Enhanced systemic antitumor efficacy of PD-1/PD-L1 blockade with immunological response induced by photodynamic therapy.

BACKGROUND: Photodynamic therapy (PDT) is an antitumor therapy and has traditionally been regarded as a localized therapy in itself. However, recent reports have shown that it not only exerts a direct cytotoxic effect on cancer cells but also enhances body's tumor immunity. We hypothesized that the immunological response induced by PDT could potentially enhance the efficacy of programmed death-1 (PD-1) / programmed death-ligand 1 (PD-L1) blockade. METHODS: The cytotoxic effects of PDT on colon 26 cells were investigated in vitro using the WST assay. We investigated whether the antitumor effect of anti-PD-1 antibodies could be amplified by the addition of PDT. We performed combination therapy by randomly allocating tumor-bearing mice to four treatment groups: control, anti-PD-1 antibodies, PDT, and a combination of anti-PD-1 antibodies and PDT. To analyze the tumor microenvironment after treatment, the tumors were resected and pathologically evaluated. RESULTS: The viability rate of colon 26 cells decreased proportionally with the laser dose. In vivo experiments for combined PDT and anti-PD-1 antibody treatment, combination therapy showed an enhanced antitumor effect compared with the control. Immunohistochemical findings of the tumor microenvironment 10 days after PDT indicated that the number of CD8+ cells, the area of Iba-1+ cells and the area expressing PD-L1 were significantly higher in tumors treated with combination therapy than in tumors treated with anti-PD-1 antibody alone, PDT alone, or the control. CONCLUSIONS: PDT increased immune cell infiltration into the tumor microenvironment. The immunological response induced by PDT may enhance the efficacy of PD-1/PD-L1 blockade.

The Surgical Stress Response and Anesthesia: A Narrative Review.

The human physiological response "to stress" includes all metabolic and hormonal changes produced by a traumatic event at the micro or macro cellular levels. The main goal of the body's first response to trauma is to keep physiological homeostasis. The perioperative non-specific adaptation response can sometimes be detrimental and can produce systemic inflammatory response syndrome (SIRS), characterized by hypermetabolism and hyper catabolism. We performed a narrative review consisting of a description of the surgical stress response's categories of changes (neurohormonal and immunological response) followed by reviewing methods found in published studies to modulate the surgical stress response perioperatively. We described various preoperative measures cited in the literature as lowering the burden of surgical trauma. This article revises the anesthetic drugs and techniques that have an impact on the surgical stress response and proven immune-modulatory effects. We also tried to name present knowledge gaps requiring future research. Our review concludes that proper preoperative measures, adequate general anesthetics, multimodal analgesia, early postoperative mobilization, and early enteral nutrition can decrease the stress response to surgery and ease patient recovery. Anesthetics and analgesics used during the perioperative period may modulate the innate and adaptive immune system and inflammatory system, with a consecutive impact on cancer recurrence and long-term outcomes.

Clinical outcomes and immunological response to SARS-CoV-2 infection among people living with HIV.

People living with HIV (PLWH) usually suffer from co-infections and co-morbidities including respiratory tract infections. SARS-CoV-2 has been reported to cause respiratory infections. There are uncertainties in the disease severity and immunological response among PLWH who are co-infected with COVID-19. This review outlines the current knowledge on the clinical outcomes and immunological response to SARS-CoV-2 among PLWH. Literature was searched in Google scholar, Scopus, PubMed, and Science Direct conforming with the Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) guidelines from studies published from January 2020 to June 2023. A total of 81 studies from 25 countries were identified, and RT-PCR was used in confirming COVID-19 in 80 of the studies. Fifty-seven studies assessed risk factors and clinical outcomes in HIV patients co-infected with COVID-19. Thirty-nine of the studies indicated the following factors being associated with severe outcomes in HIV/SARS-CoV-2: older age, the male sex, African American race, smoking, obesity, cardiovascular diseases, low CD4+ count, high viral load, tuberculosis, high levels of inflammatory markers, chronic kidney disease, hypertension, diabetes, interruption, and delayed initiation of ART. The severe outcomes are patients' hospitalization, admission at intensive care unit, mechanical ventilation, and death. Twenty (20) studies, however, reported no difference in clinical presentation among co-infected compared to mono-infected individuals. Immune response to SARS-CoV-2 infection was investigated in 25 studies, with some of the studies reporting high levels of inflammatory markers, T cell exhaustion and lower positive conversion rate of IgG in PLWH. There is scanty information on the cytokines that predisposes to severity among HIV/SARS-CoV-2 co-infected individuals on combined ART. More research work should be carried out to validate co-infection-related cytokines and/or immune markers to SARS-CoV-2 among PLWH.

Immunological Signatures in Blood and Urine in 80 Individuals Hospitalized during the Initial Phase of COVID-19 Pandemic with Quantified Nicotine Exposure.

This research analyzes immunological response patterns to SARS-CoV-2 infection in blood and urine in individuals with serum cotinine-confirmed exposure to nicotine. Samples of blood and urine were obtained from a total of 80 patients admitted to hospital within 24 h of admission (tadm), 48 h later (t48h), and 7 days later (t7d) if patients remained hospitalized or at discharge. Serum cotinine above 3.75 ng/mL was deemed as biologically significant exposure to nicotine. Viral load was measured with serum SARS-CoV-2 S-spike protein. Titer of IgG, IgA, and IgM against S- and N-protein assessed specific antiviral responses. Cellular destruction was measured by high mobility group box protein-1 (HMGB-1) serum levels and heat shock protein 60 (Hsp-60). Serum interleukin 6 (IL-6), and ferritin gauged non-specific inflammation. The immunological profile was assessed with O-link. Serum titers of IgA were lower at tadm in smokers vs. nonsmokers (p = 0.0397). IgM at t48h was lower in cotinine-positive individuals (p = 0.0188). IgG did not differ between cotinine-positive and negative individuals. HMGB-1 at admission was elevated in cotinine positive individuals. Patients with positive cotinine did not exhibit increased markers of non-specific inflammation and tissue destruction. The blood immunological profile had distinctive differences at admission (MIC A/B↓), 48 h (CCL19↓, MCP-3↓, CD28↑, CD8↓, IFNγ↓, IL-12↓, GZNB↓, MIC A/B↓) or 7 days (CD28↓) in the cotinine-positive group. The urine immunological profile showed a profile with minimal overlap with blood as the following markers being affected at tadm (CCL20↑, CXCL5↑, CD8↑, IL-12↑, MIC A/B↑, GZNH↑, TNFRS14↑), t48h (CCL20↓, TRAIL↓) and t7d (EGF↑, ADA↑) in patients with a cotinine-positive test. Here, we showed a distinctive immunological profile in hospitalized COVID-19 patients with confirmed exposure to nicotine.

Vaccine Responses in Patients with Liver Cirrhosis: From the Immune System to the Gut Microbiota.

Vaccines prevent a significant number of deaths annually. However, certain populations do not respond adequately to vaccination due to impaired immune systems. Cirrhosis, a condition marked by a profound disruption of immunity, impairs the normal immunization process. Critical vaccines for cirrhotic patients, such as the hepatitis A virus (HAV), hepatitis B virus (HBV), influenza, pneumococcal, and coronavirus disease 19 (COVID-19), often elicit suboptimal responses in these individuals. The humoral response, essential for immunization, is less effective in cirrhosis due to a decline in B memory cells and an increase in plasma blasts, which interfere with the creation of a long-lasting response to antigen vaccination. Additionally, some T cell subtypes exhibit reduced activation in cirrhosis. Nonetheless, the persistence of memory T cell activity, while not preventing infections, may help to attenuate the severity of diseases in these patients. Alongside that, the impairment of innate immunity, particularly in dendritic cells (DCs), prevents the normal priming of adaptive immunity, interrupting the immunization process at its onset. Furthermore, cirrhosis disrupts the gut-liver axis balance, causing dysbiosis, reduced production of short-chain fatty acids (SCFAs), increased intestinal permeability, and bacterial translocation. Undermining the physiological activity of the immune system, these alterations could impact the vaccine response. Enhancing the understanding of the molecular and cellular factors contributing to impaired vaccination responses in cirrhotic patients is crucial for improving vaccine efficacy in this population and developing better prevention strategies.

Minimal Bacterial Cell JCVI-syn3B as a Chassis to Investigate Interactions between Bacteria and Mammalian Cells.

Mycoplasmas are atypical bacteria with small genomes that necessitate colonization of their respective animal or plant hosts as obligate parasites, whether as pathogens, or commensals. Some can grow axenically in specialized complex media yet show only host-cell-dependent growth in cell culture, where they can survive chronically and often through interactions involving surface colonization or internalization. To develop a mycoplasma-based system to identify genes mediating such interactions, we exploited genetically tractable strains of the goat pathogen Mycoplasma mycoides (Mmc) with synthetic designer genomes representing the complete natural organism (minus virulence factors; JCVI-syn1.0) or its reduced counterpart (JCVI-syn3B) containing only those genes supporting axenic growth. By measuring growth of surviving organisms, physical association with cultured human cells (HEK-293T, HeLa), and induction of phagocytosis by human myeloid cells (dHL-60), we determined that JCVI-syn1.0 contained a set of eight genes (MMSYN1-0179 to MMSYN1-0186, dispensable for axenic growth) conferring survival, attachment, and phagocytosis phenotypes. JCVI-syn3B lacked these phenotypes, but insertion of these genes restored cell attachment and phagocytosis, although not survival. These results indicate that JCVI-syn3B may be a powerful living platform to analyze the role of specific gene sets, from any organism, on the interaction with diverse mammalian cells in culture.

The seroepidemiology of immunoglobulin G antibodies against pertussis toxin and filamentous hemagglutinin in the east of China during the COVID-19 pandemic.

This study employed sero-epidemiological methods to estimate the incidence of pertussis within a healthy population located in eastern China. The aim was to gain deeper insights into the epidemiological characteristics and burden of pertussis within the country. Blood samples were collected from healthy individuals in Jiangsu Province between June 2019 and December 2022. The levels of IgG antibodies against pertussis toxin (anti-PT) and filamentous hemagglutinin (anti-FHA) in the serum were quantitatively measured using enzyme-linked immunosorbent assay (ELISA). Additionally, pertussis case data reported in Jiangsu Province were collected from the China Information System for Disease Control and Prevention and compared with the results of this study. In 2022, the reported incidence of pertussis stood at 1.0 per 100,000 individuals, marking the highest rate observed in the past two decades. Among 1,909 patients examined, the geometric mean concentration (GMC) of anti-PT IgG antibody was 20.2 (18.5-21.9) IU/ml, while that of anti-FHA IgG antibody was 27.0 (25.4-28.7) IU/ml. The IgG-PT and IgG-FHA seropositivity rate (>20.0 IU/ml) was highest in the 1 ~ 2 y old group and decreased rapidly to the lowest in the 3 ~ 4 y old group and then increased gradually with age. The estimated rate of pertussis infection based on seroprevalence was approximately 25,625-fold higher than the reported notification rate in the ≥15 year age group. Our findings highlight decreased immunity post-vaccination, stressing the importance of additional booster shots for adolescents and adults to maintain immunity and reduce severe illness. Additionally, they offer vital guidance for policymakers to enhance immunization strategies.

Impacts of pyraclostrobin on intestinal health and the intestinal microbiota in common carp (Cyprinus carpio L.).

Pyraclostrobin (PYR) is a strobilurin fungicide that is commonly used in agriculture, and its use in agriculture may lead to an increase in its residue in the aquatic environment and may have a deleterious influence on the intestinal health of aquatic creatures. Here, common carp were chronically exposed to PYR (0, 0.5, or 5.0 µg/L) for 30 d to determine its effect on the physical and immunological barrier and intestinal microbiota in the intestine. PYR exposure caused significant histological changes; altered the mRNA expression levels of occludin, claudin-2, and zonula occludens-1 (ZO-1); induced oxidative stress in the common carp intestine; and increased the serum D-lactate and diamine oxidase (DAO) levels. Moreover, PYR significantly increased the protein expression levels of tumour necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1ß), and IL-6 while decreasing the level of transforming growth factor beta (TGF-ß). Further studies revealed that PYR significantly reduced lysozyme (LZM) and acid phosphatase (ACP) activities as well as complement 3 (C3) and immunoglobulin M (IgM) levels. Furthermore, PYR decreased gut microbial diversity while increasing the abundance of pathogenic bacteria such as Aeromonas and Shewanella, causing an intestinal microbial disturbances in common carp. These results imply that PYR has a negative impact on fish intestinal health and may pose serious health risks to fish by disrupting the intestinal microbiota, physical barrier, and immunological barrier in common carp.

The protective effects of BMSA1 and BMSA5-1-1 proteins against Babesia microti infection.

The intracellular parasite Babesia microti is among the most significant species causing human babesiosis and is an emerging threat to human health worldwide. Unravelling the pathogenic molecular mechanisms of babesiosis is crucial in developing new diagnostic and preventive methods. This study assessed how priming with B. microti surface antigen 1 (BHSA 1) and seroreactive antigen 5-1-1 (BHSA 5-1-1) mediate protection against B. microti infection. The results showed that 500 µg/ml rBMSA1 and rBMSA5-1-1 partially inhibited the invasion of B. microti in vitro by 42.0 ± 3.0%, and 48.0 ± 2.1%, respectively. Blood smears revealed that peak infection at 7 days post-infection (dpi) was 19.6%, 24.7%, and 46.7% in the rBMSA1, rBmSA5-1-1, compared to the control groups (healthy mice infected with B. microti only), respectively. Routine blood tests showed higher white blood cell, red blood cell counts, and haemoglobin levels in the 2 groups (BMSA1 and BMSA5 5-1-1) than in the infection control group at 0-28 dpi. Moreover, the 2 groups had higher serum interferon-γ, tumor necrosis factor-α and Interleukin-17A levels, and lower IL-10 levels than the infection control group throughout the study. These 2 potential vaccine candidate proteins partially inhibit in vitro and in vivo B. microti infection and enhance host immunological response against B. microti infection.

An Update on the Pathogenesis of Fascioliasis: What Do We Know?

Fasciola hepatica is a trematode parasite distributed worldwide. It is known to cause disease in mammals, producing significant economic loses to livestock industry and burden to human health. After ingestion, the parasites migrate through the liver and mature in the bile ducts. A better understanding of the parasite's immunopathogenesis would help to develop efficacious therapeutics and vaccines. Currently, much of our knowledge comes from in vitro and in vivo studies in animal models. Relatively little is known about the host-parasite interactions in humans. Here, we provide a narrative review of what is currently know about the pathogenesis and host immune responses to F. hepatica summarizing the evidence available from the multiple hosts that this parasite infects.

Enantiomer-Dependent Supramolecular Immunosuppressive Modulation for Tissue Reconstruction.

Modulating the properties of biomaterials in terms of the host immune response is critical for tissue repair and regeneration. However, it is unclear how the preference for the cellular microenvironment manipulates the chiral immune responses under physiological or pathological conditions. Here, we reported that in vivo and in vitro oligopeptide immunosuppressive modulation was achieved by manipulation of macrophage polarization using chiral tetrapeptide (Ac-FFFK-OH, marked as FFFK) supramolecular polymers. The results suggested that chiral FFFK nanofibers can serve as a defense mechanism in the restoration of tissue homeostasis by upregulating macrophage M2 polarization via the Src-STAT6 axis. More importantly, transiently acting STAT6, insufficient to induce a sustained polarization program, then passes the baton to EGR2, thereby continuously maintaining the M2 polarization program. It is worth noting that the L-chirality exhibits a more potent effect in inducing macrophage M2 polarization than does the D-chirality, leading to enhanced tissue reconstruction. These findings elucidate the crucial molecular signals that mediate chirality-dependent supramolecular immunosuppression in damaged tissues while also providing an effective chiral supramolecular strategy for regulating macrophage M2 polarization and promoting tissue injury repair based on the self-assembling chiral peptide design.

Detection of serum interleukin-18 level and neutrophil/lymphocyte ratio in patients with antineutrophil cytoplasmic antibody-associated vasculitis and its clinical significance.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of autoimmune diseases. This study aimed to investigate the clinical significance of changes in interleukin-18 (IL-18) and neutrophil/lymphocyte ratio (NLR) in the pathogenesis of AAV and the impact of NLR on the prognosis of patients. The clinical data of 52 AAV patients (AAV group) who met the conditions of hospitalization, 30 patients with mild mesangial proliferative glomerulonephritis (disease controls), and 30 healthy volunteers (normal controls) in Nephrology Department of Liuzhou People's Hospital from May 2020 to August 2022 were selected. A total of 52 AAV patients were divided into active phase (>15 points) and remission phase (≤15 points) based on the Birmingham vasculitis activity score (BVAS). Serum IL-18 level was detected by enzyme-linked immunosorbent assay in three groups. Pearson product moment correlation analysis was performed to investigate the correlation between serum IL-18 levels and clinical laboratory indicators, and receiver operating characteristic (ROC) curve analysis was performed on serum IL-18, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) levels, and NLR in AAV patients. The levels of serum creatinine, parathyroid hormone, ß2-microglobulin (ß2-MG), ESR, CRP, and IL-18 in active stage of AAV were significantly higher than those in remission stage of AAV. Moreover, the serum IL-18 level of active AAV patients was significantly higher than that of disease control group (P < 0.05). The levels of eGFR, hemoglobin, and complement C3 were significantly lower than those during the remission (P < 0.05). Pearson product moment correlation analysis showed that serum IL-18 level in AAV patients was positively correlated with BVAS score and ESR level. The area under the curve of serum IL-18, NLR, CRP, ESR levels evaluated by ROC curve was 0.921, 0.899, 0.83, and 0.75, respectively. Kaplan-Meier survival curve showed that the cumulative survival rate of patients in low NLR group was significantly higher than that in high NLR group (68.36 vs 42.89%), with significant difference (Log-Rank = 6.745, P = 0.025 < 0.05). IL-18 may be adopted as one of the important biological markers to judge the disease of AAV, and the cumulative survival rate of patients with high NLR is low, which may be applied as an indicator to evaluate the poor prognosis of patients with AAV.

Trends and the associated factors of optimal immunological response and virological response in late anti-retroviral therapy initiation HIV cases in Taiwan from 2009 to 2020.

BACKGROUND: Late cART initiation (CD4 count ≤200 cells/µL or AIDS-defining opportunistic illnesses [AOIs] at cART initiation) impedes CD4 count recovery and virologic suppression after cART initiation. However, studies to evaluate trends of and modifiable factors for optimal immunological response (IR) and virological response (VR) in people living with HIV (PLWH) with late cART initiation with the current HIV treatment strategies are limited. METHODS: We retrospectively identified 475 PLWH with late cART initiation in 2009-2020. Patients were grouped based on the presence of IR (CD4 count ≥200 cells/µL) or VR (plasma viral load [PVL] ≤ 50 copies/mL) within 18 months after cART initiation (403 [84.8%] IR(+) and 72 [15.2%] IR(-); 422 [88.8%] VR(+) and 53 [11.2%] VR(-)). We used Joinpoint regression to identify IR (+) and VR(+) proportion changes. RESULTS: From 2009 to 2020, the proportion of IR(+) patients remained unchanged (75% to 90%, P = 0.102), whereas that of VR(+) patients increased significantly (75% to 95%, P = 0.007). No join point was identified for either IR(+) or VR(+), and the annual percentage change was 0.56% (nonsignificant) and 1.35% (significant) for IR(+) and VR(+), respectively. Compared to IR(-) patients, IR(+) patients were more likely to have a higher pre-cART PVL, to start with a first-line INSTI-based regimen, or to start cART within 14 days of HIV diagnosis but were less likely to have chronic kidney disease, composite AOIs, or a lower pre-cART CD4 count. Compared to VR(-) patients, VR(+) patients were more likely to start a single-tablet regimen but were less likely to have a higher pre-cART PVL. CONCLUSIONS: Our study identified several modifiable factors for optimal IR (rapid cART initiation and INSTI-based regimen initiation) and for optimal VR (STR initiation) among late initiators, which may guide early treatment modifications to reduce their AIDS-defining event incidence and mortality.

New Immunological Markers in Chromoblastomycosis-The Importance of PD-1 and PD-L1 Molecules in Human Infection.

The pathogenesis of chromoblastomycosis (CBM) is associated with Th2 and/or T regulatory immune responses, while resistance is associated with a Th1 response. However, even in the presence of IFN-γ, fungi persist in the lesions, and the reason for this persistence is unknown. To clarify the factors associated with pathogenesis, this study aimed to determine the polarization of the cellular immune response and the densities of cells that express markers of exhaustion in the skin of CBM patients. In the skin of patients with CBM, a moderate inflammatory infiltrate was observed, characterized primarily by the occurrence of histiocytes. Analysis of fungal density allowed us to divide patients into groups that exhibited low and high fungal densities; however, the intensity of the inflammatory response was not related to mycotic loads. Furthermore, patients with CBM exhibited a significant increase in the number of CD4+ and CD8+ cells associated with a high density of IL-10-, IL-17-, and IFN-γ-producing cells, indicating the presence of a chronic and mixed cellular immune response, which was also independent of fungal load. A significant increase in the number of PD-1+ and PD-L1+ cells was observed, which may be associated with the maintenance of the fungus in the skin and the progression of the disease.

Immunological Nuances and Complications of Pediatric Organ Transplant: A Narrative Review.

Organ transplantation is considered an exaggerated immune state in which the body reacts in an elaborate cascade of reactions against the lifesaving graft transplanted. Unrepairable organ damage is the main indication for a pediatric patient to undergo a transplant. The host and the donor must fulfill the criteria for a successful transplant to have as few side effects as possible. There has been much-needed research in the domain of surgery of organ transplantation, thereby extending into the pediatric age group. This article elaborates on the post-transplant management, the immuno-biochemistry aspect, and its post-surgery treatment. The post-surgery period requires great emphasis as morbidity and mortality are highest. There is much to understand about managing transplant patients to avoid complications such as infections, hypertension, or side effects of immunosuppressive drugs. The treating clinician faces the challenges of managing the dose and frequency of immuno-suppressive medicines to prevent complications in the patients. If the dose is inadequate, there are chances of graft rejection. If the immuno-suppression is prolonged, there may be chances of infections in the patient. This article aims to summarize the mechanism of graft rejection and put forth the need for further research about creating a universal protocol for managing a patient's immune system post-transplant. The authors hope this protocol will help the clinician better understand the patient's current state and help in appropriately using immuno-suppressive drugs. It calls upon the need for a reliable and easily repeatable battery of investigations that will help solve this dilemma.

Does Nirmatrelvir/Ritonavir Influence the Immune Response against SARS-CoV-2, Independently from Rebound?

Recurrence of coronavirus disease 19 (COVID-19) symptoms and SARS-CoV-2 viral load relapse have been reported in people treated with nirmatrelvir/ritonavir (NM/r). However, little is understood about the etiology of this phenomenon. Our aim was to investigate the relation between the host's immune response and viral rebound. We described three cases of COVID-19 rebound that occurred after treatment with nirmatrelvir/ritonavir (group A). In addition, we compared spike-specific antibody response and plasma cytokine/chemokine patterns of the rebound cases with those of (i) control patients treated with nirmatrelvir/ritonavir who did not show rebound (group B), and (ii) subjects not treated with any anti-SARS-CoV-2 drug (group C). The anti-spike antibodies and plasma cytokines/chemokines were similar in groups A and B. However, we observed a higher anti-BA.2 spike IgG response in patients without antiviral treatment (group C) [geometric mean titer 210,807, 5.1- and 8.2-fold higher compared to group A (p = 0.039) and group B (p = 0.032)]. Moreover, the patients receiving antiviral treatment (groups A-B) showed higher circulating levels of platelet-derived growth factor subunit B (PDGF-BB) and vascular endothelial growth Factors (VEGF) and lower levels of interleukin-9 (IL-9), interleukine-1 receptor antagonist (IL-1 RA), and regulated upon activation normal T cell expressed and presumably secreted chemokine (RANTES) when compared to group C. In conclusion, we observed lower anti-spike IgG levels and different cytokine patterns in nirmatrelvir/ritonavir-treated patients compared to those not treated with anti-SARS-CoV-2 drugs. This suggests that early antiviral treatment, by reducing viral load and antigen presentation, could mitigate the immune response against SARS-CoV-2. The clinical relevance of such observation should be further investigated in larger populations.

The functional response of human monocyte-derived macrophages to serum amyloid A and Mycobacterium tuberculosis infection.

Introduction: In the course of tuberculosis (TB), the level of major acute phase protein, namely serum amyloid A (hSAA-1), increases up to a hundredfold in the pleural fluids of infected individuals. Tubercle bacilli infecting the human host can be opsonized by hSAA-1, which affects bacterial entry into human macrophages and their intracellular multiplication. Methods: We applied global RNA sequencing to evaluate the functional response of human monocyte-derived macrophages (MDMs), isolated from healthy blood donors, under elevated hSAA-1 conditions and during infection with nonopsonized and hSAA-1-opsonized Mycobacterium tuberculosis (Mtb). In the same infection model, we also examined the functional response of mycobacteria to the intracellular environment of macrophages in the presence and absence of hSAA-1. The RNASeq analysis was validated using qPCR. The functional response of MDMs to hSAA-1 and/or tubercle bacilli was also evaluated for selected cytokines at the protein level by applying the Milliplex system. Findings: Transcriptomes of MDMs cultured in the presence of hSAA-1 or infected with Mtb showed a high degree of similarity for both upregulated and downregulated genes involved mainly in processes related to cell division and immune response, respectively. Among the most induced genes, across both hSAA-1 and Mtb infection conditions, CXCL8, CCL15, CCL5, IL-1ß, and receptors for IL-7 and IL-2 were identified. We also observed the same pattern of upregulated pro-inflammatory cytokines (TNFα, IL-6, IL-12, IL-18, IL-23, and IL-1) and downregulated anti-inflammatory cytokines (IL-10, TGFß, and antimicrobial peptide cathelicidin) in the hSAA-1 treated-MDMs or the phagocytes infected with tubercle bacilli. At this early stage of infection, Mtb genes affected by the inside microenvironment of MDMs are strictly involved in iron scavenging, adaptation to hypoxia, low pH, and increasing levels of CO2. The genes for the synthesis and transport of virulence lipids, but not cholesterol/fatty acid degradation, were also upregulated. Conclusion: Elevated serum hSAA-1 levels in tuberculosis enhance the response of host phagocytes to infection, including macrophages that have not yet been in contact with mycobacteria. SAA induces antigen processing and presentation processes by professional phagocytes reversing the inhibition caused by Mtb infection.

Immunomodulatory functions of microorganisms in tissue regenerative healing.

External pathogenic microorganisms and commensal microorganisms in the body have either harmful or beneficial impacts on the regenerative repair of tissues, and the immune system plays a crucial regulatory role in this process. This review summarises our current understanding of microorganism-immune system interactions, with a focus on how these interactions impact the renewal and repair ability of tissues, including skin, bone, gut, liver, and nerves. This review concludes with a discussion of the mechanisms by which microbes act on various types of immune cells to affect tissue regeneration, offers potential strategies for using microbial therapies to enhance the regenerative repair function of tissues, and suggest novel therapeutic approaches for regenerative medicine. STATEMENT OF SIGNIFICANCE: Microbiological communities have crucial impacts on human health and illness by participating in energy collection and storage and performing various metabolic processes. External pathogenic microorganisms and commensal microorganisms in the body have either harmful or beneficial impacts on the regenerative repair of tissues, and the immune system plays a critical regulatory role in this process. This study reviews the important correlation between microorganisms and the immune system and investigates the mechanism of various microorganism that participate in the regeneration and repair of tissues and organs by modulating immune system.

Calcium electroporation of esophageal cancer induces gene expression changes: a sub-study of a phase I clinical trial.

PURPOSE: In this study, we aim to investigate gene expression changes in tumor samples obtained from patients with esophageal cancer treated with calcium electroporation. Previously, local treatment with calcium electroporation has been shown to induce gene expression alterations, potentially contributing to a more tumor-hostile microenvironment. METHODS: In this sub-study of a phase I clinical trial, we included five patients with esophageal cancer treated with calcium electroporation. We compared cancer-associated gene expression patterns in tumor samples before and after treatment. Furthermore, we used linear support vector regression to predict the cellular composition of tumor samples. RESULTS: Using differential expression analysis, we identified the downregulation of CXCL14 and upregulation of CCL21, ANGPTL4, and CRABP2 genes. We also found a decreased predicted proportion of dendritic cells while the proportion of neutrophils was increased. CONCLUSION: This study provides evidence that calcium electroporation for esophageal cancer induces local transcriptional changes and possibly alters the cellular composition of the tumor microenvironment. The results are explorative, larger studies are needed to confirm and further correlate our findings with clinical outcomes.