Protective Effects and Mechanisms of Huangqi Decoction Against Radiation-Induced Bystander Effects / Efectos Protectores y Mecanismos de la Decocción de Huangqi Contra los Efectos Secundarios Inducidos por la Radiación

SUMMARY: The 12C6+ heavy ion beam irradiation can cause bystander effects. The inflammatory cytokines, endocrine hormones and apoptotic proteins may be involved in 12C6+ irradiation-induced bystander effects. This study characterized the protective effects and mechanisms of Huangqi decoction (HQD) against 12C6+ radiation induced bystander effects. Wistar rats were randomly divided into control, 12C6+ heavy ion irradiation model, and high-dose/medium-dose/low-dose HQD groups. HE staining assessed the pathological changes of brain and kidney. Peripheral blood chemical indicators as well as inflammatory factors and endocrine hormones were detected. Apoptosis was measured with TUNEL. Proliferating cell nuclear antigen (PCNA) expression was determined with real-time PCR and Western blot.Irradiation induced pathological damage to the brain and kidney tissues. After irradiation, the numbers of white blood cells (WBC) and monocyte, and the expression of interleukin (IL)-2, corticotropin-releasing hormone (CRH) and PCNA decreased. The damage was accompanied by increased expression of IL-1β, IL-6, corticosterone (CORT) and adrenocorticotropic hormone (ACTH) as well as increased neuronal apoptosis. These effects were indicative of radiation-induced bystander effects. Administration of HQD attenuated the pathological damage to brain and kidney tissues, and increased the numbers of WBC, neutrophils, lymphocyte and monocytes, as well as the expression of IL-2, CRH and PCNA. It also decreased the expression of IL-1β, IL-6, CORT and ACTH as well as neuronal apoptosis. HQD exhibits protective effects against 12C6+ radiation-induced bystander effects. The underlying mechanism may involve the promotion of the production of peripheral blood cells, inhibition of inflammatory factors and apoptosis, and regulation of endocrine hormones.

La irradiación con haz de iones pesados 12C6+ puede provocar efectos secundarios. Las citoquinas inflamatorias, las hormonas endocrinas y las proteínas apoptóticas pueden estar involucradas en los efectos secundarios inducidos por la irradiación 12C6+. Este estudio caracterizó los efectos y mecanismos protectores de la decocción de Huangqi (HQD) contra los efectos externos inducidos por la radiación 12C6+. Las ratas Wistar se dividieron aleatoriamente en grupos control, modelo de irradiación de iones pesados 12C6+ y grupos de dosis alta/media/baja de HQD. La tinción con HE evaluó los cambios patológicos del cerebro y el riñón. Se detectaron indicadores químicos de sangre periférica, así como factores inflamatorios y hormonas endocrinas. La apoptosis se midió con TUNEL. La expresión del antígeno nuclear de células en proliferación (PCNA) se determinó mediante PCR en tiempo real y transferencia Western blot. La irradiación indujo daños patológicos en los tejidos cerebrales y renales. Después de la irradiación, disminuyó el número de glóbulos blancos (WBC) y monocitos, y la expresión de interleucina (IL)-2, hormona liberadora de corticotropina (CRH) y PCNA. El daño estuvo acompañado por una mayor expresión de IL-1β, IL-6, corticosterona (CORT) y hormona adrenocorticotrópica (ACTH), así como un aumento de la apoptosis neuronal. Estas alteraciones fueron indicativas de efectos inducidos por la radiación. La administración de HQD atenuó el daño patológico a los tejidos cerebrales y renales, y aumentó el número de leucocitos y monocitos, así como la expresión de IL-2, CRH y PCNA. También disminuyó la expresión de IL-1β, IL-6, CORT y ACTH, así como la apoptosis neuronal. HQD exhibe mecanismos protectores contra los efectos externos inducidos por la radiación 12C6+. El mecanismo subyacente puede implicar la promoción de la producción de células sanguíneas periféricas, la inhibición de factores inflamatorios y la apoptosis y la regulación de hormonas endocrinas.

Association of Antibiotic Exposure With Survival and Toxicity in Patients With Melanoma Receiving Immunotherapy.

BACKGROUND: Gut microbial diversity is associated with improved response to immune checkpoint inhibitors (ICI). Based on the known detrimental impact that antibiotics have on microbiome diversity, we hypothesized that antibiotic receipt prior to ICI would be associated with decreased survival. METHODS: Patients with stage III and IV melanoma treated with ICI between 2008 and 2019 were selected from an institutional database. A window of antibiotic receipt within 3 months prior to the first infusion of ICI was prespecified. The primary outcome was overall survival (OS), and secondary outcomes were melanoma-specific mortality and immune-mediated colitis requiring intravenous steroids. All statistical tests were two-sided. RESULTS: There were 568 patients in our database of which 114 received antibiotics prior to ICI. Of the patients, 35.9% had stage III disease. On multivariable Cox proportional hazards analysis of patients with stage IV disease, the antibiotic-exposed group had statistically significantly worse OS (hazard ratio [HR] = 1.81, 95% confidence interval [CI] = 1.27 to 2.57; P <.001). The same effect was observed among antibiotic-exposed patients with stage III disease (HR = 2.78, 95% CI = 1.31 to 5.87; P =.007). When limited to only patients who received adjuvant ICI (n = 89), antibiotic-exposed patients also had statistically significantly worse OS (HR = 4.84, 95% CI = 1.09 to 21.50; P =.04). The antibiotic group had a greater incidence of colitis (HR = 2.14, 95% CI = 1.02 to 4.52; P =.046). CONCLUSION: Patients with stage III and IV melanoma exposed to antibiotics prior to ICI had statistically significantly worse OS than unexposed patients. Antibiotic exposure was associated with greater incidence of moderate to severe immune-mediated colitis. Given the large number of antibiotics prescribed annually, physicians should be judicious with their use in cancer populations likely to receive ICI.

Immune Checkpoints in Viral Infections.

As evidence has mounted that virus-infected cells, such as cancer cells, negatively regulate the function of T-cells via immune checkpoints, it has become increasingly clear that viral infections similarly exploit immune checkpoints as an immune system escape mechanism. Although immune checkpoint therapy has been successfully used in cancer treatment, numerous studies have suggested that such therapy may also be highly relevant for treating viral infection, especially chronic viral infections. However, it has not yet been applied in this manner. Here, we reviewed recent findings regarding immune checkpoints in viral infections, including COVID-19, and discussed the role of immune checkpoints in different viral infections, as well as the potential for applying immune checkpoint blockades as antiviral therapy.

Integrating Immunotherapy and Targeted Therapy in Cancer Treatment: Mechanistic Insights and Clinical Implications.

Small-molecule targeted therapies have demonstrated outstanding potential in the clinic. These drugs are designed to minimize adverse effects by selectively attacking cancer cells while exerting minimal damage to normal cells. Although initial response to targeted therapies may be high, yielding positive response rates and often improving survival for an important percentage of patients, resistance often limits long-term effectiveness. On the other hand, immunotherapy has demonstrated durable results, yet for a limited number of patients. Growing evidence indicates that some targeted agents can modulate different components of the antitumor immune response. These include immune sensitization by inhibiting tumor cell-intrinsic immune evasion programs or enhancing antigenicity, as well as direct effects on immune effector and immunosuppressive cells. The combination of these two approaches, therefore, has the potential to result in synergistic and durable outcomes for patients. In this review, we focus on the latest advances on integrating immunotherapy with small-molecule targeted inhibitors. In particular, we discuss how specific oncogenic events differentially affect immune response, and the implications of these findings on the rational design of effective combinations of immunotherapy and targeted therapies.

Neutralizing Complement C5a Protects Mice with Pneumococcal Pulmonary Sepsis.

BACKGROUND: Community-acquired pneumonia and associated sepsis cause high mortality despite antibiotic treatment. Uncontrolled inflammatory host responses contribute to the unfavorable outcome by driving lung and extrapulmonary organ failure. The complement fragment C5a holds significant proinflammatory functions and is associated with tissue damage in various inflammatory conditions. The authors hypothesized that C5a concentrations are increased in pneumonia and C5a neutralization promotes barrier stabilization in the lung and is protective in pneumococcal pulmonary sepsis. METHODS: The authors investigated regulation of C5a in pneumonia in a prospective patient cohort and in experimental pneumonia. Two complementary models of murine pneumococcal pneumonia were applied. Female mice were treated with NOX-D19, a C5a-neutralizing L-RNA-aptamer. Lung, liver, and kidney injury and the inflammatory response were assessed by measuring pulmonary permeability (primary outcome), pulmonary and blood leukocytes, cytokine concentrations in lung and blood, and bacterial load in lung, spleen, and blood, and performing histologic analyses of tissue damage, apoptosis, and fibrin deposition (n = 5 to 13). RESULTS: In hospitalized patients with pneumonia (n = 395), higher serum C5a concentrations were observed compared to healthy subjects (n = 24; 6.3 nmol/l [3.9 to 10.0] vs. 4.5 nmol/l [3.8 to 6.6], median [25 to 75% interquartile range]; difference: 1.4 [95% CI, 0.1 to 2.9]; P = 0.029). Neutralization of C5a in mice resulted in lower pulmonary permeability in pneumococcal pneumonia (1.38 ± 0.89 vs. 3.29 ± 2.34, mean ± SD; difference: 1.90 [95% CI, 0.15 to 3.66]; P = 0.035; n = 10 or 11) or combined severe pneumonia and mechanical ventilation (2.56 ± 1.17 vs. 7.31 ± 5.22; difference: 4.76 [95% CI, 1.22 to 8.30]; P = 0.011; n = 9 or 10). Further, C5a neutralization led to lower blood granulocyte colony-stimulating factor concentrations and protected against sepsis-associated liver injury. CONCLUSIONS: Systemic C5a is elevated in pneumonia patients. Neutralizing C5a protected against lung and liver injury in pneumococcal pneumonia in mice. Early neutralization of C5a might be a promising adjunctive treatment strategy to improve outcome in community-acquired pneumonia.

Immune checkpoint inhibitors and tuberculosis: an old disease in a new context.

Tuberculosis, the leading cause of infection-related death in developing regions, is a leading cause of morbidity and mortality worldwide. Screening for, and treatment of, latent Mycobacterium tuberculosis infection is routine before initiation of anti-tumour necrosis factor α (anti-TNFα) agents in the management of psoriasis, Crohn's disease, and rheumatoid arthritis. By contrast, screening for latent tuberculosis before immune checkpoint inhibitor treatment in cancer is not routine, despite the increasing number of reports of primary infection with M tuberculosis or reactivation of latent M tuberculosis infection during such treatment. We present our experience with M tuberculosis screening in 70 patients who underwent immune checkpoint inhibitor therapy for metastatic skin cancer. Based on our understanding of the interaction between M tuberculosis and the immune system, we present the argument for tuberculosis screening before immune checkpoint inhibitor therapy and its use when considering anti-TNFα treatment for severe immune-related adverse events. We call for increased vigilance during immune checkpoint inhibition until its effects on tuberculosis pathophysiology are fully ascertained.

Tumor immune microenvironment modulation-based drug delivery strategies for cancer immunotherapy.

The past years have witnessed promising clinical feedback for anti-cancer immunotherapies, which have become one of the hot research topics; however, they are limited by poor delivery kinetics, narrow patient response profiles, and systemic side effects. To the best of our knowledge, the development of cancer is highly associated with the immune system, especially the tumor immune microenvironment (TIME). Based on the comprehensive understanding of the complexity and diversity of TIME, drug delivery strategies focused on the modulation of TIME can be of great significance for directing and improving cancer immunotherapy. This review highlights the TIME modulation in cancer immunotherapy and summarizes the versatile TIME modulation-based cancer immunotherapeutic strategies, medicative principles and accessory biotechniques for further clinical transformation. Remarkably, the recent advances of cancer immunotherapeutic drug delivery systems and future prospects of TIME modulation-based drug delivery systems for much more controlled and precise cancer immunotherapy will be emphatically discussed.

Pathogen Evasion of Chemokine Response Through Suppression of CXCL10.

Clearance of intracellular pathogens, such as Leishmania (L.) major, depends on an immune response with well-regulated cytokine signaling. Here we describe a pathogen-mediated mechanism of evading CXCL10, a chemokine with diverse antimicrobial functions, including T cell recruitment. Infection with L. major in a human monocyte cell line induced robust CXCL10 transcription without increasing extracellular CXCL10 protein concentrations. We found that this transcriptionally independent suppression of CXCL10 is mediated by the virulence factor and protease, glycoprotein-63 (gp63). Specifically, GP63 cleaves CXCL10 after amino acid A81 at the base of a C-terminal alpha-helix. Cytokine cleavage by GP63 demonstrated specificity, as GP63 cleaved CXCL10 and its homologs, which all bind the CXCR3 receptor, but not distantly related chemokines, such as CXCL8 and CCL22. Further characterization demonstrated that CXCL10 cleavage activity by GP63 was produced by both extracellular promastigotes and intracellular amastigotes. Crucially, CXCL10 cleavage impaired T cell chemotaxis in vitro, indicating that cleaved CXCL10 cannot signal through CXCR3. Ultimately, we propose CXCL10 suppression is a convergent mechanism of immune evasion, as Salmonella enterica and Chlamydia trachomatis also suppress CXCL10. This commonality suggests that counteracting CXCL10 suppression may provide a generalizable therapeutic strategy against intracellular pathogens. Importance: Leishmaniasis, an infectious disease that annually affects over one million people, is caused by intracellular parasites that have evolved to evade the host's attempts to eliminate the parasite. Cutaneous leishmaniasis results in disfiguring skin lesions if the host immune system does not appropriately respond to infection. A family of molecules called chemokines coordinate recruitment of the immune cells required to eliminate infection. Here, we demonstrate a novel mechanism that Leishmania (L.) spp. employ to suppress host chemokines: a Leishmania-encoded protease cleaves chemokines known to recruit T cells that fight off infection. We observe that other common human intracellular pathogens, including Chlamydia trachomatis and Salmonella enterica, reduce levels of the same chemokines, suggesting a strong selective pressure to avoid this component of the immune response. Our study provides new insights into how intracellular pathogens interact with the host immune response to enhance pathogen survival.

Leptin and Its Derivatives: A Potential Target for Autoimmune Diseases.

Leptin is an adipocyte-derived hormone product of the obese (ob) gene. Leptin plays an important regulatory role as an immunomodulatory factor in the maintenance and homeostasis of immune functions. Indeed, the role of leptin as an immunomodulator in inflammatory and immune responses has attracted increasing attention in recent years. Leptin mostly affects responses through the immunomodulation of monocytes, dendritic cells, neutrophils, NK cells, and dendritic cells in addition to modulating T and B cell development and functions. Leptin is also an important inflammatory regulator, wherein higher expression influences the secretion rates of IL-6, C-reactive proteins, and TNF-α. Moreover, leptin is highly involved in processes related to human metabolism, inflammatory reactions, cellular development, and diseases, including hematopoiesis. Owing to its diverse immunerelated functions, leptin has been explored as a potential target for therapeutic development in the treatment of autoimmune diseases.

CD69 Targeting Enhances Anti-vaccinia Virus Immunity.

CD69 is highly expressed on the leukocyte surface upon viral infection, and its regulatory role in the vaccinia virus (VACV) immune response has been recently demonstrated using CD69-/- mice. Here, we show augmented control of VACV infection using the anti-human CD69 monoclonal antibody (MAb) 2.8 as both preventive and therapeutic treatment for mice expressing human CD69. This control was related to increased natural killer (NK) cell reactivity and increased numbers of cytokine-producing T and NK cells in the periphery. Moreover, similarly increased immunity and protection against VACV were reproduced over both long and short periods in anti-mouse CD69 MAb 2.2-treated immunocompetent wild-type (WT) mice and immunodeficient Rag2-/- CD69+/+ mice. This result was not due to synergy between infection and anti-CD69 treatment since, in the absence of infection, anti-human CD69 targeting induced immune activation, which was characterized by mobilization, proliferation, and enhanced survival of immune cells as well as marked production of several innate proinflammatory cytokines by immune cells. Additionally, we showed that the rapid leukocyte effect induced by anti-CD69 MAb treatment was dependent on mTOR signaling. These properties suggest the potential of CD69-targeted therapy as an antiviral adjuvant to prevent derived infections.IMPORTANCE In this study, we demonstrate the influence of human and mouse anti-CD69 therapies on the immune response to VACV infection. We report that targeting CD69 increases the leukocyte numbers in the secondary lymphoid organs during infection and improves the capacity to clear the viral infection. Targeting CD69 increases the numbers of gamma interferon (IFN-γ)- and tumor necrosis factor alpha (TNF-α)-producing NK and T cells. In mice expressing human CD69, treatment with an anti-CD69 MAb produces increases in cytokine production, survival, and proliferation mediated in part by mTOR signaling. These results, together with the fact that we have mainly worked with a human-CD69 transgenic model, reveal CD69 as a treatment target to enhance vaccine protectiveness.

Suppression of Stromal Interferon Signaling by Human Papillomavirus 16.

Human papillomaviruses (HPVs) infect squamous epithelia and cause several important cancers. Immune evasion is critical for viral persistence. Fibroblasts in the stromal microenvironment provide growth signals and cytokines that are required for proper epithelial differentiation, maintenance, and immune responses and are critical in the development of many cancers. In this study, we examined the role of epithelial-stromal interactions in the HPV16 life cycle using organotypic (raft) cultures as a model. Rafts were created using uninfected human foreskin keratinocytes (HFKs) and HFKs containing either wild-type HPV16 or HPV16 with a stop mutation to prevent the expression of the viral oncogene E5. Microarray analysis revealed significant changes in gene expression patterns in the stroma in response to HPV16, some of which were E5 dependent. Interferon (IFN)-stimulated genes (ISGs) and extracellular matrix remodeling genes were suppressed, the most prominent pathways affected. STAT1, IFNAR1, IRF3, and IRF7 were knocked down in stromal fibroblasts using lentiviral short hairpin RNA (shRNA) transduction. HPV late gene expression and viral copy number in the epithelium were increased when the stromal IFN pathway was disrupted, indicating that the stroma helps control the late phase of the HPV life cycle in the epithelium. Increased late gene expression correlated with increased late keratinocyte differentiation but not decreased IFN signaling in the epithelium. These studies show HPV16 has a paracrine effect on stromal innate immunity, reveal a new role for E5 as a stromal innate immune suppressor, and suggest that stromal IFN signaling may influence keratinocyte differentiation.IMPORTANCE The persistence of high-risk human papillomavirus (HPV) infections is the key risk factor for developing HPV-associated cancers. The ability of HPV to evade host immunity is a critical component of its ability to persist. The environment surrounding a tumor is increasingly understood to be critical in cancer development, including immune evasion. Our studies show that HPV can suppress the expression of immune-related genes in neighboring fibroblasts in a three-dimensional (3D) model of human epithelium. This finding is significant, because it indicates that HPV can control innate immunity not only in the infected cell but also in the microenvironment. In addition, the ability of HPV to regulate stromal gene expression depends in part on the viral oncogene E5, revealing a new function for this protein as an immune evasion factor.

Wound Healing Potential of the Standardized Extract of Boswellia serrata on Experimental Diabetic Foot Ulcer via Inhibition of Inflammatory, Angiogenetic and Apoptotic Markers.

The aim of the present study was to evaluate the wound healing potential and possible mechanism of action of the standardized extract of Boswellia serrata against the experimental model of diabetic foot ulcer. α-Boswellic acid was isolated from the standardized extract of B. serrata and characterized (HPLC, 1H-NMR, 13C-NMR, ESI-MS). Diabetes was induced in Sprague-Dawley rats by streptozotocin (55 mg/kg, i. p.), and wounds were created on the dorsal surface of the hind paw. B. serrata (100, 200, and 400 mg/kg, p. o.) was administered to the rats for 16 days. The HPLC analysis showed a single peak with a retention time of 12.51 min. The compound was identified with ESI-MS [M + Na]+ = 455.37 as α-boswellic acid. Treatment with B. serrata (200 and 400 mg/kg) significantly increased the rate of wound contraction via modulation of oxido-nitrosative stress and elevated the hydroxyproline level at the wound area. reverse transcription-PCR analysis revealed that streptozotocin-induced increases in TNF-α, interleukin-1ß, interleukin-6, nuclear factor-kappa-light-chain-enhancer of activated B cells, and Bcl-2-associated X protein, and decreases in angiopoietin-1, Tie2, transforming growth factor beta 1, vascular endothelial growth factor, and collagen-1 mRNA expression were significantly inhibited by B. serrata. It also significantly reduced wound cellular necrosis as evaluated by flow cytometry using propidium iodide fluorescence intensity. Streptozotocin-induced histopathological alterations were also significantly ameliorated by B. serrata. In conclusion, standardized extracts of B. serrata exert its wound healing potential via orchestrating mechanisms, which include the inhibition of oxido-inflammatory markers (oxido-nitrosative stress, TNF-α, interleukins, and nuclear factor-kappa-light-chain-enhancer of activated B cells), increased collagen synthesis (hydroxyproline and collagen-1) and angiogenesis (Ang-1/Tie2), promoting growth factors (transforming growth factor beta 1 and vascular endothelial growth factor), and inhibition of apoptosis (Bcl-2-associated X protein) to accelerate wound healing in experimental delayed diabetic foot ulcer.

An update on enterovirus 71 infection and interferon type I response.

Enteroviruses are members of Pichornaviridae family consisting of human enterovirus group A, B, C, and D as well as nonhuman enteroviruses. Hand, foot, and mouth disease (HFMD) is a serious disease which is usually seen in the Asia-Pacific region in children. Enterovirus 71 and coxsackievirus A16 are two important viruses responsible for HFMD which are members of group A enterovirus. IFN α and ß are two cytokines, which have a major activity in the innate immune system against viral infections. Most of the viruses have some weapons against these cytokines. EV71 has two main proteases called 2A and 3C, which are important for polyprotein processing and virus maturation. Several studies have indicated that they have a significant effect on different cellular pathways such as interferon production and signaling pathway. The aim of this study was to investigate the latest findings about the interaction of 2A and 3C protease of EV71 and IFN production/signaling pathway and their inhibitory effects on this pathway.

GM-CSF targeted immunomodulation affects host response to M. tuberculosis infection.

Host directed immunomodulation represents potential new adjuvant therapies in infectious diseases such as tuberculosis. Major cytokines like TNFα exert a multifold role in host control of mycobacterial infections. GM-CSF and its receptor are over-expressed during acute M. tuberculosis infection and we asked how GM-CSF neutralization might affect host response, both in immunocompetent and in immunocompromised TNFα-deficient mice. GM-CSF neutralizing antibodies, at a dose effectively preventing acute lung inflammation, did not affect M. tuberculosis bacterial burden, but increased the number of granuloma in wild-type mice. We next assessed whether GM-CSF neutralization might affect the control of M. tuberculosis by isoniazid/rifampicin chemotherapy. GM-CSF neutralization compromised the bacterial control under sub-optimal isoniazid/rifampicin treatment in TNFα-deficient mice, leading to exacerbated lung inflammation with necrotic granulomatous structures and high numbers of intracellular M. tuberculosis bacilli. In vitro, GM-CSF neutralization promoted M2 anti-inflammatory phenotype in M. bovis BCG infected macrophages, with reduced mycobactericidal NO production and higher intracellular M. bovis BCG burden. Thus, GM-CSF pathway overexpression during acute M. tuberculosis infection contributes to an efficient M1 response, and interfering with GM-CSF pathway in the course of infection may impair the host inflammatory response against M. tuberculosis.

Blockade of the C5a-C5aR axis alleviates lung damage in hDPP4-transgenic mice infected with MERS-CoV.

The pathogenesis of highly pathogenic Middle East respiratory syndrome coronavirus (MERS-CoV) remains poorly understood. In a previous study, we established an hDPP4-transgenic (hDPP4-Tg) mouse model in which MERS-CoV infection causes severe acute respiratory failure and high mortality accompanied by an elevated secretion of cytokines and chemokines. Since excessive complement activation is an important factor that contributes to acute lung injury after viral infection, in this study, we investigated the role of complement in MERS-CoV-induced lung damage. Our study showed that complement was excessively activated in MERS-CoV-infected hDPP4-Tg mice through observations of increased concentrations of the C5a and C5b-9 complement activation products in sera and lung tissues, respectively. Interestingly, blocking C5a production by targeting its receptor, C5aR, alleviated lung and spleen tissue damage and reduced inflammatory responses. More importantly, anti-C5aR antibody treatment led to decreased viral replication in lung tissues. Furthermore, compared with the sham treatment control, apoptosis of splenic cells was less pronounced in the splenic white pulp of treated mice, and greater number of proliferating splenic cells, particularly in the red pulp, was observed. These data indicate that (1) dysregulated host immune responses contribute to the severe outcome of MERS; (2) excessive complement activation, triggered by MERS-CoV infection, promote such dysregulation; and (3) blockade of the C5a-C5aR axis lead to the decreased tissue damage induced by MERS-CoV infection, as manifested by reduced apoptosis and T cell regeneration in the spleen. Therefore, the results of this study suggest a new strategy for clinical intervention and adjunctive treatment in MERS-CoV cases.

Grass Carp Reovirus VP41 Targets Fish MITA To Abrogate the Interferon Response.

Although fish possess an efficient interferon (IFN) system to defend against aquatic virus infection, grass carp reovirus (GCRV) still causes hemorrhagic disease in grass carp. To date, GCRV's strategy for evading the fish IFN response is still unknown. Here, we report that GCRV VP41 inhibits fish IFN production by suppressing the phosphorylation of mediator of IFN regulatory factor 3 (IRF3) activation (MITA). First, the activation of the IFN promoter (IFNpro) stimulated by mitochondrial antiviral signaling protein (MAVS) and MITA was decreased by the overexpression of VP41, whereas such activation induced by TANK-binding kinase 1 (TBK1) was not affected. Second, VP41 was colocalized in the cellular endoplasmic reticulum (ER) and associated with MITA. Furthermore, as a phosphorylation substrate of TBK1, VP41 significantly decreased the phosphorylation of MITA. Truncation assays indicated that the transmembrane (TM) region of VP41 was indispensable for the suppression of IFNpro activity. Finally, after infection with GCRV, VP41 blunted the transcription of host IFN and facilitated viral RNA synthesis. Taken together, our findings suggest that GCRV VP41 prevents the fish IFN response by attenuating the phosphorylation of MITA for viral evasion.IMPORTANCE MITA is thought to act as an adaptor protein to facilitate the phosphorylation of IRF3 by TBK1 upon viral infection, and it plays a critical role in innate antiviral responses. Here, we report that GCRV VP41 colocalizes with MITA at the ER and reduces MITA phosphorylation by acting as a decoy substrate of TBK1, thus inhibiting IFN production. These findings reveal GCRV's strategy for evading the host IFN response for the first time.

Complement inhibition by Sarcoptes scabiei protects Streptococcus pyogenes - An in vitro study to unravel the molecular mechanisms behind the poorly understood predilection of S. pyogenes to infect mite-induced skin lesions.

BACKGROUND: On a global scale scabies is one of the most common dermatological conditions, imposing a considerable economic burden on individuals, communities and health systems. There is substantial epidemiological evidence that in tropical regions scabies is often causing pyoderma and subsequently serious illness due to invasion by opportunistic bacteria. The health burden due to complicated scabies causing cellulitis, bacteraemia and sepsis, heart and kidney diseases in resource-poor communities is extreme. Co-infections of group A streptococcus (GAS) and scabies mites is a common phenomenon in the tropics. Both pathogens produce multiple complement inhibitors to overcome the host innate defence. We investigated the relative role of classical (CP), lectin (LP) and alternative pathways (AP) towards a pyodermic GAS isolate 88/30 in the presence of a scabies mite complement inhibitor, SMSB4. METHODOLOGY/PRINCIPAL FINDINGS: Opsonophagocytosis assays in fresh blood showed baseline immunity towards GAS. The role of innate immunity was investigated by deposition of the first complement components of each pathway, specifically C1q, FB and MBL from normal human serum on GAS. C1q deposition was the highest followed by FB deposition while MBL deposition was undetectable, suggesting that CP and AP may be mainly activated by GAS. We confirmed this result using sera depleted of either C1q or FB, and serum deficient in MBL. Recombinant SMSB4 was produced and purified from Pichia pastoris. SMSB4 reduced the baseline immunity against GAS by decreasing the formation of CP- and AP-C3 convertases, subsequently affecting opsonisation and the release of anaphylatoxin. CONCLUSIONS/SIGNIFICANCE: Our results indicate that the complement-inhibitory function of SMSB4 promotes the survival of GAS in vitro and inferably in the microenvironment of the mite-infested skin. Understanding the tripartite interactions between host, parasite and microbial pathogens at a molecular level may serve as a basis to develop improved intervention strategies targeting scabies and associated bacterial infections.

[Drug therapy of lymphomas]. / A limfómák gyógyszeres terápiája.

The therapy of lymphomas has undergone a major expansion during the last decade. Novel therapeutic targets have appeared beyond classical chemotherapeutic combinations. These novel drugs have very pronounced action across lymphoma types, and their toxicity profile is usually better tolerable compared to standard chemotherapies. These new therapies are enabling us to offer treatment to those patients who have refractory disease, and we had no option to treat them before these drugs. The author describes several new therapeutic options. New chemotherapeutic drugs are pixantrone and bendamustin. Monoclonal antibodies, like rituximab, ofatumumab, obinotuzumab are described, and conjugated antibodies like brentuximab vedotin and inotuzumab ozogamicin are also discussed. The bispecific antibody blinatumomab can modulate the immune response, and the new class of immune checkpoint inhibitors (pembrolizumab, nivolumab) is also discussed. Therapies targeting the epigenetic regulatory network are also important. Several studies reported promising results of abexinostat, vorinostat, belinostat and panobinostat. The new class of immunomodulatory drugs (imids) is also growing, results with thalidomid and lenalidomid are discussed. The proteasome inhibitors are offering new combinations, with the use of bortezomid, carfilzomib, ixazomib. All these new drugs described above offer to the physician several therapeutic options to better treat patients with lymphoma.

Control of immune ligands by members of a cytomegalovirus gene expansion suppresses natural killer cell activation.

The human cytomegalovirus (HCMV) US12 family consists of ten sequentially arranged genes (US12-21) with poorly characterized function. We now identify novel natural killer (NK) cell evasion functions for four members: US12, US14, US18 and US20. Using a systematic multiplexed proteomics approach to quantify ~1300 cell surface and ~7200 whole cell proteins, we demonstrate that the US12 family selectively targets plasma membrane proteins and plays key roles in regulating NK ligands, adhesion molecules and cytokine receptors. US18 and US20 work in concert to suppress cell surface expression of the critical NKp30 ligand B7-H6 thus inhibiting NK cell activation. The US12 family is therefore identified as a major new hub of immune regulation.

A Three-Day Consecutive Fingolimod Administration Improves Neurological Functions and Modulates Multiple Immune Responses of CCI Mice.

Excessive inflammation after traumatic brain injury (TBI) is a major cause of secondary TBI. Though several inflammatory biomarkers have been postulated as the risk factors of TBI, there has not been any comprehensive description of them. Fingolimod, a new kind of immunomodulatory agent which can diminish various kinds of inflammatory responses, has shown additional therapeutic effects in the treatment of intracranial cerebral hematoma (ICH), ischemia, spinal cord injury (SCI), and many other CNS disorders. However, its therapeutic application has not been confirmed in TBI. Thus, we hypothesized that a 3-day consecutive fingolimod administration could broadly modulate the inflammatory reactions and improve the outcomes of TBI. The TBI models of C57/BL6 mice were established with the controlled cortical impact injury (CCI) system. A 3-day consecutive fingolimod therapy (given at 1, 24, and 48 h post injury) was performed at a dose of 1 mg/kg. The flow cytometry, immunoflourence, cytokine array, and ELISA were all applied to evaluate the immune cells and inflammatory markers in the injured brains. Immunohistochemical staining with anti-APP antibody was performed to assess the axonal damage. The neurological functions of these TBI models were assessed by mNSS/Rota-rod and Morris water maze (MWM). The brain water content and integrity of the blood-brain barrier (BBB) were also observed. On the 3rd day after TBI, the accumulation of inflammatory cytokines and chemokines reached the peak and administration of fingolimod reduced as many as 20 kinds of cytokines and chemokines. Fingolimod decreased infiltrated T lymphocytes and NK cells but increased the percentage of regulatory T (Treg) cells, and the concentration of IL-10 on the 3rd day after TBI. Fingolimod also notably attenuated the general activated microglia but augmented the M2/M1 ratio accompanied by decreased axonal damage. The neurological functions were improved after the fingolimod treatment accompanied with alleviation of the brain edema and BBB damage. This study suggests that the 3-day consecutive fingolimod administration extensively modulates multiple immuno-inflammatory responses and improves the neurological deficits after TBI, and therefore, it may be a new approach to the treatment of secondary TBI.