T cell aging increases the risk of viral infection-related morbidity and mortality and reduces vaccine efficacy in the elderly. A major hallmark of T cell aging is the loss of quiescence and shift toward terminal differentiation during homeostasis. However, how aging impacts the differentiation program of virus-specific T cells during infection is unclear. Here, in a murine coronavirus (MHV) infection model with age-associated increased mortality, we demonstrate that aging impairs, instead of promoting, the terminal differentiation program of virus-specific CD8+ T cells. Upon infection, CD8+ and CD4+ T cells in old mice showed marked reduction in clonal expansion and upregulation of immune checkpoints associated with T cell exhaustion. Bulk and single-cell transcriptomics showed that aging upregulated the T cell exhaustion transcriptional program associated with TOX in virus-specific CD8+ T cells and shifted the myeloid compartment from immunostimulatory to immunosuppressive phenotype. In addition, aging downregulated the transcriptional program of terminally differentiated effector CD8+ T cells and diminished the CX3CR1+ cytotoxic effector lineage. Mechanistically, virus-specific CD8+ T cells from infected aged mice displayed defects in inducing transcription factors ZEB2 and KLF2, which were required for terminal differentiation of effector CD8+ T cells. Together, our study shows that aging impairs terminal differentiation and promotes exhaustion of virus-specific CD8+ T cells responding to coronavirus infection through dysregulating expression of lineage-defining transcription factors.

Cancer stem cells (CSCs) are a distinct subpopulation of cancer cells with the capacity to constantly self-renew and differentiate, and they are the main driver in the progression of cancer resistance and relapse. The tumor microenvironment (TME) constructed by CSCs is the "soil" adapted to tumor growth, helping CSCs evade immune killing, enhance their chemical resistance, and promote cancer progression.

We aim to elaborate the tight connection between CSCs and immunosuppressive components of the TME. We attempt to summarize and provide a therapeutic strategy to eradicate CSCs based on the destruction of the tumor ecological niche.

This review is focused on three main key concepts. First, we highlight that CSCs recruit and transform normal cells to construct the TME, which further provides ecological niche support for CSCs. Second, we describe the main characteristics of the immunosuppressive components of the TME, targeting strategies and summarize the progress of corresponding drugs in clinical trials. Third, we explore the multilevel insights of the TME to serve as an ecological niche for CSCs.

COVID-19 patients in intensive care units (ICUs) requiring invasive mechanical ventilation (IMV) have few available treatment options. PANAMO, a multicenter, double-blind, randomized, placebo-controlled phase 3 study of vilobelimab, which blocks the inflammatory process caused by complement component 5a, demonstrated a significant mortality benefit at 28 and 60 days in these patients. A cost-effectiveness analysis was conducted to assess the incremental cost per quality-adjusted life-year (QALY).

A Markov model was used to estimate QALYs and the incremental cost-effectiveness ratio (ICER) of vilobelimab plus standard of care (SOC) versus SOC alone. The model simulated progression from severe COVID-19 to survival or death over a lifetime horizon. Outcomes data (COVID-19 all-cause mortality and renal replacement therapy) were incorporated from the PANAMO trial. COVID-19 mortality estimates were based on Centers for Disease Control and Prevention age-specific survival data. Utility values and hospital costs came from the literature. Vilobelimab cost was obtained from RED BOOK Online.

For COVID-19 ICU patients, total costs of care were $103,414 (SOC) and $132,247 (SOC plus vilobelimab), respectively, resulting in an incremental cost of $28,833. SOC provided 6.70 QALYs versus 7.99 QALYs for vilobelimab, an additional 1.29 QALYs. The ICER for vilobelimab plus SOC versus SOC alone was $22,287/QALY. Probabilistic sensitivity analysis demonstrated the robustness of the cost-effectiveness result as vilobelimab plus SOC was favored at a willingness-to-pay threshold of $50,000 in over 81% of iterations.

Vilobelimab provides a cost-effective option to treat ICU patients with severe COVID-19 receiving IMV compared to SOC, at well below the commonly accepted $50,000 US willingness-to-pay threshold.

Acute lung injury (ALI), a leading pulmonary inflammatory disorder, is associated with high morbidity and mortality rates. AXL, a member of the TAM family, plays a significant role in the innate immune and inflammatory responses. This study aimed to evaluate the therapeutic potential of C1632 and its mechanisms in the treatment of LPS-induced ALI/ARDS. The results demonstrated that C1632 pretreatment inhibited the transcription, expression, and secretion of LPS-induced inflammatory factors (IL-6, TNF-α) and vascular adhesion molecules (VCAM-1, ICAM-1). Furthermore, it reduced inflammatory cell infiltration in the lungs, thereby alleviating LPS-induced histopathological changes and lung injury in mice. Mechanistically, C1632 suppressed AXL transcription and expression, which inhibited the activation of the MAPK/NF-κB signaling pathway triggered by LPS stimulation. Both in vitro and in vivo studies confirmed that C1632 administration did not exhibit significant cytotoxicity. Additionally, it did not cause functional or structural damage to the liver and kidneys in mice, nor did it induce other acute toxic effects. In summary, these findings suggest that AXL is a novel target for MAPK/NF-κB signaling pathway mediated anti-inflammatory treatment and C1632 is a promising therapeutic agent for ALI/ARDS treatment.

The canonical complement-mediated lysis of mature red blood cells (RBCs) leads to severe pathogenesis. However, inhibition strategies targeting complement are not always as efficient as expected, indicating that unknown mechanisms are awaiting elucidation. In this study, we investigate the intracellular events in mature RBCs following complement activation. The collected evidence demonstrates that complement-induced hemolysis is a caspase-8-dependent programmed RBC death. Furthermore, short NLRP3 (miniNLRP3) fragments in RBCs are identified to engage in the assembly of NLRP3-apoptosis-associated speck-like protein containing a CARD (ASC)-caspase-8 complex. Activated caspase-8 directly induces the proteolysis of β-spectrin, thereby disrupting the skeletal network of the RBC membrane, a process we refer to as spectosis. Spectosis signaling is also activated in autoimmune hemolytic anemia or paroxysmal nocturnal hemoglobinuria, and the inhibition of spectosis significantly reduced complement-induced hemolysis. These findings reveal a programmed death cascade in mature RBCs, which may have important implications for the treatment of hemolytic disorders.

Intrahepatic cholangiocarcinoma (ICC) is known for its diverse cell types and resistance to standard treatments, highlighting the importance of understanding its tumor microenvironment (TME) for improved prognostic accuracy and therapeutic innovation. Our study used a multi-omics approach to analyze the ICC TME in both human and mouse samples, linking survival outcomes to the complex cellular interactions within the TME. We discovered a dedifferentiation phenomenon in ICC cells driven by the Yes-associated protein (YAP) pathway, influenced by tumor-associated macrophages (TAMs). Conversely, ICC cells promoted an immunosuppressive environment in TAMs. Targeting TAMs in a transgenic mouse model disrupted this loop, enhancing T cell responses and suggesting a novel immunotherapy avenue for ICC. Our findings reveal a reciprocal dedifferentiation-immunosuppression loop between ICC cells and TAMs, advocating TAM targeting as a promising therapy and highlighting the potential of macrophage modulation in ICC treatment.

After the coronavirus disease 2019 (COVID-19) pandemic, the postacute effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have gradually attracted attention. To precisely evaluate the health status of convalescent patients with COVID-19, we analyzed symptom and proteome data of 442 plasma samples from healthy controls, hospitalized patients, and convalescent patients 6 or 12 months after SARS-CoV-2 infection. Symptoms analysis revealed distinct relationships in convalescent patients. Results of plasma protein expression levels showed that C1QA, C1QB, C2, CFH, CFHR1, and F10, which regulate the complement system and coagulation, remained highly expressed even at the 12-month follow-up compared with their levels in healthy individuals. By combining symptom and proteome data, 442 plasma samples were categorized into three subtypes: S1 (metabolism-healthy), S2 (COVID-19 retention), and S3 (long COVID). We speculated that convalescent patients reporting hair loss could have a better health status than those experiencing headaches and dyspnea. Compared to other convalescent patients, those reporting sleep disorders, appetite decrease, and muscle weakness may need more attention because they were classified into the S2 subtype, which had the most samples from hospitalized patients with COVID-19. Subtyping convalescent patients with COVID-19 may enable personalized treatments tailored to individual needs. This study provides valuable plasma proteomic datasets for further studies associated with long COVID.

Horseshoe bats are natural hosts of zoonotic viruses, yet the genetic basis of their antiviral immunity is poorly understood. Here we generated two new chromosomal-level genome assemblies for horseshoe bat species (Rhinolophus) and three close relatives, and show that, during their diversification, horseshoe bats underwent extensive chromosomal rearrangements and gene expansions linked to segmental duplications. These expansions have generated new adaptive variations in type I interferons and the interferon-stimulated gene ANXA2R, which potentially enhance antiviral states, as suggested by our functional assays. Genome-wide selection screens, including of candidate introgressed regions, uncover numerous putative molecular adaptations linked to immunity, including in viral receptors. By expanding taxon coverage to ten horseshoe bat species, we identify new variants of the SARS-CoV-2 receptor ACE2, and report convergent functionally important residues that could explain wider patterns of susceptibility across mammals. We conclude that horseshoe bats have numerous signatures of adaptation, including some potentially related to immune response to viruses, in genomic regions with diverse and multiscale mutational changes.

Mycoplasma pneumoniae is an important human respiratory pathogen that causes mild-to-moderate community-acquired M. pneumoniae pneumonia (MPP), particularly in children. RNA editing plays a vital role in pathogen infection and host immune response, but it remains largely unknown how it could be involved in the epigenetic regulation of host response to M. pneumoniae infection. In the present study, we performed an epitranscriptomic analysis of adenosine to inosine (A-to-I) editing in 39 bronchoalveolar lavage fluid (BALF) samples from the severe side (SS) and the opposite side (OS) of patients with MPP. Our editome profiling identified 87 differential RNA editing (DRE) events in 50 genes, especially missense editing events that recoded C-C motif chemokine receptor-like 2 (CCRL2, p.K147R) and cyclin I (CCNI, p.R75G). The expression of adenosine deaminase acting on RNA (ADAR) significantly increased on SS compared to OS and positively correlated with the average RNA editing level and individual DRE events. Meanwhile, functional enrichment analysis showed that DRE was observed in genes primarily associated with the negative regulation of innate immune response, type I interferon production, and cytokine production. Further comparison of SS between complicated MPP (CMPP) and non-complicated MPP (NCMPP) revealed RNA editing events associated with MPP complications, with a higher ADAR expression in CMPP than NCMPP. By identifying DRE events as biomarkers associated with MPP severity and complications, our editome profiling provides new insight into the potential role played by A-to-I RNA editing in modulating the host's immune system during M. pneumoniae infection.IMPORTANCEOur research investigates how Mycoplasma pneumoniae, a common respiratory pathogen, influences how our cells modify their genetic instructions. By studying RNA editing changes in bronchoalveolar lavage fluid from patients with M. pneumoniae pneumonia, we aim to investigate how M. pneumoniae infection alters epigenetics and contributes to the disease severity and complications. Understanding such epigenetic alterations not only sheds light on the mechanisms underlying M. pneumoniae infection but also holds potential implications for developing better diagnostic tools and therapies. Ultimately, this work may facilitate the design of more targeted treatments to alleviate the impact of respiratory infections caused by the pathogen. Our findings may also offer broader insights into how microbial infections reshape immune processes, highlighting the importance of RNA editing in host-pathogen interactions.

Prognostic biomarkers have been widely studied in COVID-19, but their levels may be influenced by treatment strategies. This study examined plasma biomarkers and proteomic survival prediction in two unvaccinated hospitalized COVID-19 cohorts receiving different treatments. In a derivation cohort (n = 126) from early 2020, we performed plasma proteomic profiling and evaluated innate and complement system immune markers. A proteomic model based on differentially expressed proteins predicted 30-day mortality with an area under the curve (AUC) of 0.81. The model was tested in a validation cohort (n = 80) from late 2020, where patients received remdesivir and dexamethasone, and performed with an AUC of 0.75. Biomarker levels varied considerably between cohorts, sometimes in opposite directions, highlighting the impact of treatment regimens on biomarker expression. These findings underscore the need to account for treatment effects when developing prognostic models, as treatment differences may limit their generalizability across populations.

During the coronavirus disease 2019 (COVID-19) pandemic, significant challenges have been encountered in managing patients with chronic diseases. This study aimed to evaluate the effects of the pandemic on follow-up and treatment adherence in patients receiving immunoglobulin replacement therapy (IRT).

A study examining the changes in IRT application methods was conducted between March 2020 and September 2021. An online message line, under the control of nurses and doctors, was established for our patients, and their usage rates for this communication system were recorded.

A total of 169 patients, 93 males and 76 females, were included in the study. Among the patients, 124 (73.4%) received intravenous immunoglobulin (IVIG), and 45 (26.6%) received subcutaneous immunoglobulin (SCIG) treatment. Male sex was more common in both the IVIG and SCIG groups. Although all patients in the subcutaneous treatment group continued the treatments regularly, this rate was 80.6% in the IVIG group. During the pandemic, 26 patients switched from IVIG to SCIG treatment. Furthermore, 24 patients interrupted immunoglobulin treatment for various reasons. Patients who received subcutaneous treatment took a long break from their hospital controls, although they applied them properly at home. Routine immunoglobulin trough values were measured in only 17 (37.7%) patients who were on SCIG. In the presence of symptoms, 100% of SCIG patients contacted the remote medical team via the online message line, compared to 48.3% of IVIG patients.

During the pandemic, the route of immunoglobulin treatment should be individualized based on each patient's characteristics and expectations. Telehealth services have emerged as a crucial tool for monitoring patients with chronic disorders, facilitating effective communication and personalized care.

In recent years, the incidence of acute respiratory distress syndrome (ARDS) has been gradually increasing. Despite advances in supportive care, ARDS remains a significant cause of morbidity and mortality in critically ill patients. ARDS is characterized by acute hypoxaemic respiratory failure with diffuse pulmonary inflammation and bilateral edema due to excessive alveolocapillary permeability in patients with non-cardiogenic pulmonary diseases. Over the past seven decades, our understanding of the pathology and clinical characteristics of ARDS has evolved significantly, yet it remains an area of active research and discovery. ARDS is highly heterogeneous, including diverse pathological causes, clinical presentations, and treatment responses, presenting a significant challenge for clinicians and researchers. In this review, we comprehensively discuss the latest advancements in ARDS research, focusing on its heterogeneity, pathophysiological mechanisms, and emerging therapeutic approaches, such as cellular therapy, immunotherapy, and targeted therapy. Moreover, we also examine the pathological characteristics of COVID-19-related ARDS and discuss the corresponding therapeutic approaches. In the face of challenges posed by ARDS heterogeneity, recent advancements offer hope for improved patient outcomes. Further research is essential to translate these findings into effective clinical interventions and personalized treatment approaches for ARDS, ultimately leading to better outcomes for patients suffering from ARDS.

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), a rapidly progressing respiratory failure condition, results in a high mortality rate, especially in severe cases. Numerous trials have investigated various pharmacotherapy approaches, but their effectiveness remains uncertain. Here, we present an inhaled nanoformulation of fingolimod (FTY720)-nobiletin (NOB)- poly(lactic-co-glycolic) acid (PLGA) nanoparticles (NPs) with good biocompatibility and a sustained-release pharmacological effect. The formulation decreases the toxicity of FTY720 and increases the bioavailability of NOB since we use PLGA with a high biocompatibility to encapsulate FTY720 and NOB at the same time. In vitro, in comparison to treatment with the pure drug, we demonstrated that FTY720-NOB-PLGA NPs can reduce interleukin-6 (IL-6) and reactive oxygen species (ROS) release by macrophages after lipopolysaccharide (LPS) stimulation more efficiently. In vivo, we used an inhalation tower system that allowed the exposure of unanesthetized mice to aerosolized FTY720-NOB-PLGA NPs under controlled conditions. We demonstrated that inhaled FTY720-NOB-PLGA NPs can attenuate lung injury after LPS exposure by suppressing cytokine release, such as IL-6 and tumor necrosis factor-α (TNF-α). The trigger pathway of ALI, including nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and p38 mitogen-activated protein kinase, was also efficiently inhibited. Furthermore, the inhalation treatment provided a good safety profile, without detrimental effects on biochemical markers and lung function. We provided the feasibility of administering inhalation of NPs noninvasively with continuous monitoring of lung function. The aerosolized FTY720-NOB-PLGA NPs we developed show excellent promise for acute lung injury therapy in the future.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced coronavirus disease 2019 (COVID-19) pandemic has challenged the current understanding of the complement cascade mechanisms of host immune responses during infection-induced nonresolvable lung disease. While the complement system is involved in opsonization and phagocytosis of the invading pathogens, uncontrolled complement activation also leads to aberrant autophagic response and tissue damage. Our recent study revealed unique pathologic and fibrotic signature genes associated with epithelial bronchiolization in the lung tissues of patients with nonresolvable COVID-19 (NR-COVID-19) requiring lung transplantation. However, there is a knowledge gap if complement components are modulated to contribute to tissue damage and the fibrotic phenotype during NR-COVID-19. We, therefore, aimed to study the role of the complement factors and their corresponding regulatory proteins in the pathogenesis of NR-COVID-19. We further examined the association of complement components with mediators of the host autophagic response. We observed significant upregulation of the expression of the classical pathway factor C1qrs and alternative complement factors C3 and C5a, as well as the anaphylatoxin receptor C5aR1, in NR-COVID-19 lung tissues. Of note, complement regulatory protein, decay accelerating factor (DAF; CD55) was significantly downregulated at both transcript and protein levels in the NR-COVID-19 lungs, indicating a dampened host protective response. Furthermore, we observed significantly decreased levels of the autophagy mediators PPARγ and LC3a/b, which was corroborated by decreased expression of factor P and the C3b receptor CR1, indicating impaired clearance of damaged cells that may contribute to the fibrotic phenotype in NR-COVID-19 patients. Thus, our study revealed previously unrecognized complement dysregulation associated with impaired cell death and clearance of damaged cells, which may promote NR-COVID-19 in patients, ultimately necessitating lung transplantation. The identified network of dysregulated complement cascade activity indicates the interplay of regulatory factors and the receptor-mediated modulation of host immune and autophagic responses as potential therapeutic targets for treating NR-COVID-19.

Diverse inflammatory pathology is involved in acute respiratory distress syndrome (ARDS). This study aimed to assess the role of complement component fragment 5a (C5a) receptor 2 (C5aR2) in prognosis of patients with ARDS.

A total of 64 adult patients diagnosed with ARDS were prospectively recruited to the study over a period of one year after obtaining the informed consent. The serum C5a and C5aR2were determined using ELISA Kit sandwich method. Area under receiver operating characteristic (AUROC) was used to analyse the prognostic performance of C5a, C5R2, and C5a/C5R2 ratio using MedCalc. The relationship of these biomarkers with the parameters of poor prognosis (non-recovery, hospitalization, ventilation and ICU admission) was analysed through regression using SPSSv20.

The mean age of the included participants was 49.17 (SD:14.81) years. C5a/C5aR2 ratio had better discrimination (AUC: 0.707 vs 0.699 vs 0.511) and higher specificity (78.1 vs 71.9 vs 3.1) than C5R2 and C5a in predicting the poor prognosis among ARDS patients. The increased level of C5aR2 (OR: 0.225; p = 0.009) was significantly associated with better recovery and the high C5a/C5aR2 ratio (OR: 3.281; p = 0.036) was significantly associated with non-recovery in moderate to severe patients. Additionally, steroid treatment significantly associated with better recovery in patients with a high C5a/C5aR2 ratio (OR: 0.104; p = 0.007).

The current evidence indicates that a higher levels of C5aR2 significantly associated with better recovery, whereas high levels of C5a/C5aR2 significantly associated to poor prognosis in moderate to severe ARDS patients. However, adequately powered studies are required to confirm these findings in future.

Coronavirus disease 2019 (COVID-19) causes pulmonary edema, which disrupts the lung alveoli-capillary barrier and leads to pulmonary cell apoptosis, the main cause of death. However, the molecular mechanism behind SARS-CoV-2's apoptotic activity remains unknown. Here, we revealed that SARS-CoV-2-ORF-3a mediates the pulmonary pathology associated with SARS-CoV-2, which is demonstrated by the fact that it causes lung tissue damage. The in vitro results showed that SARS-CoV-2-ORF-3a triggers cell death via the disruption of mitochondrial homeostasis, which is modulated through the regulation of Mitochondrial ATP-sensitive Potassium Channel (MitoKATP). The addition of exogenous Potassium (K+) in the form of potassium chloride (KCl) attenuated mitochondrial apoptosis along with the inflammatory interferon response (IFN-β) triggered by SARS-ORF-3a. The addition of exogenous K+ strongly suggests that dysregulation of K+ ion channel function is the central mechanism underlying the mitochondrial dysfunction and stress response induced by SARS-CoV-2-ORF-3a. Our results designate that targeting the potassium channel or its interactions with ORF-3a may represent a promising therapeutic strategy to mitigate the damaging effects of infection with SARS-CoV-2.

Neutrophils release neutrophil extracellular traps (NETs) as part of a healthy host immune response. NETs physically trap and kill pathogens as well as activating and facilitating crosstalk between immune cells and complement. Excessive or inadequately resolved NETs are implicated in the underlying pathophysiology of sepsis and other inflammatory diseases, including amplification of the inflammatory response and inducing thrombotic complications. Here, we review the growing evidence implicating neutrophils and NETs as central players in the dysregulated host immune response. We discuss potential strategies for modifying NETs to improve patient outcomes and the need for careful patient selection.

Methotrexate (MTX) is an antimetabolite drug that mimics folate and inhibits dihydrofolic acid reductase, resulting in the impairment of malignant growth in actively proliferating tissues. MTX is approved by the FDA for primarily treating non-Hodgkin lymphoma, lymphoblastic leukemia, and osteosarcoma. In addition, MTX is also prescribed as a preferred anti-rheumatic medication for the management of rheumatoid arthritis, including psoriasis, indicating that MTX has a multipronged mechanism of action. MTX is also known to exert anti-inflammatory effects, and interestingly, the role of C5a, a pro-inflammatory glycoprotein of the complement system, is well established in several chronic inflammatory diseases, including rheumatoid arthritis and psoriasis, through the recruitment of C5a receptors (C5aR1/C5aR2) expressed in both immune and non-immune cells. Notably, through drug repurposing studies, we have earlier shown that non-steroidal anti-inflammatory drugs (NSAIDS) can potentially neutralize the function of C5a. Though MTX binds to serum albumin and can affect the immune system, whether its interaction with C5a could be therapeutically beneficial due to the downregulation of both extracellular and intracellular signaling of C5a is not yet established in the literature. In the current study, we have hypothesized and provided preliminary evidence through computational studies that MTX can strongly bind to the hotspot regions on C5a involved in the interactions with its receptors, which is likely to alter the downstream signaling of C5a and contribute to the overall therapeutic efficacy of MTX.

Enterovirus A71 (EV-A71) is a common small RNA virus that is highly neuroinvasive. Emerging evidence indicates that the complement fragment C5a and its receptor C5aR1 are important drivers of neuroinflammation. However, the potential role of the C5a-C5aR1 axis in EV-A71 encephalitis remains largely elusive. Our previous studies revealed that EV-A71 can infect astrocytes and result in complement activation in vivo. Here, we investigated how complement factors interact with astrocytes to promote a severe inflammatory response upon EV-A71 infection. Our data revealed that EV-A71 infected mainly astrocytes and caused astrocyte activation in the mouse brain, which was further verified in patients with EV-A71 infection and U87-MG cells. Notably, EV-A71 infection led to activation of the C5a-C5aR1 axis in U87-MG cells, and knockdown (siC5aR1) or blockade (PMX53) of C5aR1 significantly suppressed EV-A71-induced astrocyte activation and proinflammatory cytokine (e.g., CXCL1) production. Next, the activation of the C5a-C5aR1 axis in mouse astrocytes was confirmed. Compared with C5aR1 knockout mice, wild-type mice presented more severe symptoms and lower survival rates after EV-A71 infection. C5aR1 deficiency or blockade significantly reduced EV-A71-induced pathological damage and proinflammatory cytokine production in the mouse brain. Importantly, an increased level of soluble C5a was strongly correlated with the severity of symptoms in patients with EV-A71 infection. By using confocal microscopy, primary astrocytes, and human specimens, we observed that the increase in CXCL1 levels resulted mainly from astrocytes. Neutralizing CXCL1 significantly alleviated the neuropathological changes caused by EV-A71 infection, and the production of CXCL1 in astrocytes was regulated by p38 MAPK signaling. Taken together, our findings indicate that the activation of the C5a-C5aR1 axis in astrocytes facilitates the neuropathological changes resulting from EV-A71 infection, emphasizing the potential role of p38 MAPK-mediated CXCL1 production in these alterations.

Enterovirus A71 (EV-A71) is a common small RNA virus with highly neuroinvasive tendencies. Our previous studies took the view that EV-A71 could infect astrocytes and result in complement activation in vivo. We investigated how complement interacts with astrocytes to promote a severe inflammatory response upon EV-A71 infection in the study. As expected, our data demonstrate that EV-A71 triggers robust activation of the C5a-C5aR1 axis in astrocytes and that knockout or blockade of C5aR1 in animals exposed to lethal doses of EV-A71 significantly enhances survival by diminishing the production of the chemokines CXCL1 and IL-6. In addition, neutralizing CXCL1 significantly alleviates the neuropathogenesis caused by EV-A71 infection. Thus, inhibiting the C5a-C5aR1 axis has emerged as a potential therapeutic strategy to mitigate neural damage caused by EV-A71 infection.

Single-cell technologies have enhanced our knowledge of molecular and cellular heterogeneity underlying disease. As the scale of single-cell datasets expands, linking cell-level phenotypic alterations with clinical outcomes becomes increasingly challenging. To address this, we introduce CellPhenoX, an eXplainable machine learning method to identify cell-specific phenotypes that influence clinical outcomes. CellPhenoX integrates classification models, explainable AI techniques, and a statistical framework to generate interpretable, cell-specific scores that uncover cell populations associated with relevant clinical phenotypes and interaction effects. We demonstrated the performance of CellPhenoX across diverse single-cell designs, including simulations, binary disease-control comparisons, and multi-class studies. Notably, CellPhenoX identified an activated monocyte phenotype in COVID-19, with expansion correlated with disease severity after adjusting for covariates and interactive effects. It also uncovered an inflammation-associated gradient in fibroblasts from ulcerative colitis. We anticipate that CellPhenoX holds the potential to detect clinically relevant phenotypic changes in single-cell data with multiple sources of variation, paving the way for translating single-cell findings into clinical impact.

The hemostatic system prevents and stops bleeding, maintaining circulatory integrity after injury. It directly interacts with the complement system, which is key to innate immunity. In coronavirus disease 2019 (COVID-19), dysregulation of the hemostatic and complement systems has been associated with several complications. To understand the essential balance between activation and regulation of these systems, a quantitative systems immunology model can be established. The dynamics of the components are examined under three distinct conditions: the disease state representing symptomatic COVID-19 state, an intervened disease state marked by reduced levels of regulators, and drug interventions including heparin, tranexamic acid, avdoralimab, garadacimab, and tocilizumab. Simulation results highlight key components affected, including thrombin, tissue plasminogen activator, plasmin, fibrin degradation products, interleukin 6 (IL-6), the IL-6 and IL-6R complex, and the terminal complement complex (C5b-9). We explored that the decreased levels of complement factor H and C1-inhibitor significantly elevate these components, whereas tissue factor pathway inhibitor and alpha-2-macroglobulin have more modest effects. Furthermore, our analysis reveals that drug interventions have a restorative impact on these factors. Notably, targeting thrombin and plasmin in the early stages of thrombosis and fibrinolysis can improve the overall system. Additionally, the regulation of C5b-9 could aid in lysing the virus and/or infected cells. In conclusion, this study explains the regulatory mechanisms of the hemostatic and complement systems and illustrates how the biopathway machinery sustains the balance between activation and inhibition. The knowledge that we have acquired could contribute to designing therapies that target the hemostatic and complement systems.

COVID-19, caused by SARS-CoV-2, has presented formidable challenges to global health since its emergence in late 2019. While primarily known for respiratory symptoms, it can also affect the ocular surface. This review summarizes the effects of SARS-CoV-2 on ocular surface immunity and inflammation, focusing on infection mechanisms, immune responses, and clinical manifestations. Ocular symptoms, though uncommon, include conjunctivitis, dry eye, and blurred vision. SARS-CoV-2 binds to ACE2 receptors in ocular surface epithelial cells, facilitating viral entry, replication, and local dissemination. The innate immune responses involving corneal epithelial cells and immune cells are discussed, alongside mechanisms of antigen presentation and adaptive immunity. The review also examines the roles of cytokines and chemokines in mediating ocular surface inflammation and explores the impact of cytokine storms and chronic inflammation on ocular health. Additionally, the interplay between systemic and ocular immune responses is highlighted, analyzing how systemic COVID-19 inflammation influences ocular surface health. These insights underscore the broader implications of COVID-19 beyond localized ocular infection. By consolidating current findings, this review aims to guide preventive and therapeutic strategies while identifying directions for future research to mitigate the ocular consequences of COVID-19.

Little is known about the long-term impact of diabetes on lung impairment in COVID-19 survivors over a three-year period. This study evaluated the long-term impact of diabetes on persistent radiological pulmonary abnormalities and lung function impairment in COVID-19 survivors over three years.

In this prospective, multicenter, cohort study, pulmonary sequelae were compared between COVID-19 survivors with and without diabetes. Serial chest CT scans, symptom questionnaires and pulmonary function tests were obtained 6 months, 12 months, 2 years and 3 years post-discharge. The independent predictors for lung dysfunction at the 3-year follow-up were analyzed.

A total of 278 COVID-19 survivors (63 [IQR 57-69] year-old, female: 103 [37.0%]) were included. At the 3-year follow-up, individuals in the diabetes group had higher incidences of respiratory symptoms, radiological pulmonary abnormalities and pulmonary diffusion dysfunction than those in the control group. Diabetes (OR: 2.18, 95% CI: 1.04-4.59, p = 0.034), allergy (OR: 2.26, 95% CI: 1.09-4.74, p = 0.029), female (OR: 2.70, 95% CI: 1.37-5.29, p = 0.004), severe COVID-19 (OR: 4.10, 95% CI: 1.54-10.93, p = 0.005), and fibrotic-like CT changes (OR: 5.64, 95% CI: 2.28-13.98, p < 0.001) were independent predictors of pulmonary diffusion dysfunction in COVID-19 survivors.

These results highlight the long-term deleterious effect of diabetes status on radiological pulmonary abnormalities and pulmonary dysfunction in COVID-19 survivors. This study provides important evidence support for long-term monitoring of lung abnormalities in COVID-19 recovery survivors with diabetes.

A mounting number of studies have been documenting strong pro-inflammatory and pro-fibrotic effects of carbon nanotube (CNT). However, the molecular mechanisms of single-walled CNT (SWCNT)-provoked lung injury remain to be elucidated. Here, we established a mice model of SWCNT-induced lung injury by intratracheal instillation and found that C5a-C5a receptor-1 (C5aR1) signaling was significantly activated along with abundant neutrophils recruitment in lungs at early phase post SWCNT administration, which were positively correlated with early lung inflammation and late pulmonary fibrosis. C5a-C5aR1 signaling activation and neutrophils recruitment were subsequently decreased in a time-dependent manner. Furthermore, inhibition of C5a-C5aR1 axis with C5aR1 antagonist PMX205 treatment not only dramatically reduced neutrophils recruitment and inflammatory cytokines secretion at early phase, but also effectively alleviated early lung inflammation and late pulmonary fibrosis induced by SWCNT exposure. In conclusion, our study provides novel insights into the underlying biological mechanism that C5a-C5aR1 axis regulates neutrophils recruitment-mediated lung injury induced by SWCNT, may help to develop therapeutic strategies for SWCNT-provoked lung injury.

The complex link between COVID-19 and immunometabolic diseases demonstrates the important interaction between metabolic dysfunction and immunological response during viral infections. Severe COVID-19, defined by a hyperinflammatory state, is greatly impacted by underlying chronic illnesses aggravating the cytokine storm caused by increased levels of Pro-inflammatory cytokines. Metabolic reprogramming, including increased glycolysis and altered mitochondrial function, promotes viral replication and stimulates inflammatory cytokine production, contributing to illness severity. Mitochondrial metabolism abnormalities, strongly linked to various systemic illnesses, worsen metabolic dysfunction during and after the pandemic, increasing cardiovascular consequences. Long COVID-19, defined by chronic inflammation and immune dysregulation, poses continuous problems, highlighting the need for comprehensive therapy solutions that address both immunological and metabolic aspects. Understanding these relationships shows promise for effectively managing COVID-19 and its long-term repercussions, which is the focus of this review paper.

Antibody-dependent enhancement (ADE) of infectious disease is a phenomenon whereby host antibodies increase the severity of an infection. It is well established in viral infections but ADE also has an underappreciated role during bacterial, fungal and parasitic infections. ADE can occur during both primary infections and re-infections with the same or a related pathogen; therefore, understanding the underlying mechanisms of ADE is critical for understanding the pathogenesis and progression of many infectious diseases. Here, we review the four distinct mechanisms by which antibodies increase disease severity during an infection. We discuss the most established mechanistic explanation for ADE, where cross-reactive, disease-enhancing antibodies bound to pathogens interact with Fc receptors, thereby enhancing pathogen entry or replication, ultimately increasing the total pathogen load. Additionally, we explore how some pathogenic antibodies can shield bacteria from complement-dependent killing, thereby enhancing bacterial survival. We interrogate the molecular mechanisms by which antibodies can amplify inflammation to drive severe disease, even in the absence of increased pathogen replication. We also examine emerging roles for autoantibodies in enhancing the pathogenesis of infectious diseases. Finally, we discuss how we can leverage these insights to improve vaccine design and future treatments for infectious diseases.

The factors contributing to the development of severe coronavirus disease 2019 (COVID-19) following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain unclear. Although the presence of immune complexes (ICs), formed between antibodies and their antigens, has been linked to COVID-19 severity, their role requires further investigation, and the antigens within these ICs are yet to be characterized.

Here, a C1q enzyme-liked immunosorbent assay and immune complexome analysis were used to determine IC concentrations and characterize IC antigens, respectively, in the sera of 64 unvaccinated COVID-19 patients with PCR-confirmed SARS-CoV-2 infection, enrolled at seven participating centers in 2020. For the analysis, the patients were split into the severe (n = 35) and non-severe (n = 28) groups on the basis of their COVID-19 symptoms.

We found that neither serum IC concentration nor IC antigen number was associated with COVID-19 severity. However, we identified six IC antigens, which were significantly enriched in the severe versus non-severe group. These IC antigens were all derived from human proteins, namely haptoglobin, the serum amyloid A-2 protein, the serum amyloid A-1 protein, clusterin, and lipopolysaccharide-binding protein, and complement-factor-H-related protein 3. Meanwhile, we found no association between COVID-19 severity and IC antigens derived from SARS-CoV-2 proteins. Collectively, the six IC antigens predicted COVID-19 severity with a moderate degree of accuracy (area under the receiver operating characteristic curve = 0.90, sensitivity = 94 %, specificity = 79 %).

The IC antigen signature identified in this study may have important implications for the diagnosis and treatment of severe COVID-19.

Acute respiratory distress syndrome (ARDS) is a condition affecting 10% of patients requiring admission to the intensive care unit and results from endothelial dysfunction, alveolar epithelial injury and unbalanced inflammation, leading to exudative pulmonary oedema. A significant portion of these patients experience a lung injury that fails to resolve. Persistent or worsening respiratory failure beyond 5 days after the initiation of mechanical ventilation is referred to as nonresolving ARDS. Viral and fungal pathogens can exploit the hyperinflammatory environment and altered immune landscape in ARDS, perpetuating a cycle of ongoing inflammation and lung injury, thereby contributing to the progression towards and persistence of nonresolving ARDS, even in previously immunocompetent patients. This review discusses the significance, pathophysiology, diagnostic challenges and key knowledge gaps concerning various viral and fungal pathogens in nonresolving ARDS, with a particular focus on influenza-associated and COVID-19-associated pulmonary aspergillosis and pulmonary reactivation of Herpesviridae, such as cytomegalovirus and herpes simplex virus. Diagnosing these infections is challenging due to their nonspecific clinical presentation and the inability of current tests to distinguish between fungal colonisation or asymptomatic viral shedding and clinically significant infections or reactivations. A deeper understanding of the complex interplay between these pathogens and the host immune system in the context of ARDS, combined with advances in diagnostic and therapeutic strategies, has the potential to enhance the management and prognosis of patients with nonresolving ARDS.

Lethal COVID-19 outcomes are attributed to classic cytokine storm. We revisit this using RNA sequencing of nasopharyngeal and 40 autopsy samples from patients dying of SARS-CoV-2. Subsets of the 100 top-upregulated genes in nasal swabs are upregulated in the heart, lung, kidney, and liver, but not mediastinal lymph nodes. Twenty-two of these are "noncanonical" immune genes, which we link to components of the renin-angiotensin-activation-system that manifest as increased fibrin deposition, leaky vessels, thrombotic tendency, PANoptosis, and mitochondrial dysfunction. Immunohistochemistry of mediastinal lymph nodes reveals altered architecture, excess collagen deposition, and pathogenic fibroblast infiltration. Many of the above findings are paralleled in animal models of SARS-CoV-2 infection and human peripheral blood mononuclear and whole blood samples from individuals with early and later SARS-CoV-2 variants. We then redefine cytokine storm in lethal COVID-19 as driven by upstream immune gene and mitochondrial signaling producing downstream RAAS (renin-angiotensin-aldosterone system) overactivation and organ damage, including compromised mediastinal lymph node function.