Jens-Michael Schröder

The high prevalence of Corynebacterium (C.) simulans in lesional and non-lesional psoriatic skin, and its correlation with disease severity, suggest a potential role in psoriasis pathophysiology. Previous exploratory Western blot and peptidome analyses of C. simulans extracts using IgG from psoriasis patients identified B-cell epitopes bound by natural bispecific antibodies (nBsAbs, presumably IgG4). These epitopes were primarily derived from intrinsically disordered proteins, autoantigens, and bacteriophage proteins. Subsequent analyses using pooled psoriasis serum unexpectedly revealed antigenic peptides from numerous Corynebacterium species. Taxonomic filtering identified several thousand Corynebacterium -derived epitopes across 40 species, including C. simulans , C. striatum , C. diphtheriae , common skin commensals, environmental and food-associated strains, the plant pathogen Clavibacter michiganensis , and the zoonotic pathogens C. pseudotuberculosis and C. ulcerans . Additional epitopes originated from related genera ( Prescottella , Tsukamurella , Mycobacterium , Gordonia , Nocardia , and Rhodococcus ) as well as bacteriophages of the order Caudovirales . Among the identified peptides, 183 epitopes from 46 antigens mapped to 30S and 50S ribosomal proteins. Numerous additional epitopes derived from proteins involved in transcription, translation, aminoacyl-tRNA ligases (covering 17 amino acids), transcriptional regulation, RNA processing and degradation, sigma factors, and ribosome-associated proteins. Notably, 40 epitopes originated from highly conserved FoF1-ATP synthase subunits (α, β, γ, δ). One peptide containing the catalytic Walker A nucleotide-binding motif showed sequence identity with mitochondrial FoF1-ATP synthase, suggesting potential autoimmune cross-reactivity and implicating this enzyme complex as a psoriasis-associated autoantigen candidate. Thousands of further epitopes were identified from proteins involved in respiratory chain function, stress responses, bacterial immunity, membrane transport, chaperones, cell wall biosynthesis, proteases, and peptidases, particularly ATP-dependent Clp proteases. Antigens from biosynthetic and metabolic pathways represented the most abundant nBsAb targets. In addition, 368 DECOY peptides were assigned to bacteriophage proteins. The detection of epitopes from toxin-producing species such as C. diphtheriae , C. pseudotuberculosis , and C. ulcerans further supports a potential microbial contribution to psoriasis pathogenesis. This exploratory study presents a streamlined strategy for B-cell epitope mapping of Corynebacterium antigens using IDP-enriched antigen-IgG4 complexes. The approach holds promise for the development of B-cell epitope-based vaccines targeting microbial, viral, tumor, and allergen-associated diseases.

The high abundance of Corynebacterium simulans in psoriasis skin suggests a contribution to the psoriasis aetiology. This hypothesis was tested in an exploratory study, where western blot (WB) analyses with extracts of heat‐treated C. simulans and psoriasis serum‐derived IgG exhibited a single 16 kDa‐WB‐band. Proteomic analyses revealed ribosomal proteins as candidate C. s. ‐antigens. A peptidomic analysis unexpectedly showed that psoriasis serum‐derived IgG already contained 31 immunopeptides of Corynebacteria ssp., suggesting the presence of natural bispecific antibodies (BsAbs). Moreover, peptidomic analyses gave 372 DECOY‐peptides with similarity to virus‐ and phage proteins, including Corynebacterium diphtheriae phage , and similarity to diphtheria toxin. Strikingly, a peptidomic analysis for human peptides revealed 64 epitopes of major psoriasis autoantigens such as the spacer region of filaggrin, hornerin repeats and others. Most identified immunopeptides represent potential cationic intrinsically disordered antimicrobial peptides (CIDAMPs), which are generated within the epidermis. These may form complexes with bacterial disordered protein regions, representing chimeric antigens containing discontinuous epitopes. In addition, among 128 low‐abundance immunopeptides, 48 are putatively psoriasis‐relevant such as epitope peptides of PGE2‐, vitamin D3‐ and IL‐10‐receptors. Further, 47 immunopeptides originated from tumour antigens, and the endogenous retrovirus HERV‐K. I propose that persistent infection with a toxigenic C. simulans initiates psoriasis, which is exacerbated as an autoimmune disease by CIDAMPs as autoantigens. The discovery of natural BsAbs allows the identification of antigen epitopes from microbes, viruses, autoantigens and tumour‐antigens, and may help to develop epitope‐specific peptide‐vaccines and therapeutic approaches with antigen‐specific regulatory T cells to improve immune tolerance in an autoimmune disease‐specific‐manner.

The high abundance of Corynebacterium simulans in psoriasis skin suggests a contribution to the psoriasis etiology via cell envelope components, which may cause skin inflammation and immune responses. This hypothesis was tested in an exploratory study, where Western Blot (WB) analyses with extracts of heat-treated C. simulans and psoriasis serum-derived IgG exhibited a single 16 kDa- WB-band. Proteomic analyses revealed, among others, ribosomal proteins as candidate C. s. -antigens. A peptidomic analysis unexpectedly showed that psoriasis-serum-derived IgG already contained 31 immunopeptides originating from Corynebacteria ssp ., suggesting the presence of natural bispecific antibodies (BsAbs). Moreover, peptidomic analyses revealed 372 “DECOY”-peptides with similarity to virus- and phage proteins, including Corynebacterium diphtheriae phage , and similarity to diphtheria toxin. Strikingly, upon a peptidomic analysis for peptides of human origin, 64 epitopes of major psoriasis autoantigens were identified, which originated from the spacer region of filaggrin, from hornerin repeats, SPINK9, keratin 9, caspase 14, desmoplakin, suprabasin, keratin 2, keratin1, keratin 6C, apolipoprotein A1, a Selene-binding protein, H1.8 linker histone, and the transcription factor BCLAF3. Most identified antigens represent potential “Cationic Intrinsically Disordered Antimicrobial Peptides (CIDAMPs)”, which are generated within the fully differentiated epidermis. These may form complexes with bacterial disordered protein regions, representing chimeric antigens containing discontinuous epitopes. In addition, among 128 low-abundance immunopeptides, 48 are putatively psoriasis-relevant such as epitopes of IL-12, and the receptors of PGE2, vitamin D3, and IL-10. Further, 47 immunopeptides originated from tumor antigens such as CT47A, SDCCAG3, BRCA2, MAGEA6, RNASE4, and the endogenous retrovirus HERV-K. I propose that persistent infection with a toxigenic C. simulans initiates psoriasis, which is exacerbated as an autoimmune disease by CIDAMPs as autoantigens. The discovery of natural BsAbs allows the identification of antigen epitopes from microbes, viruses, autoantigens, and tumor-antigens, and may help to develop epitope- specific peptide-vaccines and therapeutic approaches with antigen-specific regulatory T cells to improve immune tolerance in an autoimmune disease-specific-manner.

Deficiencies of the vitamins A and D have dramatic effects on the immune system and the gut barrier function, but the underlying mechanisms of this are unclear. In this study it was shown that these vitamins play a critical role in the regulation of the gastrointestinal morphology and antimicrobial defense in the small intestine, in particular in the regulation of antimicrobial peptides by specific signaling pathways. These findings offer novel approaches for dietary strategies to improve host defense against infections and to ameliorate gut barrier dysfunction.

Textbook knowledge says that inflammatory monocytes represent the key phagocytes to eliminate bacteria upon infection. This, however, is difficult to reconcile due to the large number of neutrophils seen at infection sites and with its robust microbicidal functions. The authors of this study could show that monocytes did not contribute to bacterial clearance but, after conversion to macrophages, regulated adipocyte expansion and production of the adipokine leptin. Further, the leptin function opposing ghrelin was found to be locally produced by monocytes and improved healing post-infection. This study shows that monocytes function as a cellular rheostat by regulation of leptin levels and revascularization during wound repair rather than acting as bacteria eliminating phagocytes.

SARS-CoV-2 markedly disrupts host cell epigenetic regulation. However, how SARS-CoV-2 controls the host cell epigenome remains speculative. In this study, the authors identified the SARS-CoV-2 protein ORF8 that functions as a histone mimic of the ARKS motifs in histone H3 to disrupt host cell epigenetic regulation. These findings have critical implications for understanding emerging viral strains carrying deletions and mutations in the ORF8 gene and COVID-19 pathogenesis in patients.

The papain-like protease (PLpro) can be considered a major SARS-CoV-2 therapeutic target due to its dual biological role in suppressing host innate immune responses and in ensuring viral replication. In this review, the authors summarize the challenges of targeting PLpro to generate PLpro-specific small molecules, which are promising and interesting therapeutics, targeting COVID-19.

RNA-virus infection activates retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), which causes a strong host antiviral immune response by inducing type I interferons and proinflammatory cytokines. In this review, the authors give an overview about the antiviral mechanisms of RLR signaling. They summarize how the RLR signaling cascade is strictly controlled by host regulatory mechanisms, and how RLRs participate in diseases, including SARS-CoV-2, and how SNPs or mutations in RLRs and antibodies against RLR lead to autoinflammatory diseases.

SARS-CoV-2 variants present urgent challenges for curbing the COVID-19 pandemic. Recent studies document a critical role for interferon responses in the early control of SARS-CoV-2 infection, suggesting that interferons may also influence SARS-CoV-2 evolution. In this study, the authors compared the potency of different interferons against various major variants of concern and found an increased interferon resistance, suggesting that evasion of innate immunity may be a driving force for SARS-CoV-2 evolution.

To prevent a second drug resistance crisis due to an increasing resistance of pathogenic fungi to most current antifungals, new classes of antifungal drugs are urgently needed. The authors of this study report the discovery of a high number of metal-containing compounds, which were screened by the Community for Open Drug Discovery (CO-ADD), to have potent antimicrobial activity towards strains of Candida and Cryptococcus spp and low, if any, toxicity in a moth larva model. These findings make a strong case that a more systematic and thorough study of metal-based compounds for antifungal application is warranted.