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We sought to determine whether immune reactivity occurs between anti-SARS-CoV-2 protein antibodies and human tissue antigens, and whether molecular mimicry between COVID-19 viral proteins and human tissues could be the cause. We applied both human monoclonal anti-SARS-Cov-2 antibodies (spike protein, nucleoprotein) and rabbit polyclonal anti-SARS-Cov-2 antibodies (envelope protein, membrane protein) to 55 different tissue antigens. We found that SARS-CoV-2 antibodies had reactions with 28 out of 55 tissue antigens, representing a diversity of tissue groups that included barrier proteins, gastrointestinal, thyroid and neural tissues, and more. We also did selective epitope mapping using BLAST and showed similarities and homology between spike, nucleoprotein, and many other SARS-CoV-2 proteins with the human tissue antigens mitochondria M2, F-actin and TPO. This extensive immune cross-reactivity between SARS-CoV-2 antibodies and different antigen groups may play a role in the multi-system disease process of COVID-19, influence the severity of the disease, precipitate the onset of autoimmunity in susceptible subgroups, and potentially exacerbate autoimmunity in subjects that have pre-existing autoimmune diseases. Very recently, human monoclonal antibodies were approved for use on patients with COVID-19. The human monoclonal antibodies used in this study are almost identical with these approved antibodies. Thus, our results can establish the potential risk for autoimmunity and multi-system disorders with COVID-19 that may come from cross-reactivity between our own human tissues and this dreaded virus, and thus ensure that the badly-needed vaccines and treatments being developed for it are truly safe to use against this disease.

Cancer therapies that target epigenetic repressors can mediate their effects by activating retroelements within the human genome. Retroelement transcripts can form double-stranded RNA (dsRNA) that activates the MDA5 pattern recognition receptor 1 – 6 . This state of viral mimicry leads to loss of cancer cell fitness and stimulates innate and adaptive immune responses 7 , 8 . However, the clinical efficacy of epigenetic therapies has been limited. To find targets that would synergize with the viral mimicry response, we sought to identify the immunogenic retroelements that are activated by epigenetic therapies. Here we show that intronic and intergenic SINE elements, specifically inverted-repeat Alus, are the major source of drug-induced immunogenic dsRNA. These inverted-repeat Alus are frequently located downstream of ‘orphan’ CpG islands 9 . In mammals, the ADAR1 enzyme targets and destabilizes inverted-repeat Alu dsRNA 10 , which prevents activation of the MDA5 receptor 11 . We found that ADAR1 establishes a negative-feedback loop, restricting the viral mimicry response to epigenetic therapy. Depletion of ADAR1 in patient-derived cancer cells potentiates the efficacy of epigenetic therapy, restraining tumour growth and reducing cancer initiation. Therefore, epigenetic therapies trigger viral mimicry by inducing a subset of inverted-repeats Alus, leading to an ADAR1 dependency. Our findings suggest that combining epigenetic therapies with ADAR1 inhibitors represents a promising strategy for cancer treatment. Inverted-repeat Alu elements are the main source of drug-induced immunogenic double-stranded RNAs, which are destabilized by the RNA deaminase ADAR1, thereby limiting activation of the immune response.

The phenomenon of sex-limited mimicry is phylogenetically widespread in the swallowtail butterfly genus Papilio — now, a single gene, doublesex , is shown to control supergene mimicry, a finding that is in contrast to the long-held view that supergenes are likely to be controlled by a tightly linked cluster of loci. How super is a supergene? In some butterfly species one sex — usually the female — mimics the wing pattern of a toxic species. In the 1960s the phenomenon was proposed to be under the control of a 'supergene'. More recently a consensus has emerged that supergenes are likely to be clusters of tightly linked genes, each influencing a different aspect of mimetic wing patterning. Now Marcus Kronforst and colleagues show, surprisingly, that in a classic supergene mimic, the swallowtail butterfly Papilio polytes , the supergene is truly a single gene. And another surprise: that gene is a well-known component in the sex determination pathway called doublesex . Gene expression and DNA sequence variation data suggest that isoform expression differences and protein sequence evolution also contribute to the differences between doublesex mimicry alleles. Thus the P. polytes mimicry supergene can be summed up as a fusion of previous hypotheses: single-gene control but with help from multiple functional mutations. One of the most striking examples of sexual dimorphism is sex-limited mimicry in butterflies, a phenomenon in which one sex—usually the female—mimics a toxic model species, whereas the other sex displays a different wing pattern 1 . Sex-limited mimicry is phylogenetically widespread in the swallowtail butterfly genus Papilio , in which it is often associated with female mimetic polymorphism 1 , 2 , 3 . In multiple polymorphic species, the entire wing pattern phenotype is controlled by a single Mendelian ‘supergene’ 4 . Although theoretical work has explored the evolutionary dynamics of supergene mimicry 5 , 6 , 7 , 8 , 9 , there are almost no empirical data that address the critical issue of what a mimicry supergene actually is at a functional level. Using an integrative approach combining genetic and association mapping, transcriptome and genome sequencing, and gene expression analyses, we show that a single gene, doublesex , controls supergene mimicry in Papilio polytes . This is in contrast to the long-held view that supergenes are likely to be controlled by a tightly linked cluster of loci 4 . Analysis of gene expression and DNA sequence variation indicates that isoform expression differences contribute to the functional differences between dsx mimicry alleles, and protein sequence evolution may also have a role. Our results combine elements from different hypotheses for the identity of supergenes, showing that a single gene can switch the entire wing pattern among mimicry phenotypes but may require multiple, tightly linked mutations to do so.

The approval of the first small interfering RNA (siRNA) drug Patisiran by FDA in 2018 marks a new era of RNA interference (RNAi) therapeutics. MicroRNAs (miRNA), an important post-transcriptional gene regulator, are also the subject of both basic research and clinical trials. Both siRNA and miRNA mimics are ~21 nucleotides RNA duplexes inducing mRNA silencing. Given the well performance of siRNA, researchers ask whether miRNA mimics are unnecessary or developed siRNA technology can pave the way for the emergence of miRNA mimic drugs. Through comprehensive comparison of siRNA and miRNA, we focus on (1) the common features and lessons learnt from the success of siRNAs; (2) the unique characteristics of miRNA that potentially offer additional therapeutic advantages and opportunities; (3) key areas of ongoing research that will contribute to clinical application of miRNA mimics. In conclusion, miRNA mimics have unique properties and advantages which cannot be fully matched by siRNA in clinical applications. MiRNAs are endogenous molecules and the gene silencing effects of miRNA mimics can be regulated or buffered to ameliorate or eliminate off-target effects. An in-depth understanding of the differences between siRNA and miRNA mimics will facilitate the development of miRNA mimic drugs.

Systemic lupus erythematosus (SLE) is an autoimmune disease featuring enhanced expression of type I interferon (IFN) and autoantibody production triggering inflammation of, and damage to, multiple organs. Continuing research efforts focus on how gut microbes trigger systemic autoimmunity and SLE. The gut microbial communities of mice and humans with lupus have been investigated via high-throughput sequencing. The Firmicutes-to-Bacteroidetes ratio is consistently reduced in SLE patients, regardless of ethnicity. The relative abundance of Lactobacillus differs from the animal model used (MRL/lpr mice or NZB/W F1 mice). This may indicate that interactions between gut microbes and the host, rather than the enrichment of certain gut microbes, are especially significant in terms of SLE development. Enterococcus gallinarum and Lactobacillus reuteri, both of which are possible gut pathobionts, become translocated into systemic tissue if the gut epithelial barrier is impaired. The microbes then interact with the host immune systems, activating the type I IFN pathway and inducing autoantibody production. In addition, molecular mimicry may critically link the gut microbiome to SLE. Gut commensals of SLE patients share protein epitopes with the Ro60 autoantigen. Ruminococcus gnavus strain cross-reacted with native DNA, triggering an anti-double-stranded DNA antibody response. Expansion of R. gnavus in SLE patients paralleled an increase in disease activity and lupus nephritis. Such insights into the link between the gut microbiota and SLE enhance our understanding of SLE pathogenesis and will identify biomarkers predicting active disease.

Helminth parasites defy immune exclusion through sophisticated evasion mechanisms, including activation of host immunosuppressive regulatory T (Treg) cells. The mouse parasite Heligmosomoides polygyrus can expand the host Treg population by secreting products that activate TGF-β signalling, but the identity of the active molecule is unknown. Here we identify an H. polygyrus TGF-β mimic ( Hp- TGM) that replicates the biological and functional properties of TGF-β, including binding to mammalian TGF-β receptors and inducing mouse and human Foxp3 + Treg cells. Hp- TGM has no homology with mammalian TGF-β or other members of the TGF-β family, but is a member of the complement control protein superfamily. Thus, our data indicate that through convergent evolution, the parasite has acquired a protein with cytokine-like function that is able to exploit an endogenous pathway of immunoregulation in the host. Heligmosomoides polygyrus can activate mammalian TGF-β signalling pathways, but how it does so is not known. Here the authors identify and isolate a H. polygyrus TFG-β mimic that can bind both mammalian TGF-β receptor subunits, activate Smad signalling and generate inducible regulatory T cells.

Tumor-associated peptide-human leukocyte antigen complexes (pHLAs) represent the largest pool of cell surface-expressed cancer-specific epitopes, making them attractive targets for cancer therapies. Soluble bispecific molecules that incorporate an anti-CD3 effector function are being developed to redirect T cells against these targets using 2 different approaches. The first achieves pHLA recognition via affinity-enhanced versions of natural TCRs (e.g., immune-mobilizing monoclonal T cell receptors against cancer [ImmTAC] molecules), whereas the second harnesses an antibody-based format (TCR-mimic antibodies). For both classes of reagent, target specificity is vital, considering the vast universe of potential pHLA molecules that can be presented on healthy cells. Here, we made use of structural, biochemical, and computational approaches to investigate the molecular rules underpinning the reactivity patterns of pHLA-targeting bispecifics. We demonstrate that affinity-enhanced TCRs engage pHLA using a comparatively broad and balanced energetic footprint, with interactions distributed over several HLA and peptide side chains. As ImmTAC molecules, these TCRs also retained a greater degree of pHLA selectivity, with less off-target activity in cellular assays. Conversely, TCR-mimic antibodies tended to exhibit binding modes focused more toward hot spots on the HLA surface and exhibited a greater degree of crossreactivity. Our findings extend our understanding of the basic principles that underpin pHLA selectivity and exemplify a number of molecular approaches that can be used to probe the specificity of pHLA-targeting molecules, aiding the development of future reagents.

Over the last decade, great enthusiasm has evolved for microRNA (miRNA) therapeutics. Part of the excitement stems from the fact that a miRNA often regulates numerous related mRNAs. As such, modulation of a single miRNA allows for parallel regulation of multiple genes involved in a particular disease. While many studies have shown therapeutic efficacy using miRNA inhibitors, efforts to restore or increase the function of a miRNA have been lagging behind. The miR‐29 family has gained a lot of attention for its clear function in tissue fibrosis. This fibroblast‐enriched miRNA family is downregulated in fibrotic diseases which induces a coordinate increase of many extracellular matrix genes. Here, we show that intravenous injection of synthetic RNA duplexes can increase miR‐29 levels in vivo for several days. Moreover, therapeutic delivery of these miR‐29 mimics during bleomycin‐induced pulmonary fibrosis restores endogenous miR‐29 function whereby decreasing collagen expression and blocking and reversing pulmonary fibrosis. Our data support the feasibility of using miRNA mimics to therapeutically increase miRNAs and indicate miR‐29 to be a potent therapeutic miRNA for treating pulmonary fibrosis. Synopsis Therapeutic delivery of miR‐29 mimics during bleomycin‐induced pulmonary fibrosis in mice restores endogenous miR‐29 function thereby decreasing collagen expression and blocking and reversing pulmonary fibrosis. MicroRNA mimics can be used to increase levels of miRNAs in vivo in a time and dose‐dependent manner. miR‐29 mimic does not affect target gene expression under basal conditions. miR‐29 mimic can block and reverse aspects of bleomycin‐induced pulmonary fibrosis. Graphical Abstract Therapeutic delivery of miR‐29 mimics during bleomycin‐induced pulmonary fibrosis in mice restores endogenous miR‐29 function whereby decreasing collagen expression and blocking and reversing pulmonary fibrosis.

Evolution of supergenes The toxic butterfly Heliconius numata , found in forests across South America, mimics the wing patterns of several species of another family of toxic butterflies, Melinaea sp., in order to deter predators more effectively. This example of Müllerian mimicry is under the control of a classic 'supergene', a tight gene cluster usually inherited as a single unit. H. numata is particularly adept at mimicry, able to copy as many as seven different wing patterns. A study of the individual wing-pattern morphs in H. numata shows that different genomic rearrangements at the single supergene P locus tighten the genetic linkage between loci that are otherwise free to recombine in other closely related species. The resulting supergene acts as a simple switch that once thrown, selects which one of a range of complex adaptive phenotypes the butterfly displays. Supergenes are tight clusters of loci that facilitate the co-segregation of adaptive variation, providing integrated control of complex adaptive phenotypes 1 . Polymorphic supergenes, in which specific combinations of traits are maintained within a single population, were first described for ‘pin’ and ‘thrum’ floral types in Primula 1 and Fagopyrum 2 , but classic examples are also found in insect mimicry 3 , 4 , 5 and snail morphology 6 . Understanding the evolutionary mechanisms that generate these co-adapted gene sets, as well as the mode of limiting the production of unfit recombinant forms, remains a substantial challenge 7 , 8 , 9 , 10 . Here we show that individual wing-pattern morphs in the polymorphic mimetic butterfly Heliconius numata are associated with different genomic rearrangements at the supergene locus P . These rearrangements tighten the genetic linkage between at least two colour-pattern loci that are known to recombine in closely related species 9 , 10 , 11 , with complete suppression of recombination being observed in experimental crosses across a 400-kilobase interval containing at least 18 genes. In natural populations, notable patterns of linkage disequilibrium (LD) are observed across the entire P region. The resulting divergent haplotype clades and inversion breakpoints are found in complete association with wing-pattern morphs. Our results indicate that allelic combinations at known wing-patterning loci have become locked together in a polymorphic rearrangement at the P locus, forming a supergene that acts as a simple switch between complex adaptive phenotypes found in sympatry. These findings highlight how genomic rearrangements can have a central role in the coexistence of adaptive phenotypes involving several genes acting in concert, by locally limiting recombination and gene flow.

Cancer is one of the most dreaded diseases worldwide. Conventional treatments such as surgery, chemotherapy, and radiotherapy have limitations and adverse effects. Cancer immunotherapy and targeted therapies offer new treatment options. Parasite-based cancer therapy shows promise in fighting tumors. Some parasites have anti-cancer properties through multi-mechanistic strategies, with the molecular mimicry theory as a leading explanation for parasites’ anti-cancer effects. This study aimed to explore the existence of shared antigenic proteins between parasites ( Trichinella spiralis , Schistosoma mansoni , and Toxoplasma gondii ) and cancer cell lines (MCF-7 human breast cancer and A549 human lung cancer). Polyclonal antisera against T. spiralis , S. mansoni , and T. gondii parasites were generated in rabbits. Antibody reactivity with extracts of MCF-7 and A549 cancer cells was detected using SDS-PAGE and immunoblotting. Results documented the molecular mimicry between parasites and cancers as it revealed cross-reactive bands when using T. spiralis antibodies against MCF-7 and A549 cancer cell extracts at approximate molecular weights of 70 and 35 kDa, and with S. mansoni antibodies at an approximate molecular weight of 80 kDa. Toxoplasma gondii antibodies neither reacted with MCF-7 human breast cancer nor A549 human lung cancer cell extracts. Results of this study could establish a foundation for subsequent investigation among a broad range of parasites for molecular mimicry with cancers. Identification, molecular characterization, and investigation of the anti-neoplastic activity of these cross-reactive antigens could shed light on new pathways for the potential development of a novel class of innovative cancer vaccine candidates and therapeutic antibodies of parasitic origin for cancer immunotherapy and targeted therapy.