enhancement of proliferation, migration, and invasion in other tumoral cells, induction of metastasis in distant organs, stimulation of angiogenesis in the endothelial cells, and modulation of macrophage polarization. Hypoxic EVs also contribute to several non-malignant diseases. This review summarizes the effect of hypoxia on EVs cargo in malignant and nonmalignant diseases of different organs.

Background/Objectives: The COVID-19 pandemic has posed a significant challenge to global healthcare systems and has prompted a need for a better understanding of the molecular mechanisms underlying SARS-CoV-2 infection. This study aims to analyze differential gene expression in COVID-19 patients to identify regulatory genes influencing key pathways involved in disease progression. Methods: We conducted a transcriptomic analysis of patients admitted to the Infectious Disease Department of City Hospital No. 40, confirmed with SARS-CoV-2 via PCR. The study received ethical approval (protocol No. 171, 18 May 2020), and all participants provided informed consent. Total RNA was extracted from blood samples, followed by RNA sequencing using the DNBSEQ-G400 platform. Differential gene expression was analyzed using the Mann-Whitney test, and Gene Ontology enrichment analysis was performed to identify relevant biological processes. Results: Our analysis revealed significant number of differentially expressed genes within studied groups (severity, outcome, cytokine storm and paired samples). These genes are involved in key regulatory and signal transduction pathways governing immune responses, intercellular communication, and the metabolism of various compounds. Furthermore, we identified genes ALOX15, PRL, FLT3, S100A8, S100A12, IL4, IL13, and a few others as master regulators within the studied pathways, which represent promising candidates for further investigation as potential therapeutic targets. Conclusions: This study highlights critical gene expression changes associated with COVID-19 severity and outcomes, identifying potential biomarkers. Our findings contribute to the understanding of the molecular drivers of COVID-19 and suggest new avenues for therapeutic interventions aimed at modulating immune responses.

The antibody-mediated immune response is crucial for the development of protective immunity against SARS-CoV-2, the virus responsible for the COVID-19 pandemic. Understanding the interaction between SARS-CoV-2 and the immune system is critical because new variants emerge as a result of the virus's ongoing evolution. Understanding the function of B cells in the SARS-CoV-2 infection process is critical for developing effective and long-lasting vaccines against this virus. Triggered by the innate immune response, B cells transform into memory B cells (MBCs). It is fascinating to observe how MBCs provide enduring immune defence, not only eradicating the infection but also safeguarding against future reinfection. If there is a lack of B cell activation or if the B cells are not functioning properly, it can lead to a serious manifestation of the disease and make immunisation less effective. Individuals with disruptions in the B cells have shown increased production of cytokines and chemokines, resulting in a poor prognosis for the disease. Therefore, we have developed an updated review article to gain insight into the involvement of B cells in SARS-CoV-2 infection. The discussion has covered the generation, functioning, and dynamics of neutralising antibodies (nAbs). Furthermore, we have emphasised immunotherapeutics that rely on nAbs.

Hyperinflammation is a significant factor in long COVID, impacting over 65 million post-COVID-19 individuals globally. Herbal remedies, including propolis, show promise in reducing severity and pro-inflammatory cytokines. However, the natural pharmacological role of propolis in COVID-19 management remains underexplored. Employing network pharmacology and in silico techniques, we assessed propolis extract's potential in countering SARS-CoV-2-induced inflammation. We identified 80 flavonoids via LC-MS/MS QTOF and employed 11 anti-inflammatory drugs as references for inflammation target fishing. Utilizing in silico techniques encompassing target fishing, molecular docking, and dynamics, we examined propolis' effects. We identified 1105 gene targets connected to inflammation through multiple validated target predictors. By integrating SARS-CoV-2 DEGs from GSE147507 with these targets, we identify 25 inflammation-COVID-19-associated propolis targets, including STAT1, NOS2, CFB, EIF2K2, NPY5R, and BTK. Enrichment analyses highlighted primary pharmacological pathways related to Epstein-Barr virus infection and COVID-19. Molecular docking validated isokaempferide, iristectorigenin B, 3'-methoxypuerarin, cosmosiin, and baicalein-7-O-β-d-glucopyranoside, which exhibited strong binding affinity and stability with relevant genes. Moreover, our findings indicate that propolis ligands could potentially suppress reactivation of Epstein-Barr Virus infections in post-COVID-19 cases. However, this study has a limitation in that the concentration of each propolis compound has not been quantified. Therefore, further exploration of propolis compounds quantification and experimental validation are needed to support these findings.

Cytokine storm (CS) is a hyperinflammatory syndrome causing multiorgan dysfunction and high mortality, especially in patients with malignant hematologic neoplasms. Triggers include malignant neoplasm-associated hemophagocytic lymphohistiocytosis (MN-HLH), cytokine release syndrome from chimeric antigen receptor T-cell therapy (CAR-T CRS), and COVID-19, but the underlying mechanisms of inflammation and their impact on outcomes are poorly understood.

To delineate the inflammatory patterns characterizing different CS etiologies and their association with clinical outcomes.

This retrospective cohort study was conducted at the MD Anderson Cancer Center in Houston, Texas, between March 1, 2020, and November 20, 2022, using the software-as-a-service Syntropy Foundry Platform. Participants were patients with malignant hematologic neoplasms who developed CS from COVID-19 (COVID-CS), MN-HLH, or CAR-T CRS.

Diagnostic criteria for COVID-CS were developed based on surging inflammatory markers (interleukin-6, C-reactive protein, and ferritin), while diagnosis of MN-HLH and CAR-T CRS followed established guidelines.

The study compared cytokine levels, clinical characteristics, and survival outcomes across the 3 cohorts and focused on inflammatory markers, survival times, and key factors associated with survival identified through univariate and multivariable analyses.

A total of 671 patients met the inclusion criteria. Of those, 220 (33%) had CAR-T CRS, 227 (34%) had COVID-CS, and 224 (33%) had MN-HLH. Patients were predominantly male (435 [65%]), and 461 (69%) were White, with significant differences in median age (CAR-T CRS, 63 [IQR, 54-71] years; COVID-CS, 63 [IQR, 52-72] years; MN-HLH, 55 [IQR, 41-65] years; P < .001) as well as number of admission days and underlying cancer type across cohorts. Marked variations in cytokine levels and survival outcomes were observed, with the MN-HLH cohort exhibiting the highest levels of inflammatory markers (eg, median TNF-α, 105 pg/mL [IQR, 38-201 pg/mL] for MN-HLH vs 23 pg/mL [IQR, 17-42 pg/mL] for COVID-CS) and lowest fibrinogen and albumin levels. The cohort with CAR-T CRS showed substantially longer survival times compared with the cohort with COVID-CS (hazard ratio [HR], 2.93; 95% CI, 1.95-4.41) and the cohort with MN-HLH (HR, 8.12; 95% CI, 5.51-12.00). Clustering analysis showed overlapping patterns between COVID-CS and CAR-T CRS, while MN-HLH formed a distinct cluster.

This study of CS syndromes found distinct immune responses within each cohort. The distinct clinical patterns and outcomes associated with different CS etiologies emphasize the importance of early diagnosis and timely intervention.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has varied presentations from asymptomatic to death. Efforts to identify factors responsible for differential COVID-19 severity include but are not limited to genome wide association studies (GWAS) and transcriptomic analysis. More recently, variability in host epigenomic profiles have garnered attention, providing links to disease severity. However, whole epigenome analysis of the respiratory tract, the target tissue of SARS-CoV-2, remains ill-defined.

We interrogated the nasal methylome to identify pathophysiologic drivers in COVID-19 severity through whole genome bisulfite sequencing (WGBS) of nasal samples from COVID-19 positive individuals with severe and mild presentation of disease. We noted differential DNA methylation in intergenic regions and low methylated regions (LMRs), demonstrating the importance of distal regulatory elements in gene regulation in COVID-19 illness. Additionally, we demonstrated differential methylation of pathways implicated in immune cell recruitment and function, and the inflammatory response. We found significant hypermethylation of the FUT4 promoter implicating impaired neutrophil adhesion in severe disease. We also identified hypermethylation of ELF5 binding sites suggesting downregulation of ELF5 targets in the nasal cavity as a factor in COVID-19 phenotypic variability.

This study demonstrated DNA methylation as a marker of the immune response to SARS-CoV-2 infection, with enhancer-like elements playing significant roles. It is difficult to discern whether this differential methylation is a predisposing factor to severe COVID-19, or if methylation differences occur in response to disease severity. These differences in the nasal methylome may contribute to disease severity, or conversely, the nasal immune system may respond to severe infection through differential immune cell recruitment and immune function, and through differential regulation of the inflammatory response.

Discovering therapeutic molecules requires the integration of both phenotype-based drug discovery (PDD) and target-based drug discovery (TDD). However, this integration remains challenging due to the inherent heterogeneity, noise, and bias present in biomedical data. In this study, Knowledge-Guided Drug Relational Predictor (KGDRP), a graph representation learning approach is developed that effectively integrates multimodal biomedical data, including network data containing biological system information, gene expression data, and sequence data that incorporates chemical molecular structures, all within a heterogeneous graph (HG) structure. By incorporating biomedical HG (BioHG) into a heterogeneous graph neural network (HGNN)-based architecture, KGDRP exhibits a remarkable 12% improvement compared to previous methods in real-world screening scenarios. Notably, the biology-informed representation, derived from KGDRP, significantly enhance target prioritization by 26% in drug target discovery. Furthermore, zero-shot evaluation on COVID-19 exhibited a notably higher success rate in identifying diverse potential drugs. The utilization of BioHG facilitates a unique KGDRP-based analysis of cell-target-drug interactions, thereby enabling the elucidation of drug mechanisms. Overall, KGDRP provides a robust infrastructure for the seamlessly integration of multimodal data and biomedical networks, effectively accelerating PDD, guiding therapeutic target discovery, and ultimately expediting therapeutic molecule discovery.

ObjectiveThe aim of this study was to assess the ability of plasma InterLeukin-6 (IL-6) monitoring to predict the failure to switch from volume-controlled ventilation to spontaneous ventilation (SV) in patients with COVID-19-related acute respiratory distress syndrome (ARDS).MethodsWe conducted an observational, single-center and prospective cohort study in the medico-surgical intensive care unit of Avignon Hospital Center. Participants were adult patients requiring invasive mechanical ventilation for COVID-19-related ARDS between August 2021 and August 2022, who were eligible for switching from volume-controlled ventilation to SV.ResultsAmong the 35 patients included in the study, 13 (37%) successfully switched from controlled ventilation to SV, while 22 failed (63%). In the failure group, mean plasma IL-6 levels were higher than in the successful group from hour 0 (defined as the moment of the switch to SV mode) to 48 h. However, differences between groups became significant from 24 h (362.8 vs. 33.6 pg/mL, P = 0.002). Interestingly, between-group differences in plasma C-reactive protein (CRP) levels were only significant between groups from 48 h (129.3 vs. 52.2 mg/L, P = 0.017). Finally, IL-6 and CRP had a similar ability to predict the failure to switch to SV mode: area under the receiving operative curves 0.763 [95%CI: 0.633-0.893] and 0.753 [95%CI: 0.595-0.911], respectively (P = 0.87).ConclusionsIL-6 and CRP are inflammatory biomarkers predictive of failure to switch to SV mode in COVID-19 ARDS patients. Our results showed that IL-6 can detect failure earlier than CRP. However, larger multicenter studies are needed to confirm our results, particularly in other ARDS models.