TNF in Human Tuberculosis: A Double-Edged Sword

TNF, a pleiotropic proinflammatory cytokine, is important for protective immunity and immunopathology during Mycobacterium tuberculosis (Mtb) infection, which causes tuberculosis (TB) in humans. TNF is produced primarily by phagocytes in the lungs during the early stages of Mtb infection and performs diverse physiological and pathological functions by binding to its receptors in a context-dependent manner. TNF is essential for granuloma formation, chronic infection prevention, and macrophage recruitment to and activation at the site of infection. In animal models, TNF, in cooperation with chemokines, contributes to the initiation, maintenance, and clearance of mycobacteria in granulomas. Although anti-TNF therapy is effective against immune diseases such as rheumatoid arthritis, it carries the risk of reactivating TB. Furthermore, TNF-associated inflammation contributes to cachexia in patients with TB. This review focuses on the multifaceted role of TNF in the pathogenesis and prevention of TB and underscores the importance of investigating the functions of TNF and its receptors in the establishment of protective immunity against and in the pathology of TB.Such investigations will facilitate the development of therapeutic strategies that target TNF signaling, which makes beneficial and detrimental contributions to the pathogenesis of TB.

Host-Pathogen Interactions Operative during Mycobacteroides abscessus Infection

Mycobacteroides abscessus (previously Mycobacteroides abscessus; Mabc), one of rapidly growing nontuberculous mycobacteria (NTM), is an important pathogen of NTM pulmonary diseases (NTM-PDs) in both immunocompetent and immunocompromised individuals. Mabc infection is chronic and often challenging to treat due to drug resistance, motivating the development of new therapeutics. Despite this, there is a lack of understanding of the relationship between Mabc and the immune system. This review highlights recent progress in the molecular architecture of Mabc and host interactions. We discuss several microbial components that take advantage of host immune defenses, host defense pathways that can overcome Mabc pathogenesis, and how host-pathogen interactions determine the outcomes of Mabc infection. Understanding the molecular mechanisms underlying host-pathogen interactions during Mabc infection will enable the identification of biomarkers and/or drugs to control immune pathogenesis and protect against NTM infection.

COVID-19 patients upregulate toll-like receptor 4-mediated inflammatory signaling that mimics bacterial sepsis

Observational studies of the ongoing coronavirus disease 2019 (COVID-19) outbreak suggest that a cytokine storm is involved in the pathogenesis of severe illness. However, the molecular mechanisms underlying the altered pathological inflammation in COVID-19 are largely unknown. We report here that toll-like receptor (TLR) 4-mediated inflammatory signaling molecules are upregulated in peripheral blood mononuclear cells (PBMCs) from COVID-19 patients, compared with healthy controls. Among the most highly increased inflammatory mediators in severe/critically ill patients, S100A9, an alarmin and TLR4 ligand, was found as a noteworthy biomarker, because it inversely correlated with the serum albumin levels. These data support a link between TLR4 signaling and pathological inflammation during COVID-19 and contribute to develop therapeutic approaches through targeting TLR4-mediated inflammation.

Host-Pathogen Dialogues in Autophagy, Apoptosis, and Necrosis during Mycobacterial Infection

Mycobacterium tuberculosis (Mtb) is an etiologic pathogen of human tuberculosis (TB), a serious infectious disease with high morbidity and mortality. In addition, the threat of drug resistance in anti-TB therapy is of global concern. Despite this, it remains urgent to research for understanding the molecular nature of dynamic interactions between host and pathogens during TB infection. While Mtb evasion from phagolysosomal acidification is a well-known virulence mechanism, the molecular events to promote intracellular parasitism remains elusive. To combat intracellular Mtb infection, several defensive processes, including autophagy and apoptosis, are activated. In addition, Mtb-ingested phagocytes trigger inflammation, and undergo necrotic cell death, potentially harmful responses in case of uncontrolled pathological condition. In this review, we focus on Mtb evasion from phagosomal acidification, and Mtb interaction with host autophagy, apoptosis, and necrosis.Elucidation of the molecular dialogue will shed light on Mtb pathogenesis, host defense, and development of new paradigms of therapeutics.

The Roles of Chemokines in Immune Response to Mycobacterial Infection

Tuberculosis (TB), a global and deadly infectious disease caused by Mycobacterium tuberculosis (Mtb), is manifested with host immune reaction. The balanced regulation between protective immune and pathologic inflammatory responses is critical to control progression to TB. Chemokines are a large family of cytokines that play an essential role for chemotaxis of immune and inflammatory cells to the sites of infection. Numerous chemokines including CXCL10 were reported as potential biomarkers of various stages of TB infection. In addition, several chemokines and their receptors play as key players to coordinate host immune defense as innate effectors and mediators of adaptive immune responses.Accumulating evidence suggests that some chemokines, if uncontrolled, are associated with host pathological inflammation during infection. In this review, we will discuss recent advances in understanding which chemokines have potentials as diagnostic markers. In addition, we focus the roles and mechanisms by which chemokines and their receptors are involved in both host immune protection and pathology during TB infection. The controlled activation of chemokine system will determine the coordinated biological outcomes of innate immune responses during pathogenic infection.

COVID-19 Patients Upregulate Toll-like Receptor 4-mediated Inflammatory Signaling That Mimics Bacterial Sepsis

Background@#Observational studies of the ongoing coronavirus disease 2019 (COVID-19) outbreak suggest that a ‘cytokine storm’ is involved in the pathogenesis of severe illness.However, the molecular mechanisms underlying the altered pathological inflammation in COVID-19 are largely unknown. We report here that toll-like receptor (TLR) 4-mediated inflammatory signaling molecules are upregulated in peripheral blood mononuclear cells (PBMCs) from COVID-19 patients, compared with healthy controls (HC). @*Methods@#A total of 48 subjects including 28 COVID-19 patients (8 severe/critical vs. 20 mild/ moderate cases) admitted to Chungnam National University Hospital, and age/sex-matched 20 HC were enrolled in this study. PBMCs from the subjects were processed for nCounter Human Immunology gene expression assay to analyze the immune related transcriptome profiles. Recombinant proteins of severe acute respiratory syndrome coronavirus-2 (SARSCoV-2) were used to stimulate the PBMCs and monocyte-derived macrophages, and real-time polymerase chain reaction was performed to quantify the mRNA expressions of the proinflammatory cytokines/chemokines. @*Results@#Among the most highly increased inflammatory mediators in severe/critically ill patients, S100A9, an alarmin and TLR4 ligand, was found as a noteworthy biomarker, because it inversely correlated with the serum albumin levels. We also observed that recombinant S2 and nucleocapsid proteins of SARS-CoV2 significantly increased proinflammatory cytokines/chemokines and S100A9 in human primary PBMCs. @*Conclusion@#These data support a link between TLR4 signaling and pathological inflammation during COVID-19 and contribute to develop therapeutic approaches through targeting TLR4-mediated inflammation.

Vitamin D-Cathelicidin Axis: at the Crossroads between Protective Immunity and Pathological Inflammation during Infection

Vitamin D signaling plays an essential role in innate defense against intracellular microorganisms via the generation of the antimicrobial protein cathelicidin. In addition to directly binding to and killing a range of pathogens, cathelicidin acts as a secondary messenger driving vitamin D-mediated inflammation during infection. Recent studies have elucidated the biological and clinical functions of cathelicidin in the context of vitamin D signaling. The vitamin D-cathelicidin axis is involved in the activation of autophagy, which enhances antimicrobial effects against diverse pathogens. Vitamin D studies have also revealed positive and negative regulatory effects of cathelicidin on inflammatory responses to pathogenic stimuli. Diverse innate and adaptive immune signals crosstalk with functional vitamin D receptor signals to enhance the role of cathelicidin action in cell-autonomous effector systems. In this review, we discuss recent findings that demonstrate how the vitamin D-cathelicidin pathway regulates autophagy machinery, protective immune defenses, and inflammation, and contributes to immune cooperation between innate and adaptive immunity. Understanding how the vitamin D-cathelicidin axis operates in the host response to infection will create opportunities for the development of new therapeutic approaches against a variety of infectious diseases.

Host-Pathogen Dialogues in Autophagy, Apoptosis, and Necrosis during Mycobacterial Infection

Mycobacterium tuberculosis (Mtb) is an etiologic pathogen of human tuberculosis (TB), a serious infectious disease with high morbidity and mortality. In addition, the threat of drug resistance in anti-TB therapy is of global concern. Despite this, it remains urgent to research for understanding the molecular nature of dynamic interactions between host and pathogens during TB infection. While Mtb evasion from phagolysosomal acidification is a well-known virulence mechanism, the molecular events to promote intracellular parasitism remains elusive. To combat intracellular Mtb infection, several defensive processes, including autophagy and apoptosis, are activated. In addition, Mtb-ingested phagocytes trigger inflammation, and undergo necrotic cell death, potentially harmful responses in case of uncontrolled pathological condition. In this review, we focus on Mtb evasion from phagosomal acidification, and Mtb interaction with host autophagy, apoptosis, and necrosis.Elucidation of the molecular dialogue will shed light on Mtb pathogenesis, host defense, and development of new paradigms of therapeutics.

The Roles of Chemokines in Immune Response to Mycobacterial Infection

Tuberculosis (TB), a global and deadly infectious disease caused by Mycobacterium tuberculosis (Mtb), is manifested with host immune reaction. The balanced regulation between protective immune and pathologic inflammatory responses is critical to control progression to TB. Chemokines are a large family of cytokines that play an essential role for chemotaxis of immune and inflammatory cells to the sites of infection. Numerous chemokines including CXCL10 were reported as potential biomarkers of various stages of TB infection. In addition, several chemokines and their receptors play as key players to coordinate host immune defense as innate effectors and mediators of adaptive immune responses.Accumulating evidence suggests that some chemokines, if uncontrolled, are associated with host pathological inflammation during infection. In this review, we will discuss recent advances in understanding which chemokines have potentials as diagnostic markers. In addition, we focus the roles and mechanisms by which chemokines and their receptors are involved in both host immune protection and pathology during TB infection. The controlled activation of chemokine system will determine the coordinated biological outcomes of innate immune responses during pathogenic infection.

Effector Pathways of Toll-like Receptor-inducible Innate Immune Responses in Macrophages

Toll-like receptors (TLR) are well-characterized pattern recognition receptors that can recognize and respond to diverse pathogen-associated or danger-associated molecular patterns during infection. TLR signaling in macrophages triggers in the intracellular signaling pathways through the recruitment of various adaptor and signaling proteins, and results in the activation of effector mechanisms and pathways that are important for host defense to intracellular bacteria. Effector mechanisms include inflammatory responses, cytokine generation, production of reactive oxygen species, and antimicrobial proteins. Accumulating studies showed that autophagy is a key pathway in the maintenance of homeostasis and housekeeping functions during infection and inflammation. In this review, we summarize the major effector pathways and mechanisms in the activation of TLR-inducible innate immune responses in macrophages. In addition, we focus the emerging evidence of crosstalk between autophagy and TLR-mediated signaling in terms of effector function of innate immune responses. A better understanding of effector functions by the activation of TLR-mediated signaling cascades contributes to the development of new therapeutics and vaccines against various intracellular pathogenic infections.

The Effects of Staphylococci on the Degranulation of Human Mast Cell-1

Atopic dermatitis (AD) is characterized by disturbances in epidermal barrier functions and the hyperactive immune response. Staphylococcus aureus (S. aureus) can be cultured from 90% of AD skin lesions and can exacerbate or contribute to the persistent skin inflammation in AD by secreting toxins with superantigenic properties. Superantigens can induce mast cell (MC) degranulation after penetrating the epidermal barrier. The role of MCs in AD is suggested by the increase in the MC number and MC activation. MCs are activated for degranulation and mediator release by allergens that cross-link IgE molecules or by microbial products. Therefore, MCs may be critically involved in the pathogenesis of AD. However, the understanding mechanisms of MC degranulation by S. aureus in relation to AD have still not been fully elucidated. In this study, we found that live S. aureus or methicillin-resistant S. aureus (MRSA) but not heat-killed bacteria induced MC degranulation. The heat-treatment partially inhibited MC degranulation by conditioned media (CM) of S. aureus or MRSA. The calcium chelator ethylene glycol tetraacetic acid (EGTA) did not block MC degranulation induced by live S. aureus or MRSA, but EGTA-treatment partially inhibited MC degranulation by CM from S. aureus or MRSA. These results suggest that live S. aureus and MRSA can degranulate MCs via direct interaction which may be important role in AD.

The Effects of Staphylococci on the Degranulation of Human Mast Cell-1

Atopic dermatitis (AD) is characterized by disturbances in epidermal barrier functions and the hyperactive immune response. Staphylococcus aureus (S. aureus) can be cultured from 90% of AD skin lesions and can exacerbate or contribute to the persistent skin inflammation in AD by secreting toxins with superantigenic properties. Superantigens can induce mast cell (MC) degranulation after penetrating the epidermal barrier. The role of MCs in AD is suggested by the increase in the MC number and MC activation. MCs are activated for degranulation and mediator release by allergens that cross-link IgE molecules or by microbial products. Therefore, MCs may be critically involved in the pathogenesis of AD. However, the understanding mechanisms of MC degranulation by S. aureus in relation to AD have still not been fully elucidated. In this study, we found that live S. aureus or methicillin-resistant S. aureus (MRSA) but not heat-killed bacteria induced MC degranulation. The heat-treatment partially inhibited MC degranulation by conditioned media (CM) of S. aureus or MRSA. The calcium chelator ethylene glycol tetraacetic acid (EGTA) did not block MC degranulation induced by live S. aureus or MRSA, but EGTA-treatment partially inhibited MC degranulation by CM from S. aureus or MRSA. These results suggest that live S. aureus and MRSA can degranulate MCs via direct interaction which may be important role in AD.

Mitochondrial Control of Innate Immunity and Inflammation

Mitochondria are key organelles involved in energy production, functioning as the metabolic hubs of cells. Recent findings emphasize the emerging role of the mitochondrion as a key intracellular signaling platform regulating innate immune and inflammatory responses. Several mitochondrial proteins and mitochondrial reactive oxygen species have emerged as central players orchestrating the innate immune responses to pathogens and damaging ligands. This review explores our current understanding of the roles played by mitochondria in regulation of innate immunity and inflammatory responses. Recent advances in our understanding of the relationship between autophagy, mitochondria, and inflammasome activation are also briefly discussed. A comprehensive understanding of mitochondrial role in toll-like receptor-mediated innate immune responses and NLRP3 inflammasome complex activation, will facilitate development of novel therapeutics to treat various infectious, inflammatory, and autoimmune disorders.

Small Heterodimer Partner and Innate Immune Regulation

The nuclear receptor superfamily consists of the steroid and non-steroid hormone receptors and the orphan nuclear receptors. Small heterodimer partner (SHP) is an orphan family nuclear receptor that plays an essential role in the regulation of glucose and cholesterol metabolism. Recent studies reported a previously unidentified role for SHP in the regulation of innate immunity and inflammation. The innate immune system has a critical function in the initial response against a variety of microbial and danger signals. Activation of the innate immune response results in the induction of inflammatory cytokines and chemokines to promote anti-microbial effects. An excessive or uncontrolled inflammatory response is potentially harmful to the host, and can cause tissue damage or pathological threat. Therefore, the innate immune response should be tightly regulated to enhance host defense while preventing unwanted immune pathologic responses. In this review, we discuss recent studies showing that SHP is involved in the negative regulation of toll-like receptor-induced and NLRP3 (NACHT, LRR and PYD domains-containing protein 3)-mediated inflammatory responses in innate immune cells. Understanding the function of SHP in innate immune cells will allow us to prevent or modulate acute and chronic inflammation processes in cases where dysregulated innate immune activation results in damage to normal tissues.

Host immune responses to mycobacterial antigens and their implications for the development of a vaccine to control tuberculosis

Tuberculosis (TB) remains a worldwide health problem, causing around 2 million deaths per year. Despite the bacillus Calmette Guerin vaccine being available for more than 80 years, it has limited effectiveness in preventing TB, with inconsistent results in trials. This highlights the urgent need to develop an improved TB vaccine, based on a better understanding of host-pathogen interactions and immune responses during mycobacterial infection. Recent studies have revealed a potential role for autophagy, an intracellular homeostatic process, in vaccine development against TB, through enhanced immune activation. This review attempts to understand the host innate immune responses induced by a variety of protein antigens from Mycobacterium tuberculosis, and to identify future vaccine candidates against TB. We focus on recent advances in vaccine development strategies, through identification of new TB antigens using a variety of innovative tools. A new understanding of the host-pathogen relationship, and the usefulness of mycobacterial antigens as novel vaccine candidates, will contribute to the design of the next generation of vaccines, and to improving the host protective immune responses while limiting immunopathology during M. tuberculosis infection.

Characterization of Proinflammatory Responses and Innate Signaling Activation in Macrophages Infected with Mycobacterium scrofulaceum

Mycobacterium scrofulaceum is an environmental and slow-growing atypical mycobacterium. Emerging evidence suggests that M. scrofulaceum infection is associated with cervical lymphadenitis in children and pulmonary or systemic infections in immunocompromised adults. However, the nature of host innate immune responses to M. scrofulaceum remains unclear. In this study, we examined the innate immune responses in murine bone marrow-derived macrophages (BMDMs) infected with different M. scrofulaceum strains including ATCC type strains and two clinically isolated strains (rough and smooth types). All three strains resulted in the production of proinflammatory cytokines in BMDMs mediated through toll-like receptor-2 and the adaptor MyD88. Activation of MAPKs (extracellular signal-regulated kinase 1/2, and p38, and c-Jun N-terminal kinase) and nuclear receptor (NF)-kappaB together with intracellular reactive oxygen species generation were required for the expression of proinflammatory cytokines in BMDMs. In addition, the rough morphotypes of M. scrofulaceum clinical strains induced higher levels of proinflammatory cytokines, MAPK and NF-kappaB activation, and ROS production than other strains. When mice were infected with different M. scrofulaceum strains, those infected with the rough strain showed the greatest hepatosplenomegaly, granulomatous lesions, and immune cell infiltration in the lungs. Notably, the bacterial load was higher in mice infected with rough colonies than in mice infected with ATCC or smooth strains. Collectively, these data indicate that rough M. scrofulaceum induces higher inflammatory responses and virulence than ATCC or smooth strains.

Toll-like Receptors and NOD-like Receptors in Innate Immune Defense during Pathogenic Infection

In response to invading pathogens, the body immune system develops an immediate defense mechanism, i.e., innate immune response, which is detected in almost all living organisms including mammals, plants, insects, etc. Recent studies have identified numerous innate immune receptors that are able to recognize pathogen-associated molecular patterns and transduce the essential intracellular signaling cascades to mount early and successful host defenses against infectious challenge. Among innate immune receptors, we will focus on two important receptors, toll-like receptors (TLRs) and nucleotide binding oligomerization domain (Nod)-like receptors, and their major intracellular signaling pathways that culminate to activate innate immune effectors and inflammatory mediators during pathogen infection. In this review, we address the recent advances of understanding intracellular signaling mechanisms by which TLRs and NLRs activate host immune defense and inflammation. The role and regulatory mechanisms by which a subet of NLRs-associated inflammasome activation induce interleukin-1beta secretion and their relevance with host defense will be also discussed. Both TLR- and NLR-mediated intracellular signaling networks serve crucial roles in mounting resistance to bacterial and viral infection through synthesis of immune mediators and antimicrobial chemicals during infection.

NLRP3 Inflammasome and Host Protection against Bacterial Infection

The inflammasome is a multi-protein complex that induces maturation of inflammatory cytokines interleukin (IL)-1beta and IL-18 through activation of caspase-1. Several nucleotide binding oligomerization domain-like receptor family members, including NLRP3, recognize unique microbial and danger components and play a central role in inflammasome activation. The NLRP3 inflammasome is critical for maintenance of homeostasis against pathogenic infections. However, inflammasome activation acts as a double-edged sword for various bacterial infections. When the IL-1 family of cytokines is secreted excessively, they cause tissue damage and extensive inflammatory responses that are potentially hazardous for the host. Emerging evidence has shown that diverse bacterial pathogens or their components negatively regulate inflammasome activation to escape the immune response. In this review, we discuss the current knowledge of the roles and regulation of the NLRP3 inflammasome during bacterial infections. Activation and regulation of the NLRP3 inflammasome should be tightly controlled to prevent virulence and pathology during infections. Understanding the roles and regulatory mechanisms of the NLRP3 inflammasome is essential for developing potential treatment approaches against pathogenic infections.

The Role of NLR-related Protein 3 Inflammasome in Host Defense and Inflammatory Diseases / 대한배뇨장애요실금학회지

Among a number of innate receptors, the nucleotide-binding domain leucine-rich repeat containing (NLR) nucleotide oligomerization domain (NOD)-like receptor families are involved in the recognition of cytosolic pathogen- or danger-associated molecules. Activation of these specific sets of receptors leads to the assembly of a multiprotein complex, the inflammasome, leading to the activation of caspase-1 and maturation of the cytokines interleukin (IL)-1beta, IL-18, and IL-33. Among NLRs, NLR-related protein 3 (NLRP3) is one of the best-characterized receptors that activates the inflammasome. There is no doubt that NLRP3 inflammasome activation is important for host defense and effective pathogen clearance against fungal, bacterial, and viral infection. In addition, mounting evidence indicates that the NLRP3 inflammasome plays a role in a variety of inflammatory diseases, including gout, atherosclerosis, and type II diabetes, as well as under conditions of cellular stress or injury. Here, we review recent advances in our understanding of the role of the NLRP3 inflammasome in host defense and various inflammatory diseases.

Autophagy and bacterial infectious diseases

Autophagy is a housekeeping process that maintains cellular homeostasis through recycling of nutrients and degradation of damaged or aged cytoplasmic constituents. Over the past several years, accumulating evidence has suggested that autophagy can function as an intracellular innate defense pathway in response to infection with a variety of bacteria and viruses. Autophagy plays a role as a specialized immunologic effector and regulates innate immunity to exert antimicrobial defense mechanisms. Numerous bacterial pathogens have developed the ability to invade host cells or to subvert host autophagy to establish a persistent infection. In this review, we have summarized the recent advances in our understanding of the interaction between antibacterial autophagy (xenophagy) and different bacterial pathogens.