Effective Immune Response Research Articles

Prostaglandin D2 delays CD8+ T-cell responses and respiratory syncytial virus clearance in geriatric cotton rats.

Respiratory syncytial virus (RSV) infection is associated with increased rates of severe disease, hospitalization, and death in elderly individuals. Clearance of RSV is frequently delayed within this demographic, contributing to the more severe disease course. Geriatric cotton rats mimic this prolonged clearance kinetic and serve as a useful animal model for studying age-associated immunological deficits during RSV infection. Treatment with the cyclooxygenase (COX) inhibitor ibuprofen restores RSV clearance, indicating that inflammation contributes to impaired clearance in geriatric cotton rats. Here, we further characterize a compromised immune response in geriatric cotton rats and identify an inflammatory pathway that contributes to this deficiency. Dendritic cell (DC) activation and migration to mediastinal lymph nodes are decreased during early infection in geriatric cotton rats, resulting in delayed generation of cytotoxic T cells and virus clearance. Prostaglandin D2 (PGD2), which reduces DC migration through the elevation of D-type prostanoid 1 receptor (DP1 receptor), is elevated in the airways of infected geriatric cotton rats. Reducing PGD2 production by inhibiting COX-2 or PGD2 synthase improves RSV clearance kinetics through DC activation and RSV-specific CD8+ T-cell responses in geriatric cotton rats, whereas activation of DP1 receptor through an agonist resulted in delayed viral clearance in adult cotton rats. These results indicate that PGD2 contributes to delayed antigen presentation and CD8+ T-cell responses to RSV in geriatric cotton rats. Inhibiting PGD2 generation or signaling may be a useful mechanism of therapeutic intervention in elderly individuals.IMPORTANCEElderly adults are at increased risk of severe disease resulting from infection with respiratory syncytial virus (RSV), characterized in part by delayed clearance (removal of the virus from airways). Understanding the immunological factors that lead to this delayed clearance may allow for the development of therapies to improve disease outcomes in elderly individuals infected with RSV and other respiratory viruses. Here, we describe an inflammatory pathway in geriatric cotton rats, the preferred small animal laboratory model for RSV, that impairs the generation of an effective immune response. We show that inhibiting this inflammatory pathway in geriatric cotton rats improves immune parameters and speeds clearance of RSV. These results contribute to our understanding of delayed RSV clearance in elderly individuals with possible applications for improving immune responses to RSV in clinical settings.

EVALUATION OF POPULATION-LEVEL IMMUNITY TO SARS-COV-2 ACROSS BULGARIA (END OF 2023)

Background: The COVID-19 pandemic in Bulgaria was characterized by a high mortality rate and vaccination efforts yielded suboptimal results. Understanding population immunity is important as new SARS-CoV-2 variants continue to emerge. This study aimed to assess the seroprevalence of SARS-CoV-2 antibodies in the general population of Bulgaria and examine demographic variations in antibody presence. Materials and methods: In December 2023, 1895 serum samples were randomly collected from healthy individuals across all 28 provinces. Samples were tested for SARS-CoV-2 spike protein-specific IgG antibodies using ELISA method. A subset of the positive samples was subsequently tested for neutralizing antibodies. Seroprevalence was analyzed by sex, age group, and geographic region. Statistical analyses were conducted using SPSS v.26. Results: Overall seroprevalence was 91.9%, with similar rates between males (91.6%) and females (92.0%). Seroprevalence was highest in the 18-39 age group (95.1%) and lowest in those over 65 (89.3%). Regional seroprevalence ranged from 80.0% to 98.3%. Among samples tested for presence of neutralizing antibodies, 90.5% were positive, indicating effective immune response. Conclusions: The high seroprevalence suggests widespread prior exposure to SARS-CoV-2 and/or vaccination among the Bulgarian population. The strong presence of neutralizing antibodies might provide potential protection against severe disease. Targeted interventions towards older age groups could be appropriate in order to sustain immunity as COVID-19 remains a public health concern.

Comprehensive Analysis of TSPAN32 Regulatory Networks and Their Role in Immune Cell Biology

Tetraspanin 32 (TSPAN32), a member of the tetraspanin superfamily, is one of several tumor-suppressing subtransferable fragments located in the imprinted gene domain of chromosome 11p15.5, a critical tumor-suppressor gene region. Although the biology of TSPAN32 remains largely unexplored, accumulating evidence suggests its involvement in hematopoietic functions. In this study, we performed a comprehensive analysis of the expression patterns and regulatory roles of TSPAN32. Notably, TSPAN32 is highly expressed in immune cells, particularly in natural killer (NK) cells and CD8+ T cells. The observed downregulation of TSPAN32 during immune cell activation highlights its potential role as a regulator of immune cell activation and metabolic adaptations, which are crucial for effective immune responses against pathogens and tumors. Moreover, the modulation of biological processes following TSPAN32 knockout further supports its critical role in regulating immune cell physiology and responses. These findings not only shed light on the biology of TSPAN32 but also provide the basis for exploring its diagnostic, prognostic, and therapeutic potential in autoimmune and inflammatory disorders, as well as in hematopoietic cancers.

Multi-omics integration and immune profiling identify possible causal networks leading to uterine microbiome dysbiosis in dairy cows that develop metritis

BackgroundCows that develop metritis experience dysbiosis of their uterine microbiome, where opportunistic pathogens overtake uterine commensals. An effective immune response is critical for maintaining uterine health. Nonetheless, periparturient cows experience immune dysregulation, which seems to be intensified by prepartum over-condition. Herein, Bayesian networks were applied to investigate the directional correlations between prepartum body weight (BW), BW loss, pre- and postpartum systemic immune profiling and plasma metabolome, and postpartum uterine metabolome and microbiome.ResultsThe Bayesian network analysis showed a positive directional correlation between prepartum BW, prepartum BW loss, and plasma fatty acids at parturition, suggesting that heavier cows were in lower energy balance than lighter cows. There was a positive directional correlation between prepartum BW, prepartum systemic leukocyte death, immune activation, systemic inflammation, and metabolomic changes associated with oxidative stress prepartum and at parturition. Immune activation and systemic inflammation were characterized by increased proportion of circulating polymorphonuclear cells (PMN) prepartum, B-cell activation at parturition, interleukin-8 prepartum and at parturition, and interleukin-1β at parturition. These immune changes together with plasma fatty acids at parturition had a positive directional correlation with PMN extravasation postpartum, which had a positive directional correlation with uterine metabolites associated with tissue damage. These results suggest that excessive PMN migration to the uterus leads to excessive endometrial damage. The aforementioned changes had a positive directional correlation with Fusobacterium, Porphyromonas, and Bacteroides in cows that developed metritis, suggesting that excessive tissue damage may disrupt physical barriers or increase substrate availability for bacterial growth.ConclusionsThis work provides robust mechanistic hypotheses for how prepartum BW may impact peripartum immune and metabolic profiles, which may lead to uterine opportunistic pathogens overgrowth and metritis development.

In Silico-Guided Discovery of Polysaccharide Derivatives as Adjuvants in Nanoparticle Vaccines for Cancer Immunotherapy.

Cancer vaccines utilizing nanoparticle (NP) structures that integrate antigens and adjuvants to enhance delivery and stimulate immune responses are emerging as a promising avenue in cancer immunotherapy. However, the development of cancer vaccines has been significantly hindered by the low immunogenicity of tumor antigens. To address this challenge, substantial efforts have been made in developing innovative adjuvants to elicit effective immune responses. In this study, we develop a NP cancer vaccine assisted by a polysaccharide derivative adjuvant, designed through a computational strategy, to evoke effective antigen-specific antitumor immunity. Using TLR4 as the putative receptor, we conducted a comprehensive evaluation of a prescreening library consisting of 34 inulin derivatives through docking and molecular dynamics simulation. Consequently, a new derivative, benzoylated inulin (InBz), is selected as the most promising TLR4 agonist. The adjuvant effect of InBz is evaluated by fabricating InBz NPs encapsulating the model antigen ovalbumin (OVA). In vitro, InBz-OVA NPs effectively activate the TLR4 signaling pathways and facilitate dendritic cell maturation, thereby enhancing the antigen delivery and presentation. In vivo, InBz-OVA NPs outperform a commercial aluminum-based adjuvant, elicit robust antibody titers, induce antigen-specific cytotoxic T lymphocytes, and achieve significant tumor suppression in murine models. Besides, the adjuvant effects of other representative derivatives, namely, acetylated and chloroacetylated inulin, with moderate and low potential from the library, are also chemically synthesized and experimentally evaluated and found to be in agreement with computational predictions, confirming the credibility of the strategy. This study provides an effective platform for the pursuit of efficient polysaccharide-based vaccine adjuvants.

Ultrasound-triggered drug-loaded nanobubbles for enhanced T cell recruitment in cancer chemoimmunotherapy.

Chemotherapy combined with immunotherapy is a highly promising approach for treating tumors. However, chemotherapeutic drugs often fail to accumulate effectively at the tumor site after systemic administration and they lack sufficient immunogenicity to activate adaptive immunity, making an effective T-cell immune response within the tumor microenvironmentdifficult to achieve. Here, this work developed drug-loaded nanobubbles (DTX-R837@NBs) that encapsulate the chemotherapy drug docetaxel and the immune adjuvant R837 via a thin-film hydration method. Ultrasound-targeted nanobubble destruction promoted drug accumulation within tumor tissues and damaged tumor cells through the cavitation effect, inducing immunogenic cell death and releasing damage-associated molecular patterns to augment dendritic cell maturation. Notably, DTX-R837@NBs exhibited excellent contrast-enhanced ultrasound imaging capabilities, enabling the seamless integration of diagnosis and treatment. In combination with immune checkpoint blockade targeting programmed cell death protein 1 (PD-1), the generated immunological responses attacked residual tumor cells and ameliorated the immunosuppressive tumor microenvironment, inhibiting distant tumor growth and metastasis. Moreover, this strategy exhibited robust immune memory effects, effectively protecting the host and preventing tumor recurrence upon rechallenge. Overall, ultrasound-mediated DTX-R837@NBs combined with anti-PD-1 immune checkpoint blockade therapy exhibits robust antitumor efficiency, represent a promising strategy for overcoming immunotherapy resistance in cold tumors, and warrant further investigation for clinical translation.

Dose-dependent serological profiling of AdCLD-CoV19-1 vaccine in adults.

AdCLD-CoV19-1, a chimeric adenovirus-based severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine, was previously reported to elicit robust antibody responses in mice and non-human primates after a single dose. In this study, we conducted a systems serology analysis to investigate changes in humoral immune responses induced by varying doses of the AdCLD-CoV19-1 vaccine in a phase I clinical trial. Serum samples from participants receiving either a low or a high dose of the vaccine were analyzed for antibody features against prototype SARS-CoV-2 spike (S) domains (full-length S, S1, S2, and receptor binding domain), as well as Fc receptor binding and effector functions. While both low- and high-dose vaccines induced robust humoral immune responses following vaccination, the quality of antibody features differed between the dose groups. Notably, while no significant difference was observed between the groups in the induction of most S1-specific antibody features, the high-dose group exhibited higher levels of antibodies and a stronger Fc receptor binding response specific to the S2 antigen. Moreover, univariate and multivariate analyses revealed that the high-dose vaccine induced higher levels of S2-specific antibodies binding to FcγR2A and FcγR3B, closely associated with antibody-dependent neutrophil phagocytosis (ADNP). Further analysis using the Omicron BA.2 variant demonstrated that the high-dose group maintained significantly higher levels of IgG and FcγR3B binding to the S2 antigen and exhibited a significantly higher ADNP response for the S2 antigen compared with the low-dose group. These findings underscore the importance of considering diverse humoral immune responses when evaluating vaccine efficacy and provide insights for optimizing adenovirus vector-based SARS-CoV-2 vaccine doses.IMPORTANCEOptimization of vaccine dose is crucial for eliciting effective immune responses. In addition to neutralizing antibodies, non-neutralizing antibodies that mediate Fc-dependent effector functions play a key role in protection against various infectious diseases, including coronavirus disease 2019. Using a systems serology approach, we demonstrated significant dose-dependent differences in the humoral immune responses induced by the AdCLD-CoV19-1 chimeric adenovirus-based severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine, particularly against the SARS-CoV-2 spike 2 domain. These findings highlight the importance of assessing not only neutralizing antibody titers but also the quality and functionality of antibody responses when evaluating vaccine efficacy.

Transcriptional profiling of Fraxinus excelsior leaves during the early infection phase of ash dieback

Ash dieback (ADB) has been causing the progressive decline of Fraxinus excelsior trees throughout Europe, urging research and forest management to develop strategies to combat ADB. A genetically heritable component in susceptibility to this fungal disease was reported in common gardens. Thus, exploring the molecular basis of ADB susceptibility will further support breeding initiatives in the future. We performed transcriptional profiling of infected and uninfected leaves from two ash genotypes with different susceptibility to Hymenoscyphus fraxineus. Leaf rachises were sampled one week following inoculation. Differential gene expression analysis was performed to compare between treatments in each genotype (individual response) or in genotypes and treatments combined (common response). Due to the heterogeneity in the response, only DEGs were discussed that passed stringent assessment. Our results revealed that UW1, the most susceptible genotype, showed a total of 515 differentially expressed genes (DEGs), some of them possibly suggesting a self-control mechanism, hindering an effective immune response and causing increased susceptibility. On the other hand, FAR3, the least susceptible genotype with 230 DEGs, seemed to induce a contained but more efficient response, hinting toward a salicylic acid-mediated process and activating pathogen-related (like) proteins as thaumatin-like, peroxidases, and chitinases. In the common response, 512 DEGs were modulated and transcripts from the phenylpropanoid pathway were commonly altered in both genotypes. Altogether, this work comprised an initial transcriptional exploration including two selected genotypes with distinct susceptibility to ADB, however, the heterogenous response indicated the need to further improve the experimental inoculation approach. Exploring gene expression patterns in ADB susceptibility holds promise to reveal early response mechanisms, and new markers related to susceptibility, as well as to contribute to developing strategies that may help contain ADB.

Multiomic profiling of chronically activated CD4+ T cells identifies drivers of exhaustion and metabolic reprogramming.

Repeated antigen exposure leads to T-cell exhaustion, a transcriptionally and epigenetically distinct cellular state marked by loss of effector functions (e.g., cytotoxicity, cytokine production/release), up-regulation of inhibitory receptors (e.g., PD-1), and reduced proliferative capacity. Molecular pathways underlying T-cell exhaustion have been defined for CD8+ cytotoxic T cells, but which factors drive exhaustion in CD4+ T cells, that are also required for an effective immune response against a tumor or infection, remains unclear. Here, we utilize quantitative proteomic, phosphoproteomic, and metabolomic analyses to characterize the molecular basis of the dysfunctional cell state induced by chronic stimulation of CD4+ memory T cells. We identified a dynamic response encompassing both known and novel up-regulated cell surface receptors, as well as dozens of unexpected transcriptional regulators. Integrated causal network analysis of our combined data predicts the histone acetyltransferase p300 as a driver of aspects of this phenotype following chronic stimulation, which we confirmed via targeted small molecule inhibition. While our integrative analysis also revealed large-scale metabolic reprogramming, our independent investigation confirmed a global remodeling away from glycolysis to a dysfunctional fatty acid oxidation-based metabolism coincident with oxidative stress. Overall, these data provide both insights into the mechanistic basis of CD4+ T-cell exhaustion and serve as a valuable resource for future interventional studies aimed at modulating T-cell dysfunction.

Central control of dynamic gene circuits governs T cell rest and activation.

The ability of cells to maintain distinct identities and respond to transient environmental signals requires tightly controlled regulation of gene networks1-3. These dynamic regulatory circuits that respond to extracellular cues in primary human cells remain poorly defined. The need for context-dependent regulation is prominent in T cells, where distinct lineages must respond to diverse signals to mount effective immune responses and maintain homeostasis4-8. Here we performed CRISPR screens in multiple primary human CD4+ T cell contexts to identify regulators that control expression of IL-2Rα, a canonical marker of T cell activation transiently expressed by pro-inflammatory effector T cells and constitutively expressed by anti-inflammatory regulatory T cells where it is required for fitness9-11. Approximately 90% of identified regulators of IL-2Rα had effects that varied across cell types and/or stimulation states, including a subset that even had opposite effects across conditions. Using single-cell transcriptomics after pooled perturbation of context-specific screen hits, we characterized specific factors as regulators of overall rest or activation and constructed state-specific regulatory networks. MED12 - a component of the Mediator complex - serves as a dynamic orchestrator of key regulators, controlling expression of distinct sets of regulators in different T cell contexts. Immunoprecipitation-mass spectrometry revealed that MED12 interacts with the histone methylating COMPASS complex. MED12 was required for histone methylation and expression of genes encoding key context-specific regulators, including the rest maintenance factor KLF2 and the versatile regulator MYC. CRISPR ablation of MED12 blunted the cell-state transitions between rest and activation and protected from activation-induced cell death. Overall, this work leverages CRISPR screens performed across conditions to define dynamic gene circuits required to establish resting and activated T cell states.

Efficient gene deletion of Integrin alpha 4 in primary mouse CD4 T cells using CRISPR RNA pair-mediated fragmentation

The functional specialization of CD4 T lymphocytes into various subtypes, including TH1 and TFH cells, is crucial for effective immune responses. TFH cells facilitate B cell differentiation within germinal centers, while TH1 cells are vital for cell-mediated immunity against intracellular pathogens. Integrin α4, a cell surface adhesion molecule, plays significant roles in cell migration and co-stimulatory signaling. In this study, we investigated the role of Integrin α4 in regulating TFH and TH1 cell populations during acute viral infection using CRISPR-Cas9 gene editing. To effectively delete the Itga4 in primary mouse CD4 T cells, we selected various combinations of crRNAs and generated ribonucleoprotein complexes with fluorochrome-conjugated tracrRNAs and Cas9 proteins. These crRNA pairs enhanced gene deletion by generating deletions in the gene. By analyzing the effects of Itga4 deficiency on TFH and TH1 cell differentiation during acute LCMV infection, we found that optimized crRNA pairs significantly increased the TH1 cell population. Our results highlight the importance of selecting and combining appropriate crRNAs for effective CRISPR-Cas9 gene editing in primary CD4 T cells. Additionally, our study demonstrates the role of Integrin α4 in regulating the differentiation of CD4 T cells, suggesting the potential molecular mechanisms driving T cell subset differentiation through integrin targeting.

Enhancing the Deformability of the Adjuvant: Achieving Lymph Node Targeted Delivery to Elicit a Long-Lasting Immune Protection.

A key challenge in vaccine development is to inducean effective and durable immune response. Live virus vaccines induce lifelong antibody responses; however, the immune responses induced by inactivated or subunit vaccines decrease gradually. Activation of the germinal center (GC) reaction, which generates long-lived plasma cells (LLPCs), is a key mediator of long-term antibody responses. To enhance the activation of GC, lymph node-targeted delivery of the vaccine is promoted by enhancing the deformability of the delivery vector. In this study, a double emulsion is designed with strong deformability and containing chitosan nanoparticles (CSNP) in the internal aqueous phase (WNP) for efficient antigen loading, called WNP/O/W. The flexible oil layer and the internally loaded positively charged particles endow the emulsion with strong deformability, continuously enrich model antigen ovalbumin(OVA)in the lymph nodes, activate germinal center B (GC B) cells and T follicular helper (TFH) cells, induce LLPCs, and obtain high-level antibody persistence for more than 5 months, which is significantly better than the traditional oil emulsion adjuvant. Concurrently, it also improves the immune-protective effect in aged mice. Altogether, these results indicate that WNP/O/W achieves lymph node targeted delivery by strengthening deformability, generating high-intensity antibody responses, and long-lasting immune protection.

The Role of Tumor-Associated Macrophages in Cancer Immunoevasion and Therapy Resistance

Tumor-associated macrophages (TAMs) are crucial components of the tumor microenvironment, playing significant roles in cancer progression, immune evasion, and therapy resistance. Originating from circulating monocytes, TAMs can polarize into M1 and M2 phenotypes, with M2-like TAMs predominating in many cancers. This M2 polarization fosters an immunosuppressive environment that promotes tumor growth, metastasis, and resistance to therapies, including chemotherapy and immune checkpoint inhibitors. TAMs secrete various cytokines, chemokines, and growth factors that enhance tumor cell survival, promote angiogenesis, and recruit additional immunosuppressive cells such as regulatory T cells. They also express immune checkpoint molecules, further inhibiting effective anti-tumor immune responses. Given their dual role in supporting tumor survival and mediating immune evasion, TAMs represent an attractive target for therapeutic intervention. Current strategies to target TAMs include depletion, reprogramming, and combination therapies aimed at enhancing anti-tumor immunity. This review explores the complex biology of TAMs, their mechanisms of action in promoting cancer immunoevasion and therapy resistance, and the therapeutic strategies being developed to exploit their unique characteristics. By providing insights into the multifaceted roles of TAMs, this review aims to highlight potential avenues for improving cancer treatment outcomes and addressing the challenges posed by tumor-induced immune suppression. Keywords: Tumor-Associated Macrophages (TAMs), Immune Evasion, Therapy Resistance, Macrophage Polarization, Immunotherapy

Maintenance of Long-Term Effective Humoral Immune Response in Patients with COVID-19 with Homologous or Heterologous Booster Vaccines: A Retrospective Study.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and first identified in Wuhan, China, in December 2019, has led to global efforts in vaccination to mitigate rising morbidity and mortality, with vaccines proving crucial in controlling the pandemic. This study evaluated the humoral responses to the inactivated virus vaccine Sinopharm or Koxing Kerlafor, the protein subunit vaccine ZF001, and the adenoviral vector vaccine Convidecia after 18 months of inactivated virus vaccination by heterologous and homologous booster vaccination in patients with previous SARS-CoV-2 infection and healthy individuals. We discovered that patients who had recovered from the infection and then received a third vaccine dose (booster) exhibited durable immunity. Furthermore, the heterologous booster vaccine induced higher neutralizing antibody responses compared with the homologous booster. These findings offer valuable insights into the efficacy of different COVID-19 vaccine strategies following booster immunization.

PP4.8 – 00099 Activation of Immune Effector Responses in Newborns with Perinatal HIV infection

PP4.8 – 00099 Activation of Immune Effector Responses in Newborns with Perinatal HIV infection

Oral Yeast-Cell Microcapsule-Mediated DNA Vaccines Against Clostridium perfringens Induce Effective Intestinal Immunity and Modulate Gut Microbiota.

Background/Objectives:Clostridium perfringens is a common opportunistic pathogen that causes gastrointestinal diseases in livestock and poultry. Our preliminary research has demonstrated that administering oral yeast-cell microcapsule (YCM)-mediated DNA vaccines can effectively stimulate mucosal immunity, thereby preventing the occurrence of gastrointestinal diseases. Methods: In this study, the C. perfringens α-toxin gene was first cloned and the H126G and C-terminal (C247-370) mutations were created. The corresponding DNA vaccine cassettes driven by a CMV promoter were constructed and were cloned into a yeast shuttle vector. Recombinant yeast strains transformed with these shuttle vectors were then prepared as the YCMs for the subsequent oral immunization of mice. Results: Oral administration of recombinant YCMs can induce an effective immune response, and the H126G YCM performed much better than C247-370. Further evidence suggested that YCM administration may contribute to modulating the gut environment by altering gut microbiota and enhancing bacterial richness. Conclusions: Our study indicated that the oral administration of YCM-mediated DNA vaccines can induce effective intestinal immunity and may also alter the composition of the gut microbiota, suggesting a promising candidate vaccine strategy against C. perfringens-induced animal diseases.

Immunological mechanisms involved in the protection against development of pulmonary tuberculosis in naturally infected goats

Tuberculosis (TB) is a notifiable zoonotic disease caused by bacteria of the Mycobacterium tuberculosis complex (MTBC) that affects a multitude of domestic and wild species. The main lesions caused by these mycobacteria are tuberculous granulomas, which determine the organism's immune response to the disease. Although TB pathogenesis in cattle has been extensively studied, information regarding its progression in other species of interest for the maintenance and transmission of TB such as goats remains limited. This study aimed to characterise the immune response developed in the lungs of goats naturally infected with mycobacteria of MTBC by assessing key cell populations and immunomodulatory molecules involved in defending against TB. Hence, twelve 6–12-month-old Guadarrama kid goats, initially TB-free, were selected and exposed to M. bovis through close contact with other infected goats. Only animals that tested positive by any of the TB diagnostic methods at the end of the experiment were included in the final analysis (n = 9). Gross and microscopic lesions compatible with TB (TBL) in different organs, as well as local response to TB in lungs were evaluated. Our results revealed that after five months of exposure, 44.4 % (4/9) of the M. bovis-infected animals exhibited TBL in the lungs (TBLL+), characterized by a predominance of non-cavitary necrotic granulomas. TBLL+ animals showed significantly higher presence of neutrophils, macrophages (MΦs) and lymphocytes along with greater expression of interferon (IFN)-γ. Conversely, the remaining animals did not present macroscopic or microscopic TBL in the lungs (TBLL-) (5/9). However, these goats displayed elevated expression of toll-like receptors (TLR)2 and TLR4 alongside heightened expression of pro-inflammatory cytokines, inducible nitric oxide synthase (iNOS) and interleukin (IL)-10. These results suggest the potential development of an effective immune response that may suppress or delay of TBL in infected animals. Further research is needed to elucidate how these molecules, which are involved in the defence against MTBC, confer protection and modulate their expression during infection for TB control.

The Involvement of Resolvins in Pathological Mechanisms of Periodontal Disease Associated with Type 2 Diabetes: A Narrative Review.

Resolvins are specialized pro-resolving mediators (SPMs) derived from omega-3 fatty acids that play a critical role in resolving inflammation and restoring tissues to a state of health after an immune response. Their role in chronic inflammatory conditions highlights their importance in maintaining a balance between an effective immune response and the resolution of inflammation to prevent tissue damage. Periodontal disease is a chronic inflammatory condition affecting the tissues surrounding the teeth, leading to gum damage and bone loss. Chronic inflammation in periodontal disease can exacerbate systemic inflammation and influence other conditions, such as diabetes. There is a bidirectional relationship between diabetes and periodontal disease, as both are characterized by chronic inflammation and exacerbate systemic and oral health complications. This narrative review aims to synthesize the current knowledge on how resolvins influence inflammatory pathways and the tissue repair mechanism in periodontal disease in patients with type 2 diabetes. Furthermore, this review serves as a foundation for developing targeted therapeutic strategies, addressing the pressing need for effective treatments that consider both systemic and oral health outcomes.

Telomerase RNA component knockout exacerbates Staphylococcus aureus pneumonia by extensive inflammation and dysfunction of T cells.

The telomerase RNA component (Terc) constitutes a non-coding RNA critical for telomerase function, commonly associated with aging and pivotal in immunomodulation during inflammation. Our study unveils heightened susceptibility to pneumonia caused by Staphylococcus aureus (S. aureus) in Terc knockout (Tercko/ko) mice compared to both young and old infected counterparts. The exacerbated infection in Tercko/ko mice correlates with heightened inflammation, manifested by elevated interleukin-1β (IL-1β) levels and activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome within the lung. Employing mRNA sequencing methods alongside in vitro analysis of alveolar macrophages (AMs) and T cells, our study elucidates a compelling correlation between Tercko/ko, inflammation, and impaired T cell functionality. Terc deletion results in compromised T cell function, characterized by dysregulation of the T cell receptor and absence of CD247, potentially compromising the host's capacity to mount an effective immune response against S. aureus. This investigation provides insights into the intricate mechanisms governing increased vulnerability to severe pneumonia in the context of Terc deficiency, which might also contribute to aging-related pathologies, while also highlighting the influence of Terc on T cell function.

An update on recombinant vaccines against leishmaniasis.

Leishmaniasis is a parasitic disease caused by various species of the Leishmania parasite, manifesting in visceral (VL), cutaneous (CL), and mucocutaneous (MCL) forms. To combat this debilitating disease, various vaccines candidates including proteins, DNA, vectors, adjuvants, and recombinant whole parasites have been developed and tested experimentally and preclinically against several Leishmania species. Some vaccines have already entered human clinical trials. These vaccines aim to induce protective immunity using specific antigens. This review examines all efforts to develop recombinant vaccines against the parasite, analyzing successes including commercially available canine vaccines and the overall challenges faced in the quest to eradicate the disease. Additionally, recent advances in vaccine delivery systems, such as viral vectors and non-pathogenic bacteria, offer promising avenues to enhance immunogenicity and improve the targeted delivery of antigens, potentially leading to more effective and long-lasting immune responses. By understanding past and current efforts, future strategies can be refined to create more effective vaccines and ultimately control or eradicate this parasitic disease.