Biology and Life Sciences

Abstract: Background: Whether lung interstitial macrophages (IMs) are continuously replenished by blood-monocyte extravasation remains unresolved. We performed a hypothesis-driven secondary analysis of four public datasets. Methods: Dual-module scoring (MonoScore/ResidScore) was combined with vessel-distance gradient tests across the Madissoon 2023 healthy-lung atlas, the 10x PBMC 10k reference, and the Natri 2024 lung-disease cohort, using donor or slide as the statistical unit, spatially aware permutation nulls, and multiple-testing correction. Results: Among 40,634 healthy lung myeloid cells (34,912 in six axis populations), a continuous monocyte-to-resident axis placed perivascular IMs at the resident pole; batch-free intra-lung controls separated lung CD14 monocytes from perivascular IMs (AUC=0.9924), whereas cross-dataset AUCs are batch-confounded upper bounds not used for inference. Across three Visium slides (two donors), ResidScore signal per spot rose with vessel distance (3/3 slides concordant; toroidal-shift p=0.009-0.016, not surviving Bonferroni correction), while no slide showed the predicted monocyte-signal decay; block-level intervals were uninformative. In idiopathic pulmonary fibrosis (IPF), IM MonoScore was elevated (+0.088, p_adj=0.014 across 36 tests) without significant ResidScore loss or compositional change (p=0.68). Conclusions: This cross-sectional design cannot test ontogeny; it tests the spatial corollary of sustained extravasation, which steady-state adult human lung does not support — without contradicting mouse fate-mapping evidence, which addresses developmental and turnover-level origin. The perivascular niche emerges as a candidate renewal interface with a locally attenuated residency program. In IPF, IM monocytization reflects transcriptional reprogramming rather than compositional replacement.

Abstract: Background. Alveolar macrophages (AMs) are long-lived resident sentinels of the alveolar lumen. Yet no single surface readout coupled to their homeostatic program, with an explicit interpretation rule in disease, has been consolidated. CD10 (MME/neprilysin) is listed among human AM surface markers, but its performance as an identity readout and its biology have not been characterized across datasets, programs and disease states. We asked whether CD10 marks AM homeostatic identity, which programs it couples to, and how it changes in disease. Methods. We performed a secondary analysis of the Madissoon healthy human lung atlas and the Natri lung-disease atlas, with bronchoalveolar lavage (BAL) studies as literature-level reference. We quantified MME detection across compartments, co-expression programs, MME+/MME− dichotomized comparisons with sequencing-depth-matched controls, and donor-level disease statistics using the donor as the statistical unit. Results. CD10 marked resident AMs: MME was detected in 30.1% of AMs and 51.9% of proliferating AMs, versus 0.2–0.3% of monocytes. Within AMs, higher MME tracked the PPARγ lipid and TGFβ maturation programs (Pearson ρ = 0.296 with ITGB8, ρ = 0.209 with PPARG) together with a don’t-eat-me profile (3.20-fold PD-L1, 1.39-fold CD47); these couplings survived sequencing-depth-matched controls. At donor level, the MME–FABP4 coupling was reproduced (ρ = 0.472) whereas MME–PPARG was not. AM-compartment MME did not differ between idiopathic pulmonary fibrosis (IPF) and control (p = 0.92; 36 versus 44 donors), and no AM-compartment change survived FDR control in any diagnosis, whereas interstitial macrophage MME increased in IPF (p = 0.0003, FDR = 0.003) and non-IPF interstitial lung disease (p = 0.0042, FDR = 0.023). Conclusions. CD10 is a transcript-level candidate readout of AM homeostatic identity, co-expressed with the PPARγ lipid program and elevated don’t-eat-me signals. Disease-associated changes are compartment-specific, stable within AMs and induced within interstitial macrophages, consistent with compartment remodelling rather than wholesale loss; measured on tissue composition, dilution alone predicts that AM-dependent samples lose roughly half of their CD10 signal in fibrosis, quantitatively matching prior reports of resident AM depletion. Protein-level validation is pending.

Abstract: Extracellular vesicles (EVs) mediate ocular immune communication, and their biological effects depend heavily on their cell of origin, activation state, recipient tissue, and route of exposure. This narrative review examines endogenous EV signaling and therapeutic EV preparations across the ocular surface, cornea, uvea, retina, and optic nerve, distinguishing mechanistic evidence from biomarker associations and treatment outcomes. Endogenous EVs can transfer alloantigens, recruit leukocytes, and amplify glial and vascular inflammation. Conversely, EVs from selected stromal and regulatory immune cells suppress inflammation in experimental models of dry eye, keratitis, uveitis, and neuroretinal injury. Reported protective mechanisms include modulation of antigen presentation, T helper 17/regulatory T cell balance, inflammasome activity, and microglial–neurovascular interactions. These mechanisms vary among models and are not established across all ocular compartments. Small dry-eye trials support further clinical investigation, while negative results, model dependence, and limited durability constrain broader claims of efficacy. A source–state–recipient–exposure framework helps explain divergent findings and identifies translation priorities: reproducible product characterization, appropriate non-vesicular controls, mechanism-informed potency assays, and indication-specific delivery. Establishing whether endogenous EVs are required for ocular immune homeostasis, and whether administered preparations produce sustained clinical benefit without compromising host defense, remains central to the field.

Abstract: Background: Binucleated and multinucleated macrophages (cells carrying two or more nuclei in one cell body) occur in granulomas and tumors, yet their origins beyond cell–cell fusion, and the macrophage role of CD10 (MME), remain unresolved. We asked who CD10⁺ macrophages are, whether their binucleation reflects incomplete cytokinesis (failure of the final separation step of cell division), and how this state relates to phagocytic immune evasion. Methods: Analyzing 20,000 lung adenocarcinoma myeloid cells (GSE131907), we applied a three-axis discrimination rule (molecular-output level, lineage concordance, G2/M activity), a six-module prediction model, and a 35-molecule eat-me/don’t-eat-me panel. Results: CD10⁺ cells comprised 16.2% of myeloid cells (87.6% C1QC⁺ tumor-associated macrophage (TAM)-derived, predominantly normal-lung-derived alveolar macrophages) and split by origin into scavenger and inflammatory–pro-angiogenic types (Type-1 and Type-2). Transcriptome-inferred binucleated candidates constituted 27.0% of CD10⁺ cells with G2/M programs directionally elevated (consistent with incomplete cytokinesis over fusion; attenuated after library-size control); the state and its key contrasts replicated in tumor-restricted cells and an independent NSCLC atlas. The lysosome module showed the largest association (unadjusted Δ = +0.222; persists after library-size control, residual Δ = +0.068); the classifier reached an AUC of 0.77 (same-cohort, not externally validated). These cells also showed a transcript-level shift of the don’t-eat-me/eat-me balance centered on CD47 (Δ = +0.127; calreticulin unchanged)—itself both an anti-phagocytic checkpoint and a multinucleation participant. Conclusions: We hypothesize that lysosomal stress drives cytokinesis failure and barrier co-assembly, nominating the CD10⁺ binucleated state as a testable node of phagocytic immune evasion for combination checkpoint targeting.

Abstract: Interferon epsilon (IFNε), a unique type I IFN, is highly abundant in the female reproductive tract (FRT). Unlike IFNα and IFNβ, which are expressed at low or undetectable levels at the baseline and are strongly induced following pattern-recognition receptor activation, IFNε is constitutively expressed in the epithelium at mucosal tissues. Its expression is regulated by hormones and inflammatory cytokines. Its responsiveness to viral infection and Toll-like receptor activation varies across cell types. This distinctive regulatory profile positions IFNε as a preemptive component of mucosal defense. Studies in mice and human FRT tissues have established important roles for IFNε in maintaining expression of genes involved in epithelial and tissue structure as well as basal interferon-stimulated genes restricting sexually transmitted pathogens, including herpes simplex virus-2, Chlamydia, human immunodeficiency virus, and Zika virus. IFNε also shapes local immune responses, including uterine natural killer-cell recruitment and activation. However, its effects are not uniformly protective: Neisseria gonorrhoeae can exploit IFNε-dependent changes in sialic-acid metabolism to promote persistence. Recent work further broadens the IFNε paradigm beyond antimicrobial defense. IFNε-deficient mice exhibit cervicovaginal epithelial abnormalities and altered antiviral epithelial states, while IFNε has emerged as an intrinsic tumor suppressor in the fallopian tube/ovarian cancer axis. Human studies also implicate IFNε in pregnancy, cervical HPV responses, and cervical cancer, although the direction and mechanisms of these associations remain unknown. Here, we review the expression, regulation, signaling, and biological functions of IFNε in the FRT, reconcile emerging evidence for tissue- and context-specific actions, and discuss key unanswered questions concerning epithelial homeostasis, receptor usage, reproductive physiology, infection, and gynecologic malignancy.

Abstract: Flagellin activates innate, cellular and humoral immunity through Toll-like receptor 5 (TLR5), and this interaction can be exploited to improve vaccines against oncogenic human papillomavirus (HPV). The binding mechanism between flagellin-fabricated peptide vaccines (FFPVs) and TLR5, however, remains unclear. Here, three FFPV candidates (C58, C52 and C16) were designed from overlapped epitope segments in the conserved N-terminal region of the L2 minor capsid protein of HPV58, HPV52 and HPV16. These segments were predicted to induce cytotoxic T-lymphocyte, T-helper, IFNγ and B-cell responses. Each construct also carried two TLR agonist adjuvants (flagellin and RS09), two universal T-helper epitopes and defined peptide linkers. Physicochemical and immunological properties were evaluated, and three-dimensional models of the FFPVs and TLR5 were generated, refined and validated. Protein–protein docking with HADDOCK and PRODIGY ranked the TLR5-C58 complex highest, ahead of TLR5-C16 and TLR5-C52. To test the docking result, the TLR5-C58 complex was simulated for [100 ns] in explicit solvent, and the root mean square deviation, total energy, hydrogen bonds and key-residue distances were analyzed. The simulation identified a binding mode with ten key residues in the leucine-rich repeat (LRR) region of TLR5, and the binding free energies agreed with experimental reports. These findings offer a structural basis for the rational design of L2-based vaccines against cervical cancer.

Abstract: Background. Mucosal vaccination offers the possibility of establishing immune protection directly at portals of pathogen entry, but its development remains constrained by biological, technological, and implementation barriers. Objective. To integrate the major challenges limiting mucosal vaccination within a common framework and examine emerging strategies capable of addressing several of these barriers simultaneously. Results and Discussion. We consider six interconnected challenges: incomplete recognition of the determinant role of adjuvants; scarcity of safe and accessible mucosal adjuvants; the need to overcome mucosal tolerance while preserving tissue homeostasis; dependence on coldchain logistics; reliance on multidose immunization schedules to achieve protective immunity; and limited breadth of vaccine-induced cross-reactive protection. To better capture the complexity of modern vaccine platforms, we discuss expand adjuvant activity as exogenous, self-adjuvanting, or endogenous according to the origin of the immunostimulatory signal. Particular emphasis is placed on proteoliposome- and cochleate-based systems and probiotic Bacillus subtilis spores as multifunctional platforms combining antigen delivery with intrinsic immunostimulatory properties. Preclinical studies support their capacity to induce systemic IgG, mucosal secretory IgA, cellular responses, and memory response, while their heat resistance may facilitate the development of more thermostable formulations. We also discuss the Single Time Vaccination Strategy as an approach to combined-route immunization and consider glycans and other microbial structures as potential contributors to antigen-specific and cross-reactive mucosal responses. Conclusions. Future mucosal vaccine development should consider adjuvants as tools for coordinated antigen delivery, innate sensing, immune programming with polarization activity, and mucosal memory rather than solely as immune potentiators and delivery system. Probiotic spores, cochleates, and combined-route strategies provide promising examples of this integrated approach, although their translational value will require rigorous demonstration of formulation stability, mechanisms of action, safety, protective breadth, and clinical efficacy.

Abstract: Research on the healthy human oral and respiratory microbiome has expanded rapidly since 2020. The underlying data remain scattered across main texts and supplementary files. Here we describe a curated compendium of 64 records drawn from studies published between January 2020 and August 2026. The compendium covers four anatomical sites: the anterior nares, the nasopharynx, the oral cavity (saliva, tongue dorsum, supragingival plaque, and subgingival plaque), and the lower respiratory tract. Each data record states the source publication, a PMC, PubMed, or DOI identifier, the sample size, the population, the sampling site, the key quantitative values, and an evidence qualifier. Qualifiers mark pre-2020 baseline references, preprints, and review-derived values. The records encode age trajectories from birth to old age and the measured effects of diet, smoking, air pollution, cohabitation, vaccination, and oral hygiene. Nine documented gap intervals (five complete, two near, two sparse), including bronchoalveolar lavage in healthy children, are recorded as data gaps rather than extrapolated. The compendium is released as five tables with this article.

Abstract: Mycoplasma pneumoniae pneumonia (MPP) has re-emerged globally since 2023, with macrolide-resistant M. pneumoniae (MRMP) exceeding 80% of isolates in China and the Republic of Korea; because tetracyclines and fluoroquinolones are age-restricted in children, no guideline-endorsed antibiotic class outside Japan combines reliable activity against resistant strains with an unrestricted pediatric safety profile. Macrolide resistance prolongs fever and hospitalization without worsening severity, implicating dysregulated host inflammation in the residual burden. We derived an MPP host disease signature from public pediatric transcriptomes and prioritized approved compounds through four executed evidence layers: pathway enrichment, network proximity, LINCS L1000 signature reversal, and literature triangulation. Re-analysis of the largest MPP blood cohort identified 159 differentially expressed genes, and the age-adjusted MPP-versus-viral model reproduced the published signature (2,976 shared genes, 99.8% concordance). The target map converges on NLRP3-IL-1β-pyroptosis and JAK-STAT axes, with a transcriptome-supported AIM2 signal; doxycycline (z = -3.81) was significantly proximal to the disease module, whereas quercetin (z = -3.03) is discounted for annotation-density artifacts. Corticosteroids anchor Tier 1, and JAK inhibitors are the highest-priority testable hypothesis. This hypothesis-generating framework provides a reproducible template for host-directed repurposing in antimicrobial-resistant pediatric respiratory infections.

Abstract: Antibiotic disturbance of the human microbiome is usually judged by whether community composition returns to baseline. We argue that this endpoint runs on the wrong clock. The same exposures, read at two levels, give opposite answers: composition recovers in weeks, while resistance persists for months. In a 2015 trial, salivary composition recovered within about 30 days while faecal communities stayed altered for up to 12 months; in a 2007 trial, one course of azithromycin or clarithromycin raised pharyngeal carriage of macrolide-resistant streptococci by 53·4 points at day 4 with azithromycin and 50·0 points at day 8 with clarithromycin, still above baseline at day 180. We call this asymmetry composition–resistance decoupling, and propose a minimum standard that measures both clocks, with denominators, until resistance returns to baseline.

Abstract: Non-Saccharomyces yeasts are of growing interest as probiotic candidates, but strain-level charac-terization remains limited. We characterized Pichia kluyveri PK88™, isolated from coffee beans (NRRL deposit # 68561), using phenotypic assays, whole-genome sequencing, and in silico screen-ing. PK88™ was non-hemolytic and produced no detectable patulin, ochratoxin A, or aflatoxins. Genome analysis confirmed species identity (98.5–98.8% average nucleotide identity) and identi-fied no acquired antimicrobial-resistance genes, canonical virulence factors, or decarboxylases for harmful biogenic amines. By high-inoculum broth microdilution, MICs were low for echi-nocandins and amphotericin B and higher for fluconazole and posaconazole. Measured survival after acid, bile and anaerobic exposure was retained (93% at pH 2; 82–84% in bile), although sur-vival at pH 1 and under anaerobiosis was lower; hydrophobicity fell from 91% to 73–77% and auto-aggregation rose to 98–100%. PK88 supernatant inhibited Escherichia coli and Candida albi-cans in preliminary assays. In two independent experiments, Caco-2 cells exposed to PK88™ showed cytotoxicity ≤20% in every replicate up to 6 × 104 organisms/well and variable increases at higher doses. These preliminary data support further evaluation.

Abstract: Almost half of the human population lives in areas where dengue virus (DENV) is endemic and are at risk of infection. The aim of the current study was to analyze 65 publicly available bulk RNA-sequencing samples from the GEO NCBI database. We hypothesized that investigating gene expression in patients with DENV infection compared to healthy controls could identify potential therapeutic targets and augment our understanding of the intracellular transcriptomic response to DENV infection. We report various genes with significant differential expression and multiple predicted drug targets that could be repurposed to reduce the signs and symptoms associated with DENV infection.

Abstract: High-dimensional bone marrow immunomics increasingly informs the biological characterisation of multiple myeloma, yet the robustness of aspirate-derived immune phenotypes to peripheral-blood admixture, differential cellular recovery and loss of tissue architecture remains incompletely established. Existing haemodilution indices assess specimen quality but have not been comprehensively evaluated against multidimensional immune-state classification. We propose MARROW-ANCHOR, a spatially anchored validation protocol integrating patient-matched early- and later-pull marrow aspirates, peripheral blood, controlled autologous admixture, multiparameter flow cytometry, selected single-cell transcriptomic and protein profiling, and trephine-based spatial immunophenotyping. The framework distinguishes experimentally introduced blood from unmeasured pre-existing admixture and separates compositional changes from recovery-associated and within-population variation. Prespecified sham controls, participant-level replication, established marrow-quality indices and computational mixture modelling support assessment of classification stability, while independent spatial and functional measurements provide complementary biological corroboration. The primary endpoint quantifies experimentally induced classification reversal; biological misclassification requires additional independent evidence. Explicit validation criteria address technical reproducibility, analytical identifiability, model calibration, overcorrection and external generalisability. Stable classifications, contradictory measurements and failure of adjustment are retained as informative outcomes. MARROW-ANCHOR provides a falsifiable methodological framework for determining when specimen-associated uncertainty warrants qualification of marrow-derived immune interpretations before their translation into precision-medicine applications.

Abstract: Bluetongue is an economically important arboviral disease affecting domestic and wild ruminants health and well-being, caused by bluetongue virus (BTV) and transmitted by Culicoides midges. More than 30 BTV serotypes may co-circulate regionally, while current vaccines face limitations related to safety and incomplete cross-protection. Here, reverse vaccinology and immunoinformatics were used to design four serotype-specific and one multiserotype multi-epitope vaccine candidates targeting BTV-1, BTV-3, BTV-4 and BTV-8. Cytotoxic T-lymphocyte (CTL) and helper T-lymphocyte (HTL) epitopes were predicted from VP2, VP5, VP7 and NS1, and linear B-cell epitopes from VP2 and VP5. Twenty-five CTL, 24 HTL and 15 B-cell epitopes met the computational antigenicity, non-allergenicity and non-toxicity screening criteria; HTL epitopes were also predicted to induce interferon-γ. Five constructs comprising 13-25 epitopes (252-471 amino acids) were fused to bovine β-defensin 2 as a putative adjuvant. Molecular docking with bovine Toll-like receptor 4 ectodomain yielded predicted binding energies ranging from -19.6 to -10.7 kcal/mol. Molecular dynamics simulations (100 ns), immune simulation, codon optimization and in silico cloning further characterized the candidates. These computational findings support the prioritization of these constructs for experimental evaluation as potential serotype-specific and multiserotype BTV vaccine candidates.

Abstract: The oral and gastrointestinal microbiomes are increasingly recognized as interconnected ecological systems rather than isolated microbial communities. The oral cavity harbors diverse biofilm-associated microbial populations that are continuously introduced into the gastrointestinal tract through saliva, shed biofilms, and swallowed planktonic bacteria. Under homeostatic conditions, gastric acidity, bile, antimicrobial peptides, epithelial barriers, and resident gut microbiota limit the persistence of oral microbes. However, disruption of colonization resistance by inflammation, antibiotics, proton-pump inhibitors, immunosuppression, diet, or host susceptibility may allow oral-derived taxa to persist or engraft within the gut. This oral–gut microbiome axis is mediated through microbial migration, immune signaling, metabolite exchange, epithelial barrier disruption, and inflammatory feedback loops. Growing evidence links oral dysbiosis and periodontal inflammation with gastrointestinal disorders, including inflammatory bowel disease, irritable bowel syndrome, celiac disease, colitis, and colorectal cancer, as well as systemic diseases such as cardiovascular disease, metabolic disorders, neurodegenerative diseases, and autoimmune conditions. Among these, inflammatory bowel disease and colorectal cancer currently have the strongest mechanistic and translational support. Oral microbiome-based biomarkers, particularly from saliva and oral swabs, also show promise for non-invasive screening, disease monitoring, risk prediction, and personalized intervention. Nevertheless, many associations remain context-dependent, and causality is not fully established. Future progress will require longitudinal cohorts, standardized sampling pipelines, mechanistic validation, and integration of microbial, metabolic, immune, and clinical data. Understanding the oral–gut axis may expand current approaches to prevention, diagnosis, and precision management of gastrointestinal and systemic diseases.

Abstract: Staphylococcus aureus causes diverse clinical manifestations, from asymptomatic colonization to severe invasive disease. Host genetic factors influencing infection susceptibility and severity remain incompletely understood. This systematic review, conducted according to PRISMA 2020 guidelines and registered in PROSPERO, evaluated human genetic variants associated with susceptibility to S.aureus infection and colonization, with subsequent clinical outcomes. Bibliographic databases and grey literature sources were searched for observational studies (2015-2026), with risk of bias assessed using the Newcastle-Ottawa Scale. Regarding innate immunity, IL1RN*2/*2 was associated with post-traumatic S. aureus osteomyelitis, whereas the TIRAP association lost significance after adjustment. In adaptive immunity, admixture mapping linked European ancestry at HLA class II locus to bacteremia in African Americans, while CCR5Δ32 altered circulating chemokines levels without altering clinical risk. Regarding metabolism and iron regulation, GLS2 variant (rs937115) was associated with complicated bacteremia, and an intergenic CHCHD7/SDR16C5 variant (rs73596248) was linked to higher hepcidin levels and a lower risk of bacteremia. CFTR F508del genotype showed no significant association with methicillin-resistant S. aureus (MRSA) acquisition. These findings support a multifactorial host genetic network in S. aureus infection and underscore the need for larger, multi-ancestry, independently replicated studies to validate genetic markers for future risk stratification.

Abstract: This research addresses concerns related to Sick Building Syndrome (SBS) and evolving strategies for managing hazardous biological agents in indoor environments, such as toxic fungi. This pilot scale-model study investigates the impact of a photobioreactor (PBR) algae façade on the microclimate and on the growth of Aspergillus niger and A. fumigatus. Glass simulation chambers were built without a PBR (control), with a PBR on one side (partial PBR) or with a U-shaped PBR surrounding the test space (PBR; 40 × 40 × 40 cm), with two chambers per treatment. Temperature and humidity were recorded every minute, and 15 plates of each fungus (five per treatment) were exposed for 8 days. The PBR did not change the mean temperature but reduced the daily maximum temperature by 5.4 °C (39.2 vs. 44.6 °C) and kept humidity ≥ 80% RH for 23.9 h day−1, compared with 17.4 h day⁻¹ in the control chamber; the partial PBR gave intermediate values as expected. A. niger grew larger with increasing PBR coverage (control 6.0, partial PBR 9.0 and PBR 11.4 cm²; p for trend = 0.002), and A. fumigatus showed a similar but non-significant trend (6.8, 8.4 and 9.4 cm²; p for trend = 0.146). These results indicate that the algae façade can improve thermal comfort but may also favor mold growth, a crucial effect on building health that requires further study.

Abstract: Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) has become the dominant proteomic platform for fungal identification, turning a multi-day, morphology-dependent workflow into a minutes-long protein-fingerprinting assay. Yet reported performance for the same genera ranges from under 20% to over 95% depending on the study. This narrative review examines sources of heterogeneity across five domains: (1) biological and pre-analytical properties, including colony age, growth phase and dimorphism, culture medium, incubation temperature, pigmentation, and taxonomic complexity; (2) sample-processing variables, including protein-extraction chemistry, deposition technique, and matrix selection; (3) instrument-acquisition parameters, including laser intensity, shot number, signal-intensity thresholds, calibration, and cross-platform differences; (4) database and bioinformatic factors, including reference-library completeness, score-threshold interpretation, and software version; and (5) specimen type and clinical context, particularly for culture-independent workflows. The review examines how these factors affect proteomic identification of molds. First, variability attributed to fungal biology may be confounded by methodological variability: studies using standardized, validated extraction protocols may report less variability attributable to biology than studies using less-controlled methods. Second, reference-library completeness and standardized, locally validated sample preparation and deposition are particularly actionable determinants. Third, an unresolved challenge is reliable identification of rare, cryptic, melanized, dimorphic, and emerging organisms. The review concludes with evidence-informed quality-assurance practices considered in the context of CLSI M58.

Abstract: Long coronavirus disease (long COVID) and hypermobility disorders (e.g., hypermobile Ehlers-Danlos syndrome) often share comorbidities, including mast cell activation syndrome, small fiber neuropathy, and myalgic encephalomyelitis/chronic fatigue syndrome. The relationship between long COVID and hypermobility disorders, as well as the extracellular matrix (ECM), has been reported, with evidence suggesting that ECM alterations may underlie these associations. The current hypothesis posits that ECM alterations may become partly self-perpetuating, with the severe acute respiratory syndrome coronavirus 2 spike protein as a possible initial trigger. The proposed mechanism involves interactions among the spike protein, integrins, latent transforming growth factor β, mast cells, interleukin-6, and matrix metalloproteinase-9 (MMP-9). Possible feedback loops, such as those between latent transforming growth factor β and a stiffened ECM, increased sympathetic activity and a pro-inflammatory state, insulin resistance and a pro-inflammatory state, inflammation and mast cell migration, and increased blood–brain barrier permeability via MMP-9 and inflammation, are highlighted. The impact of the modified ECM on the nervous system, as described through PIEZO and N-methyl-D-aspartate receptors, is also discussed, alongside evidence for increased differentiation of T-helper 17 cells and their potentially disruptive effects on efferocytosis. This new hypothesis may have important implications for clinical practice and future research.

Abstract: Respiratory viral infections are a major cause of global morbidity and mortality, partly because they increase susceptibility to secondary bacterial pneumonia and sepsis. Coronaviruses, influenza viruses, parainfluenza viruses, rhinoviruses, and respiratory syncytial virus have each been associated with impaired macrophage antibacterial function, although the underlying evidence differs among virus families. Direct lysosomal-pH measurements and mechanistically resolved links between infection and lysosomal de-acidification are strongest for coronaviruses. Using β-coronaviruses as the primary model for the effect of direct lysosomal disruption on macrophage antimicrobial capacity, this review examines lysosomal exploitation during viral egress, impaired phagosome-lysosome fusion, E-protein-mediated proton conductance, and ORF3a-associated lysosomal injury. It further proposes that the magnitude of these effects is shaped by host-dependent immunometabolic processes. Mitochondrial dysfunction, NAD⁺ depletion, and disrupted mitochondria-lysosome coupling may reduce the ability of macrophages to preserve lysosomal acidity, autophagic competence, and bacterial killing during viral challenge. Together, these mechanisms describe how coronavirus infection compromises macrophage antibacterial defense, and how the resulting susceptibility to secondary bacterial infection is further modulated by the metabolic and inflammatory state of the host cell.