Cytokine Receptors-Regulators of Antimycobacterial Immune Response.

Cytokine receptors are critical regulators of the antimycobacterial immune response, playing a key role in initiating and coordinating the recruitment and activation of immune cells during infection. They recognize and bind specific cytokines and are involved in inducing intracellular signal transduction pathways that regulate a diverse range of biological functions, including proliferation, differentiation, metabolism and cell growth. Due to mutations in cytokine receptor genes, defective signaling may contribute to increased susceptibility to mycobacteria, allowing the pathogens to avoid killing and immune surveillance. This paper provides an overview of cytokine receptors important for the innate and adaptive immune responses against mycobacteria and discusses the implications of receptor gene defects for the course of mycobacterial infection.

Dual Nature of Relationship between Mycobacteria and Cancer.

Although the therapeutic effect of mycobacteria as antitumor agents has been known for decades, recent epidemiological and experimental studies have revealed that mycobacterium-related chronic inflammation may be a possible mechanism of cancer pathogenesis. Mycobacterium tuberculosis and non-tuberculous Mycobacterium avium complex infections have been implicated as potentially contributing to the etiology of lung cancer, whereas Mycobacterium ulcerans has been correlated with skin carcinogenesis. The risk of tumor development with chronic mycobacterial infections is thought to be a result of many host effector mechanisms acting at different stages of oncogenesis. In this paper, we focus on the nature of the relationship between mycobacteria and cancer, describing the clinical significance of mycobacteria-based cancer therapy as well as epidemiological evidence on the contribution of chronic mycobacterial infections to the increased lung cancer risk.

Host Epigenetics in Intracellular Pathogen Infections.

Some intracellular pathogens are able to avoid the defense mechanisms contributing to host epigenetic modifications. These changes trigger alterations tothe chromatin structure and on the transcriptional level of genes involved in the pathogenesis of many bacterial diseases. In this way, pathogens manipulate the host cell for their own survival. The better understanding of epigenetic consequences in bacterial infection may open the door for designing new vaccine approaches and therapeutic implications. This article characterizes selected intracellular bacterial pathogens, including Mycobacterium spp., Listeria spp., Chlamydia spp., Mycoplasma spp., Rickettsia spp., Legionella spp. and Yersinia spp., which can modulate and reprogram of defense genes in host innate immune cells.

Trained Innate Immunity Not Always Amicable.

The concept of „trained innate immunity" is understood as the ability of innate immune cells to remember invading agents and to respond nonspecifically to reinfection with increased strength. Trained immunity is orchestrated by epigenetic modifications leading to changes in gene expression and cell physiology. Although this phenomenon was originally seen mainly as a beneficial effect, since it confers broad immunological protection, enhanced immune response of reprogrammed innate immune cells might result in the development or persistence of chronic metabolic, autoimmune or neuroinfalmmatory disorders. This paper overviews several examples where the induction of trained immunity may be essential in the development of diseases characterized by flawed innate immune response.

Effect of Cyclophosphamide Treatment on Central and Effector Memory T Cells in Mice.

Immunological memory is a key feature of adaptive immunity. It provides the organism with long-lived and robust protection against infection. The important question is whether cyclophosphamide (CP), as immunosuppressive agent used in cancer therapy and in some autoimmune diseases, may act on the memory T-cell population. We investigated the effect of CP on the percentage of central memory T cells (TCM) and effector memory T cells (TEM) in the mouse model of CP-induced immunosuppression (8-10-week-old male C57BL/6 mice CP treated for 7 days at the daily dose of 50 µg/g body weight [bw], manifested the best immunosuppression status, as compared to lower doses of CP: 10 or 20 µg/g bw). The CP induced a significant decrease in the percentage of CD8+ (TCM), compared to nonimmunosuppressed mice. This effect was not observed in the case of CD4+ TCM population. The percentage of gated TEM with CD4 and CD8 phenotype was significantly decreased in CP-treated mice, as compared to the control ones. Taken together, the above data indicate that CP-induced immunosuppression in mice leads to a reduction in the abundance of central memory cells possessing preferentially CD8+ phenotype as well as to a reduction in the percentage of effector memory cells (splenocytes both CD4+ and CD8+), compared to the cells from nonimmunosuppressed mice. These findings in mice described in this article may contribute to the understanding of the complexity of the immunological responses in humans and extend research on the impact of the CP model of immunosuppression in mice and memory T-cell populations.

Infectious Agents as Stimuli of Trained Innate Immunity.

The discoveries made over the past few years have modified the current immunological paradigm. It turns out that innate immunity cells can mount some kind of immunological memory, similar to that observed in the acquired immunity and corresponding to the defense mechanisms of lower organisms, which increases their resistance to reinfection. This phenomenon is termed trained innate immunity. It is based on epigenetic changes in innate immune cells (monocytes/macrophages, NK cells) after their stimulation with various infectious or non-infectious agents. Many infectious stimuli, including bacterial or fungal cells and their components (LPS, ß-glucan, chitin) as well as viruses or even parasites are considered potent inducers of innate immune memory. Epigenetic cell reprogramming occurring at the heart of the phenomenon may provide a useful basis for designing novel prophylactic and therapeutic strategies to prevent and protect against multiple diseases. In this article, we present the current state of art on trained innate immunity occurring as a result of infectious agent induction. Additionally, we discuss the mechanisms of cell reprogramming and the implications for immune response stimulation/manipulation.

Binding of CXCL8/IL-8 to Mycobacterium tuberculosis Modulates the Innate Immune Response.

Interleukin-8 (IL-8) has been implicated in the pathogenesis of several human respiratory diseases, including tuberculosis (TB). Importantly and in direct relevance to the objectives of this report quite a few findings suggest that the presence of IL-8 may be beneficial for the host. IL-8 may aid with mounting an adequate response during infection with Mycobacterium tuberculosis (M. tb); however, the underlying mechanism remains largely unknown. The major goal of our study was to investigate the contribution of IL-8 to the inflammatory processes that are typically elicited in patients with TB. We have shown for the first time that IL-8 can directly bind to tubercle bacilli. We have also demonstrated that association of IL-8 with M. tb molecules leads to the augmentation of the ability of leukocytes (neutrophils and macrophages) to phagocyte and kill these bacilli. In addition, we have shown that significant amount of IL-8 present in the blood of TB patients associates with erythrocytes. Finally, we have noted that IL-8 is the major chemokine responsible for recruiting T lymphocytes (CD3(+), CD4(+), and CD8(+) T cells). In summary, our data suggest that the association of IL-8 with M. tb molecules may modify and possibly enhance the innate immune response in patients with TB.

[Immunosuppression - tough ally in torrid time]. / Immunosupresja ­ wymagajacy sprzymierzeniec na trudne czasy.

Immunosuppression is a condition characterized by weakened or inhibited immune response. It occurred both in humoral and cellular response. This is related to the variable levels of deficiency for each antibody class (IgG, IgM, IgA) and a decrease in the number and function of immune cells, mainly T cells which results in the inhibition of cytokine production, signaling transduction and clonal expansion. Immunosuppressive therapy is used in many fields of medicine, such as transplantology, oncology, autoimmune disorders. Immunosuppression can be induced in several ways, by the surgical resection of the organs of the immune system, physical methods using X-rays or chemical methods using pharmacological agents. The most common way to induce immunosuppression is the administration of immunosuppressive drugs, amongst others: glucocorticoids, cytostatic drugs, immunophilin-binding agents, monoclonal antibodies. Unfortunately, the desired therapeutic effects of immunosuppression may be accompanied by a number of side effects associated with both impaired immunity (susceptibility to infections, including those caused by opportunistic microorganisms), toxic effects on the tissues (nephrotoxicity, neurotoxicity), or with a direct impact on the processes of malignancy. This harmful influence can be limited by the modification of the existing drugs, looking for new ones or developing new methods for the controlled kinetics of releasing the immunosuppressive pharmaceuticals. The personalization of immunosuppressant treatment according to genetic/genomic characteristics of individual patient represents the quite innovative look into the issue of immunosuppression.

[Intestinal microbiota transplantation for the treatment of Clostridium difficile infection]. / Przeszczep jelitowej flory bakteryjnej w leczeniu choroby zwiazanej z Clostridium difficile.

The infections caused by C. difficile, responsible for the antibiotic-associated diarrhea and pseudomembranous colitis, are the growing health problem. An increasing number of C. difficile infection (CDI) cases and the phenomenon of multidrug-resistance of bacteria forces to find new, effective therapeutic methods. Intestinal microbiota transplantation ("fecal bacteriotherapy") is a promising remedy for patients suffering from recurrent, severe, not susceptible to standard treatments intestinal infection caused by C. difficile. Low cost, easy implementation and high efficiency at a short time treatment cause that it is a method increasingly tested and practiced by physicians. However, it is required to standardize the treatment procedure, as well as better understanding the biological mechanisms on which the treatment is based on.

Silencing Bruton's tyrosine kinase in alveolar neutrophils protects mice from LPS/immune complex-induced acute lung injury.

Previous observations made by our laboratory indicate that Bruton's tyrosine kinase (Btk) may play an important role in the pathophysiology of local inflammation in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). We have shown that there is cross talk between FcγRIIa and TLR4 in alveolar neutrophils from patients with ALI/ARDS and that Btk mediates the molecular cooperation between these two receptors. To study the function of Btk in vivo we have developed a unique two-hit model of ALI: LPS/immune complex (IC)-induced ALI. Furthermore, we conjugated F(ab)2 fragments of anti-neutrophil antibodies (Ly6G1A8) with specific siRNA for Btk to silence Btk specifically in alveolar neutrophils. It should be stressed that we are the first group to perform noninvasive transfections of neutrophils, both in vitro and in vivo. Importantly, our present findings indicate that silencing Btk in alveolar neutrophils has a dramatic protective effect in mice with LPS/IC-induced ALI, and that Btk regulates neutrophil survival and clearance of apoptotic neutrophils in this model. In conclusion, we put forward a hypothesis that Btk-targeted neutrophil specific therapy is a valid goal of research geared toward restoring homeostasis in lungs of patients with ALI/ARDS.

Innate Lymphoid Cells and Their Role in the Immune Response to Infections.

Over the past decade, a group of lymphocyte-like cells called innate lymphoid cells (ILCs) has gained considerable attention due to their crucial role in regulating immunity and tissue homeostasis. ILCs, lacking antigen-specific receptors, are a group of functionally differentiated effector cells that act as tissue-resident sentinels against infections. Numerous studies have elucidated the characteristics of ILC subgroups, but the mechanisms controlling protective or pathological responses to pathogens still need to be better understood. This review summarizes the functions of ILCs in the immunology of infections caused by different intracellular and extracellular pathogens and discusses their possible therapeutic potential.

Bruton's tyrosine kinase mediates FcγRIIa/Toll-like receptor-4 receptor crosstalk in human neutrophils.

Previous observations by our laboratory indicate that the presence of anti-IL-8 autoantibody:IL-8 immune complexes in lung fluids from patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) comprises an important prognostic indicator in the development and ultimate outcome of ALI/ARDS. We also showed that these complexes display proinflammatory activity toward neutrophils through the engagement of FcγRIIa receptors. Because sepsis is one of the most common risk factors for ALI/ARDS, the initial goal of our present study involved investigating the effects of LPS on the expression of FcγRIIa receptors in neutrophils. Our results indicate that LPS triggers an increase in the expression of FcγRIIa on the neutrophil surface, which leads to shortening of the molecular distance between FcγRIIa and Toll-like receptor-4 (TLR4). When such neutrophils are stimulated with anti-IL-8:IL-8 complexes, the TLR4 cascade becomes activated via the engagement of FcγRIIa. The underlying molecular mechanism has been subsequently examined and involves Bruton's tyrosine kinase (Btk). In conclusion, our study reveals the existence of Btk-dependent molecular cooperation between FcγRIIa and TLR4 signaling cascades in LPS-"primed" human neutrophils. Furthermore, we used fluorescence lifetime imaging to study the interactions between TLR4 and FcγRIIa in human alveolar neutrophils from patients with ALI/ARDS. The results from these experiments confirm the existence of the molecular cooperation between TLR4 and FcγRIIa.

Monocyte signal transduction receptors in active and latent tuberculosis.

The mechanisms that promote either resistance or susceptibility to TB disease remain insufficiently understood. Our aim was to compare the expression of cell signaling transduction receptors, CD14, TLR2, CD206, and ß2 integrin LFA-1 on monocytes from patients with active TB or nonmycobacterial lung disease and healthy individuals with M.tb latency and uninfected controls to explain the background of the differences between clinical and subclinical forms of M.tb infection. A simultaneous increase in the expression of the membrane bound mCD14 receptor and LFA-1 integrin in patients with active TB may be considered a prodrome of breaking immune control by M.tb bacilli in subjects with the latent TB and absence of clinical symptoms.

Influence of phytocenosis on the medical potential of moss extracts: the Pleurozium schreberi (Willd. ex Brid.) Mitt. case.

The question was asked "whether plant phytocenosis has an impact on the medical potential of the extracts from Pleurozium schreberi". Moss samples were collected from four different phytocoenoses: mixed forest (oak-pine forest), a forest tract in pine forest, 5-15-year-old pine forest and 50-year-old pine forest. Chemical composition of the extracts, antioxidative capacity (FRAP and ABTS·+ assays), as well as biological activities including cytotoxicity for the mouse fibroblasts L929 line (MTT reduction assay), biostatic/biocidal effect against selected bacteria and fungi (broth microdilution method followed by culture on solid media), and regenerative properties on human fibroblasts HFF-1 line (scratch assay) were tested. The conducted research clearly proves that phytocenosis determines the quality of moss extracts. The analyses showed that in every examined aspect the IV-7 extract (obtained from a specimen collected in a Pinus sylvestris L. forest, monoculture up to 15 years old) exhibited the highest values and the strongest activity. Other extracts of the same species but growing in other phytocenoses-in a mixed forest (IV-5), a forest tract in a Pinus sylvestris monoculture forest (IV-6) and in a P. sylvestris forest of pine monoculture about 50 years old (IV-8) showed much weaker activity and lower values of the above-mentioned parameters. At the same time, none of the tested extracts exerted a pro-regenerative effect. The P. schreberi extracts were characterized by a varied total content of phenolic compounds in the range from 0.63 ± 0.02 to 14.01 ± 0.25 mg/g of plant material. UPLC/MS analysis showed a varied phenolic profile of the extracts, with caffeoylquinic acid and quercetin triglucoside predominating in all of them.

Novel aspects of urokinase function in the injured lung: role of α2-macroglobulin.

The level of active urokinase (uPA) is decreased in lung fluids of patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) whereas α(2)-macroglobulin (α(2)-M), a plasma proteinase inhibitor, is a major component of these fluids. Since there have been reports describing the ability of α(2)-M to form complexes with uPA in vitro, we hypothesized that α(2)-M may interact with uPA in the lung to modulate its biological activity. Pulmonary edema fluids and lung tissues from patients with ALI/ARDS were evaluated for the presence of uPA associated with α(2)-M. Complexes between α(2)-M and uPA were detected in alveolar edema fluids as well as in lungs of patients with ALI/ARDS where they were located mainly in close proximity to epithelial cells. While uPA bound to α(2)-M retains its amidolytic activity towards low-molecular-weight substrates, it is not inhibited by its main physiological inhibitor, plasminogen activator inhibitor 1. We also investigated the functional consequences of formation of complexes between uPA and α(2)-M in vitro. We found that when α(2)-M:uPA complexes were added to cultures of human bronchial epithelial cells (BEAS-2B), activation of nuclear factor-κB as well as production of interleukin-6 and -8 was substantially suppressed compared with the addition of uPA alone. Our findings indicate for the first time that the function of uPA in patients with ALI/ARDS may be modulated by α(2)-M and that the effects may include the regulation of the fibrinolytic and signaling activities of uPA.

Interaction of Helicobacter pylori with C-type lectin dendritic cell-specific ICAM grabbing nonintegrin.

In this study we asked whether Helicobacter pylori whole cells and lipopolysaccharide (LPS) utilize sugar moieties of Lewis (Le) antigenic determinants to interact with DC-SIGN (dendritic cell specific ICAM grabbing nonintegrin) receptor on dendritic cells (DCs). For this purpose the soluble DC-SIGN/Fc adhesion assay and the THP-1 leukemia cells with induced expression of DC-SIGN were used. We showed that the binding specificity of DC-SIGN with H. pylori Le(X/Y) positive whole cells and H. pylori LPS of Le(X/Y) type was fucose dependent, whereas in Le(XY) negative H. pylori strains and LPS preparations without Lewis determinants, this binding was galactose dependent. The binding of soluble synthetic Le(X) and Le(Y) to the DC-SIGN-like receptor on THP-1 cells was also observed. In conclusion, the Le(XY) dependent as well as independent binding of H. pylori whole cells and H. pylori LPS to DC-SIGN was described. Moreover, we demonstrated that THP-1 cells may serve as an in vitro model for the assessment of H. pylori-DC-SIGN interactions mediated by Le(X) and Le(Y) determinants.

Latent M. tuberculosis infection--pathogenesis, diagnosis, treatment and prevention strategies.

One third of the earths population is infected with Mycobacterium tuberculosis (Mtb), but only 5-10% of the infected individuals develop active tuberculosis (TB) over their lifetime. The remaining 90-95% stay healthy and are called latently infected individuals. They are the biggest reservoir of the tubercle bacilli and identifying the cases of latent TB is a part of the global plan of TB control. From the clinical point of view detection of latent TB infections (LTBI) in individuals with the highest active TB risk including cases of HIV infection, autoimmune inflammatory diseases or cancer, is a priority. This review summarizes the recent findings in the pathogenesis of latent TB, its diagnosis, treatment and prevention.

Corrigendum to: Diversity and Functionality of Mycobacterial Mycolic Acids in Relation to Host-pathogen Interactions.

The author requested to revise the acknowledgements section of the following article [1]. In this correction, the acknowledgements have been revised in the article entitled "Diversity and Functionality of Mycobacterial Mycolic Acids in Relation to Host-pathogen Interactions" in the journal Current Medicinal Chemistry, 2017, 24(38), 4267-4278. Details of corrections are provided here. The original article can be found online at http://dx.doi.org/10.2174/0929867324666170823130445 We regret any errors and apologize to the readers. Original ACKNOWLEDGEMENTS This work was supported by National Science Centre (Poland) under grant no. 2016/21/B/NZ7/01771 and 2013/11/B/NZ6/01304. Corrected ACKNOWLEDGEMENTS This work was supported by National Science Centre (Poland) under grant no. 2013/11/B/NZ6/01304.

BCG and SARS-CoV-2-What Have We Learned?

Despite controversy over the protective effect of the BCG (Bacille Calmette-Guérin) vaccine in preventing pulmonary tuberculosis (TB) in adults, it has been used worldwide since 1921. Although the first reports in the 1930s had noted a remarkable decrease in child mortality after BCG immunization, this could not be explained solely by a decrease in mortality from TB. These observations gave rise to the suggestion of nonspecific beneficial effects of BCG vaccination, beyond the desired protection against M. tuberculosis. The existence of an innate immunity-training mechanism based on epigenetic changes was demonstrated several years ago. The emergence of the pandemic caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2) in 2019 revived the debate about whether the BCG vaccine can affect the immune response against the virus or other unrelated pathogens. Due to the mortality of the coronavirus disease (COVID-19), it is important to verify each factor that may have a potential protective value against the severe course of COVID-19, complications, and death. This paper reviews the results of numerous retrospective studies and prospective trials which shed light on the potential of a century-old vaccine to mitigate the pandemic impact of the new virus. It should be noted, however, that although there are numerous studies intending to verify the hypothesis that the BCG vaccine may have a beneficial effect on COVID-19, there is no definitive evidence on the efficacy of the BCG vaccine against SARS-CoV-2.

Mycobacterium bovis Wild-Type BCG or Recombinant BCG Secreting Murine IL-18 (rBCG/IL-18) Strains in Driving Immune Responses in Immunocompetent or Immunosuppressed Mice.

Mycobacterium tuberculosis infections remain a global health problem in immunosuppressed patients. The effectiveness of BCG (Bacillus Calmette−Guérin), an anti-tuberculosis vaccine, is unsatisfactory. Finding a new vaccine candidate is a priority. We compared numerous immune markers in BCG-susceptible C57BL/6 and BCG-resistant C3H mice who had been injected with 0.9% NaCl (control) or with wild-type BCG or recombinant BCG secreting interleukin (IL)-18 (rBCG/IL-18) and in immunized mice who were immunocompromised with cyclophosphamide (CTX). The inoculation of rBCG/IL-18 in immunocompetent mice increased the percentage of bone marrow myeloblasts and promyelocytes, which were further elevated in the rBCG/IL-18/CTX-treated mice: C57BL/6 mice­3.0% and 11.4% (control) vs. 18.6% and 42.4%, respectively; C3H mice­1.1% and 7.7% (control) vs. 18.4% and 44.9%, respectively, p < 0.05. The bone marrow cells showed an increased mean fluorescence index (MFI) in the CD34 adhesion molecules: C57BL/6 mice­4.0 × 103 (control) vs. 6.2 × 103; C3H mice­4.0 × 103 (control) vs. 8.0 × 103, p < 0.05. Even in the CTX-treated mice, the rBCG/IL-18 mobilized macrophages for phagocytosis, C57BL/6 mice­4% (control) vs. 8%; C3H mice­2% (control) vs. 6%, and in immunocompetent mice, C57BL/6 induced the spleen homing of effector memory CD4+ and CD8+ T cells (TEM), 15% (control) vs. 28% and 8% (control) vs. 22%, respectively, p < 0.05. In conclusion, rBCG/IL-18 effectively induced selected immune determinants that were maintained even in immunocompromised mice.