Pathological Immune Responses Research Articles

Role of IL-33/ST2 Axis in Chronic Inflammatory Neurological Disorderss

Abstract Interleukin-33 (IL-33) is a member of IL-1 family of cytokines, produced constitutively by fibroblasts, endothelial cells, and epithelial cells. IL-33 can be released passively from cells during tissue damage and cell necrosis, suggesting that it may act as an alarmin. Function of IL-33 is mediated by its interaction with ST2 molecule that is expressed on many immune cells: Th2 lymphocytes, NK, NKT and mast cells, monocytes, dendritic cells and granulocytes. IL-33/ST2 pathway plays, often dual, roles in different physiological and inflammatory processes, mediating both, pathological immune responses and tissue repair. Expression of IL-33 in the central nervous system (CNS) is significantly enhanced during various pathological processes, indicating its important role in the pathogenesis of neurological inflammatory and degenerative diseases. In this review the biological features, expression of IL-33 and its ligand ST2 in CNS, and the role of IL- 33/ST2 pathway in development of Alzheimer’s disease and multiple sclerosis are discussed.

The intestinal microbiota and improving the efficacy of COVID-19 vaccinations.

Most COVID-19 cases are mild or asymptomatic and recover well, suggesting that effective immune responses ensue, which successfully eliminate SARS-CoV-2 viruses. However, a small proportion of patients develop severe COVID-19 with pathological immune responses. This indicates that a strong immune system balanced with anti-inflammatory mechanisms is critical for the recovery from SARS-CoV-2 infections. Many vaccines against SARS-CoV-2 have now been developed for eliciting effective immune responses to protect from SARS-CoV-2 infections or reduce the severity of the disease if infected. Although uncommon, serious morbidity and mortality have resulted from both COVID-19 vaccine adverse reactions and lack of efficacy, and further improvement of efficacy and prevention of adverse effects are urgently warranted. Many factors could affect efficacy of these vaccines to achieve optimal immune responses. Dysregulation of the gut microbiota (gut dysbiosis) could be an important risk factor as the gut microbiota is associated with the development and maintenance of an effective immune system response. In this narrative review, we discuss the immune responses to SARS-CoV-2, how COVID-19 vaccines elicit protective immune responses, gut dysbiosis involvement in inefficacy and adverse effects of COVID-19 vaccines and the modulation of the gut microbiota by functional foods to improve COVID-19 vaccine immunisations.

Corticosteroid Treatment Impairs Epithelial Regeneration, Limiting Intestinal Recovery in Experimental Graft Vs Host Disease

Corticosteroids (CS) represent first-line treatment for gastrointestinal graft vs host disease (GI GVHD), and CS failure is associated with severe morbidity and mortality. While the immune system is the intended target of CS treatment, the glucocorticoid receptor (GR) is widely expressed, and there is limited understanding of the direct effects of CS on intestinal epithelium following immune-mediated damage.We thus investigated how CS treatment could impact intestinal homeostasis and regeneration following experimental bone marrow transplantation (BMT). In healthy C57BL/6 (B6) mice, in vivo administration of clinically relevant CS doses reduced Ki67 + epithelial proliferation in the ileum (p<0.001; Fig. 1A) without inducing crypt loss or overt pathology. Given the numerous potential effects of systemic administration, we next utilized ex vivo small intestine (SI) organoid cultures to explore direct effects of CS on murine and human epithelium. Assessing a variety of clinically relevant CS agents, we found that methylprednisolone (MP), dexamethasone, and budesonide all decreased murine organoid size without affecting organoid number (p<0.05; only MP shown; Fig. 1B). We also identified that GR-deficient (Nr3c1 -/-) organoids were significantly resistant to growth inhibition by MP (p<0.05), indicating a direct GR-mediated effect of CS on intestinal epithelium leading to reduced growth. Furthermore, MP treatment significantly decreased the size of human organoids generated from primary duodenal tissue without affecting organoid numbers (p<0.001). Organoid culture models were thus highly consistent with the findings from in vivo CS treatment.We next investigated CS effects on epithelial cells during immune-mediated damage. Pre-treatment of mice with 2 mg/kg MP x 7 days in vivo prior to crypt harvest and organoid culture increased organoid sensitivity to T-cell-mediating killing ex vivo (p<0.05). Additionally, modeling steroid-refractory disease, GR-deficient (Nr3c1 -/-) T cells mediated greater killing of SI organoids if co-cultures were performed in the presence of MP (p<0.01). We next investigated CS-mediated effects on epithelial damage in vivo, treating with MP x 7 days starting on day 7 after MHC-mismatched BMT, once GVHD had already been established. Vehicle-treated mice demonstrated GVHD-associated T cell activation, lymphocytic tissue infiltration, and ileal crypt loss compared to BM only controls, as well as increased height and Ki67 + cell frequency in residual crypts reflecting damage-induced regeneration (p<0.001, Fig. 2A-C). Modeling steroid-refractory disease, systemic CS treatment failed to reduce T cell activation or lymphocytic infiltration. However, MP treatment appeared to attenuate regeneration and worsen intestinal pathology, as evidenced by exacerbated crypt loss in association with reduced crypt height and Ki67 + cell frequency (p<0.01; Fig. 2A-C).Despite potential harmful side effects, CS are frequently necessary for treatment of clinical GVHD. We hypothesized that CS-mediated epithelial suppression could be mitigated by concurrent administration of agents capable of inducing tissue regeneration. Interleukin-(IL)-22 has been shown to promote epithelial proliferation and recovery following GI damage. We thus investigated whether IL-22 treatment could counterbalance CS-induced impairment of epithelial recovery in GVHD. Indeed, addition of IL-22 to MP-treated organoids promoted organoid growth without inducing toxicity/organoid loss in both murine and human SI organoid cultures (p<0.001; Fig. 3A and B). Moreover, IL-22 administration in vivo with F-652, a clinical grade recombinant human IL-22 dimer, reversed MP-mediated crypt loss and reduction of crypt height and Ki67 + cell frequency in mice with GVHD (p<0.001; Fig. 3C).In summary, these findings indicate that CS treatment can suppress epithelial proliferation in the intestines and exacerbate GI damage if it fails to control the pathologic immune response. However, deleterious CS side effects can be counterbalanced by promotion of epithelial regeneration, providing rationale for combining immunosuppression with tissue-supporting therapeutics such as IL-22 to optimize intestinal recovery in GVHD. [Display omitted] DisclosuresBlazar: Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; BlueRock Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rheos Medicines: Research Funding; Equilibre Pharmaceuticals Corp: Research Funding; Carisma Therapeutics, Inc: Research Funding; Tmunity Therapeutics: Other: Co-founder. Hanash: Evive Biotech: Ended employment in the past 24 months.

Acute optic neuritis: What do complementary tests add to diagnosis?

IntroductionOptic neuritis (ON) is the inflammation of the optic nerve due in many cases, to a pathological immune response. Since its symptoms can be subtle, diagnosis is sometimes challenging. The value of complementary tests for diagnosis and prognosis of ON was demonstrated in retrospective analysis, but their utility in the acute period of ON has been scarcely studied. The aim of this study is to determine the usefulness of clinical assessment, optical coherence tomography (OCT), visual evoked potentials (VEP) and orbit magnetic resonance imaging (MRI) for making diagnosis and prognosis of acute ON (AON). Materials and methodsA cross-sectional study was conducted including patients with ON within 90 days of symptom onset. A complete neuro-ophthalmological evaluation, OCT, VEP and MRI were carried out, determining in each case its sensitivity, specificity and predictive values in the diagnosis of ON and the assessment of its severity. Results75 eyes of 34 patients with ON were included. Regarding diagnosis, low contrast visual acuity (LCVA) displayed the highest sensitivity (100%), being superior than the sensitivity of all complementary tools, always below 80%. Orbit MRI abnormal findings has a Specificity of 100% to confirm diagnosis. Regarding severity assessment and prognosis, Ganglion cell +inner plexiform layer (GCIP) thickness, but not retinal nerve fibre layer (RNFL), correlates significantly with patients’ visual acuity (VA) (p < 0.05). Furthermore, both P100latency and VEP's amplitude showed to be significantly associated with VA (p < 0.05) in the acute period. The combination of two predictors (measurement of RNFL and GCIP) are capable of explaining 60% of the variation of the patient's visual acuity, with statistical significance (p = 0.02) ConclusionsIn depth neuro-ophthalmological assessment during the acute phase of ON, including contrast sensitivity measurement, proved to be superior to complementary tests for diagnosis, surpassing the performance of OCT and VEP. However, these tools can add to prognosis, as GCIP thickness and VEP's amplitude correlate with disease severity and its findings could encourage prompt aggressive treatments in AON.

Microbiota instruct IL-17A-producing innate lymphoid cells to promote skin inflammation in cutaneous leishmaniasis.

Innate lymphoid cells (ILCs) comprise a heterogeneous population of immune cells that maintain barrier function and can initiate a protective or pathological immune response upon infection. Here we show the involvement of IL-17A-producing ILCs in microbiota-driven immunopathology in cutaneous leishmaniasis. IL-17A-producing ILCs were RORγt+ and were enriched in Leishmania major infected skin, and topical colonization with Staphylococcus epidermidis before L. major infection exacerbated the skin inflammatory responses and IL-17A-producing RORγt+ ILC accumulation without impacting type 1 immune responses. IL-17A responses in ILCs were directed by Batf3 dependent CD103+ dendritic cells and IL-23. Moreover, experiments using Rag1-/- mice established that IL-17A+ ILCs were sufficient in driving the inflammatory responses as depletion of ILCs or neutralization of IL-17A diminished the microbiota mediated immunopathology. Taken together, this study indicates that the skin microbiota promotes RORγt+ IL-17A-producing ILCs, which augment the skin inflammation in cutaneous leishmaniasis.

The Roles of Tissue-Resident Memory T Cells in Lung Diseases.

The unique environment of the lungs is protected by complex immune interactions. Human lung tissue-resident memory T cells (TRM) have been shown to position at the pathogen entry points and play an essential role in fighting against viral and bacterial pathogens at the frontline through direct mechanisms and also by orchestrating the adaptive immune system through crosstalk. Recent evidence suggests that TRM cells also play a vital part in slowing down carcinogenesis and preventing the spread of solid tumors. Less beneficially, lung TRM cells can promote pathologic inflammation, causing chronic airway inflammatory changes such as asthma and fibrosis. TRM cells from infiltrating recipient T cells may also mediate allograft immunopathology, hence lung damage in patients after lung transplantations. Several therapeutic strategies targeting TRM cells have been developed. This review will summarize recent advances in understanding the establishment and maintenance of TRM cells in the lung, describe their roles in different lung diseases, and discuss how the TRM cells may guide future immunotherapies targeting infectious diseases, cancers and pathologic immune responses.

Regulatory T Cells: Regulation of Identity and Function.

T regulatory cells suppress a variety of immune responses to self-antigens and play a role in peripheral tolerance maintenance by limiting autoimmune disorders, and other pathological immune responses such as limiting immune reactivity to oncoprotein encoded antigens. Forkhead box P3 (FOXP3) expression is required for Treg stability and affects functional activity. Mutations in the master regulator FOXP3 and related components have been linked to autoimmune diseases in humans, such as IPEX, and a scurfy-like phenotype in mice. Several lines of evidence indicate that Treg use a variety of immunosuppressive mechanisms to limit an immune response by targeting effector cells, including secretion of immunoregulatory cytokines, granzyme/perforin-mediated cell cytolysis, metabolic perturbation, directing the maturation and function of antigen-presenting cells (APC) and secretion of extracellular vesicles for the development of immunological tolerance. In this review, several regulatory mechanisms have been highlighted and discussed.

A digital health platform for assisting the diagnosis and monitoring of COVID-19 progression: An adjuvant approach for augmenting the antiviral response and mitigating the immune-mediated target organ damage

Coronavirus disease 2019 (COVID-19), which is a respiratory illness associated with high mortality, has been classified as a pandemic. The major obstacles for the clinicians to contain the disease are limited information availability, difficulty in disease diagnosis, predicting disease prognosis, and lack of disease monitoring tools. Additionally, the lack of valid therapies has further contributed to the difficulties in containing the pandemic. Recent studies have reported that the dysregulation of the immune system leads to an ineffective antiviral response and promotes pathological immune response, which manifests as ARDS, myocarditis, and hepatitis. In this study, a novel platform has been described for disseminating information to physicians for the diagnosis and monitoring of patients with COVID-19. An adjuvant approach using compounds that can potentiate antiviral immune response and mitigate COVID-19-induced immune-mediated target organ damage has been presented. A prolonged beneficial effect is achieved by implementing algorithm-based individualized variability measures in the treatment regimen.

Brief psychotic disorder occurring after Covid-19 in a patient with no history of psychiatric diseases - a case report

Abstract Introduction: Although the typical symptoms of SARS-CoV-2 infection are respiratory symptoms, it has been shown that the virus can also attack the central nervous system (CNS) causing neurological and psychiatric symptoms. Aim: The aim of the study was to present a case of a 52-year-old woman, previously untreated for psychiatric diseases, who developed brief psychotic disorder occurring after Covid-19 infection. Case report: A patient in the biological treatment of asthma, came for a follow-up visit, during which the doctor diagnosed psychopathological symptoms in the form of delusions, never previously observed. The interview showed that the patient was discharged from the Isolation ward 10 days before, where she was hospitalized because of SARS-CoV-2 infection. Discussion: There are several theories regarding the mechanisms of pathogenesis of neuropsychiatric symptoms in the course of Covid-19 infection. Much space in the literature is devoted to pathological immune responses. One of the reasons for the development of delusions in the described patient could therefore be the acute phase of the inflammatory reaction in the course of SARS-CoV-2 infection.

ABC Transporters in T Cell-Mediated Physiological and Pathological Immune Responses.

ATP-binding cassette (ABC) transporters represent a heterogeneous group of ATP-dependent transport proteins, which facilitate the import and/or export of various substrates, including lipids, sugars, amino acids and peptides, ions, and drugs. ABC transporters are involved in a variety of physiological processes in different human tissues. More recent studies have demonstrated that ABC transporters also regulate the development and function of different T cell populations, such as thymocytes, Natural Killer T cells, CD8+ T cells, and CD4+ T helper cells, including regulatory T cells. Here, we review the current knowledge on ABC transporters in these T cell populations by summarizing how ABC transporters regulate the function of the individual cell types and how this affects the immunity to viruses and tumors, and the course of autoimmune diseases. Furthermore, we provide a perspective on how a better understanding of the function of ABC transporters in T cells might provide promising novel avenues for the therapy of autoimmunity and to improve immunity to infection and cancer.

Secretome screening reveals immunomodulating functions of IFN\u03b1-7, PAP and GDF-7 on regulatory T-cells

Regulatory T cells (Tregs) are the key cells regulating peripheral autoreactive T lymphocytes. Tregs exert their function by suppressing effector T cells. Tregs have been shown to play essential roles in the control of a variety of physiological and pathological immune responses. However, Tregs are unstable and can lose the expression of FOXP3 and suppressive functions as a consequence of outer stimuli. Available literature suggests that secreted proteins regulate Treg functional states, such as differentiation, proliferation and suppressive function. Identification of secreted proteins that affect Treg cell function are highly interesting for both therapeutic and diagnostic purposes in either hyperactive or immunosuppressed populations. Here, we report a phenotypic screening of a human secretome library in human Treg cells utilising a high throughput flow cytometry technology. Screening a library of 575 secreted proteins allowed us to identify proteins stabilising or destabilising the Treg phenotype as suggested by changes in expression of Treg marker proteins FOXP3 and/or CTLA4. Four proteins including GDF-7, IL-10, PAP and IFNα-7 were identified as positive regulators that increased FOXP3 and/or CTLA4 expression. PAP is a phosphatase. A catalytic-dead version of the protein did not induce an increase in FOXP3 expression. Ten interferon proteins were identified as negative regulators that reduced the expression of both CTLA4 and FOXP3, without affecting cell viability. A transcriptomics analysis supported the differential effect on Tregs of IFNα-7 versus other IFNα proteins, indicating differences in JAK/STAT signaling. A conformational model experiment confirmed a tenfold reduction in IFNAR-mediated ISG transcription for IFNα-7 compared to IFNα-10. This further strengthened the theory of a shift in downstream messaging upon external stimulation. As a summary, we have identified four positive regulators of FOXP3 and/or CTLA4 expression. Further exploration of these Treg modulators and their method of action has the potential to aid the discovery of novel therapies for both autoimmune and infectious diseases as well as for cancer.

Recombinant Bet v 1-BanLec chimera modulates functional characteristics of peritoneal murine macrophages by promoting IL-10 secretion

Allergen-specific immunotherapy (AIT) is a desensitizing treatment for allergic diseases that corrects the underlined pathological immune response to innocuous protein antigens, called allergens. Recombinant allergens employed in the AIT allowed the production of well-defined formulations that possessed consistent quality but were often less efficient than natural allergen extracts. Combining recombinant allergens with an adjuvant or immunomodulatory agent could improve AIT efficacy. This study aimed to perform structural and functional characterization of newly designed recombinant chimera composed of the Bet v 1, the major birch pollen allergen, and Banana Lectin (BanLec), TLR2, and CD14 binding protein, for the application in AIT. rBet v 1-BanLec chimera was designed in silico and expressed as a soluble fraction in Escherichia coli. Purified rBet v 1-BanLec (33.4 kDa) retained BanLec-associated biological activity of carbohydrate-binding and preserved IgE reactive epitopes of Bet v 1. The chimera revealed secondary structures with predominant β sheets. The immunomodulatory capacity of rBet v 1-BanLec tested on macrophages showed changes in myeloperoxidase activity, reduced NO production, and significant alterations in the production of cytokines when compared to both rBanLec and rBet v 1. Comparing to rBet v 1, rBet v 1-BanLec was demonstrated to be more efficient promoter of IL-10 production as well as weaker inducer of NO production and secretion of pro-inflammatory cytokines TNFα, and IL-6. The ability of rBet v 1-BanLec to promote IL-10 in together with the preserved 3D structure of Bet v 1 part implies that the construct might exert a beneficial effect in the allergen-specific immunotherapy.

MTOR signaling mediates ILC3-driven immunopathology

Innate lymphoid cells (ILCs) have a protective immune function at mucosal tissues but can also contribute to immunopathology. Previous work has shown that the serine/threonine kinase mammalian target of rapamycin complex 1 (mTORC1) is involved in generating protective ILC3 cytokine responses during bacterial infection. However, whether mTORC1 also regulates IFN-γ-mediated immunopathology has not been investigated. In addition, the role of mTORC2 in ILC3s is unknown. Using mice specifically defective for either mTORC1 or mTORC2 in ILC3s, we show that both mTOR complexes regulate the maintenance of ILC3s at steady state and pathological immune response during colitis. mTORC1 and to a lesser extend mTORC2 promote the proliferation of ILC3s in the small intestine. Upon activation, intestinal ILC3s produce less IFN-γ in the absence of mTOR signaling. During colitis, loss of both mTOR complexes in colonic ILC3s results in the reduced production of inflammatory mediators, recruitment of neutrophils and immunopathology. Similarly, treatment with rapamycin after colitis induction ameliorates the disease. Collectively, our data show a critical role for both mTOR complexes in controlling ILC3 cell numbers and ILC3-driven inflammation in the intestine.

Early use of tocilizumab in patients with severe pneumonia secondary to severe acute respiratory syndrome coronavirus 2 infection and poor prognostic criteria: Impact on mortality rate and intensive care unit admission.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2, keeps spreading globally. Evidence suggests that a subgroup of patients with severe symptomatology might have cytokine storms, which increases mortality. The use of interleukin-6 (IL-6) inhibitors may help in controlling the pathological immune response to the virus. Tocilizumab, a monoclonal antibody against IL-6, stands as an optional treatment for COVID-19 patients presenting this inflammatory hyper-response.We conducted a retrospective, observational, cohort study including 50 patients affected by COVID-19 with severe pneumonia and poor prognosis criteria, who have also undergone standard treatment; 36 of these patients additionally received tocilizumab in an early stage. The need for intensive care unit (ICU) admission, mortality, recovery of respiratory function, and improvement of biochemical and hematological parameters were compared between cohorts.Most patients were men, non-smokers and the most frequently reported comorbidities were hypertension and diabetes. Recurrent symptoms were fever, cough, and dyspnoea. 54.8% of patients from the tocilizumab group needed intubation, while in the control group 85.7% needed it. Treatment with tocilizumab significatively increased IL-6 levels, (554.45; CI 95% 186.69, 1032.93; P < .05) while C-reactive protein mean levels were reduced (–108.19; CI 95% –140.15, –75.33; P < .05), but no significant difference was found between cohorts. In comparison with the controls, tocilizumab reduced mortality (25.0% vs 42.9%, P = .021) and the number of ICU admissions (63.9% vs 100.0%, P = .021). 44.1% of patients treated with tocilizumab showed favorable radiological evolution, when compared with 15.4% of patients from the control group.Tocilizumab may improve clinical symptoms and mitigate deterioration observed in severe COVID-19 patients, and could be considered as an effective therapeutic option in subjects experiencing a significant inflammatory response to the disease.

Neutrophils at the crossroads of acute viral infections and severity

Neutrophils are versatile immune effector cells essential for mounting a first-line defense against invading pathogens. However, uncontrolled activation can lead to severe life-threatening complications. Neutrophils exist as a heterogeneous population, and their interaction with pathogens and other immune cells may shape the outcome of the host immune response. Diverse classes of viruses, including the recently identified novel SARS-CoV-2, have shown to alter the various aspects of neutrophil biology, offering possibilities for selective intervention. Here, we review heterogeneity within the neutrophil population, highlighting the functional consequences of circulating phenotypes and their critical involvement in exaggerating protective and pathological immune responses against the viruses. We discuss the recent findings of neutrophil extracellular traps (NETs) in COVID-19 pathology and cover other viruses, where neutrophil biology and NETs are crucial for developing disease severity. In the end, we have also pointed out the areas where neutrophil-mediated responses can be finely tuned to outline opportunities for therapeutic manipulation in controlling inflammation against viral infection.

Monoclonal Antibodies in Treating Food Allergy: A New Therapeutic Horizon.

Food allergy (FA) is a pathological immune response, potentially deadly, induced by exposure to an innocuous and specific food allergen. To date, there is no specific treatment for FAs; thus, dietary avoidance and symptomatic medications represent the standard treatment for managing them. Recently, several therapeutic strategies for FAs, such as sublingual and epicutaneous immunotherapy and monoclonal antibodies, have shown long-term safety and benefits in clinical practice. This review summarizes the current evidence on changes in treating FA, focusing on monoclonal antibodies, which have recently provided encouraging data as therapeutic weapons modifying the disease course.

The immune regulatory effects of tetrahedral framework nucleic acid on human T cells via the mitogen-activated protein kinase pathway.

ObjectivesAutoimmune diseases are a heterogeneous group of diseases which lose the immunological tolerance to self‐antigens. It is well recognized that irregularly provoked T cells participate in the pathological immune responses. As a novel nanomaterial with promising applications, tetrahedral framework nucleic acid (TFNA) nanostructure was found to have immune regulatory effects on T cells in this study.Materials and MethodsTo verify the successful fabrication of TFNA, the morphology of TFNA was observed by atomic force microscopy (AFM) and dynamic light scattering. The regulatory effect of TFNA was evaluated by flow cytometry after cocultured with CD3+ T cells isolated from healthy donors. Moreover, the associated signaling pathways were investigated. Finally, we verified our results on the T cells from patients with neuromyelitis optica spectrum disorder (NMOSD), which is a typical autoimmune disease induced by T cells.ResultsWe revealed the alternative regulatory functions of TFNA in human primary T cells with steady status via the JNK signaling pathway. Moreover, by inhibiting both JNK and ERK phosphorylation, TFNA exhibited significant suppressive effects on IFNγ secretion from provoking T cells without affecting TNF secretion. Similar immune regulatory effects of TFNA were also observed in autoreactive T cells from patients with NMOSD.ConclusionsOverall, our results revealed a potential application of TFNA in regulating the adaptive immune system, as well as shed a light on the treatment of T cell–mediated autoimmune diseases.

Streptococcus pyogenes ("Group A Streptococcus"), a Highly Adapted Human Pathogen-Potential Implications of Its Virulence Regulation for Epidemiology and Disease Management.

Streptococcus pyogenes (group A streptococci; GAS) is an exclusively human pathogen. It causes a variety of suppurative and non-suppurative diseases in people of all ages worldwide. Not all can be successfully treated with antibiotics. A licensed vaccine, in spite of its global importance, is not yet available. GAS express an arsenal of virulence factors responsible for pathological immune reactions. The transcription of all these virulence factors is under the control of three types of virulence-related regulators: (i) two-component systems (TCS), (ii) stand-alone regulators, and (iii) non-coding RNAs. This review summarizes major TCS and stand-alone transcriptional regulatory systems, which are directly associated with virulence control. It is suggested that this treasure of knowledge on the genetics of virulence regulation should be better harnessed for new therapies and prevention methods for GAS infections, thereby changing its global epidemiology for the better.

Multi-omic profiling reveals widespread dysregulation of innate immunity and hematopoiesis in COVID-19.

Our understanding of protective versus pathological immune responses to SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), is limited by inadequate profiling of patients at the extremes of the disease severity spectrum. Here, we performed multi-omic single-cell immune profiling of 64 COVID-19 patients across the full range of disease severity, from outpatients with mild disease to fatal cases. Our transcriptomic, epigenomic, and proteomic analyses revealed widespread dysfunction of peripheral innate immunity in severe and fatal COVID-19, including prominent hyperactivation signatures in neutrophils and NK cells. We also identified chromatin accessibility changes at NF-κB binding sites within cytokine gene loci as a potential mechanism for the striking lack of pro-inflammatory cytokine production observed in monocytes in severe and fatal COVID-19. We further demonstrated that emergency myelopoiesis is a prominent feature of fatal COVID-19. Collectively, our results reveal disease severity-associated immune phenotypes in COVID-19 and identify pathogenesis-associated pathways that are potential targets for therapeutic intervention.

Modulatory Potential of Cannabidiol on the Opioid-Induced Inflammatory Response.

Opioids are effective analgesics; however, there are many negative consequences of chronic use. One important side effect of chronic opioid use is the continuous engagement of the immune response that can exacerbate chronic pain. The opioid, morphine, initiates a Toll-like receptor 4 (TLR4) signaling cascade that drives the activation of NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome proteins, resulting in cytokine production and effectively creating a positive feedback loop for continuous TLR4 activation. In addition to driving cytokine production, morphine drives changes in proinflammatory lipid signaling. The alteration of both cytokine and lipid signaling systems by morphine suggests that its chronic use leads to a pathological immune response that would benefit from targeted therapy. Engaging the endogenous cannabinoid system has shown therapeutic benefit, particularly regarding its anti-inflammatory and immunosuppressive effects. Promising preclinical and clinical investigations suggest that cannabidiol (CBD) is an effective adjuvant for treatment of symptoms of opioid use disorders; however, the mechanism through which CBD drives this outcome is unclear. One potential source of insight into this mechanism is in how CBD regulates immune regulators such as cytokines and lipid signaling systems, including endocannabinoids and related immune-responsive lipids. In this review, we outline the immune response to chronic opioid use as well as CBD in the context of a lipopolysaccharide-induced immune response and speculate on the mechanism of CBD as a modulator of chronic opioid-induced immune system dysregulation.