Although tuberculosis poses a significant health threat to the global population, it is a challenge to develop new and effective therapeutic strategies. Nitric oxide (NO) and inducible NO synthase (iNOS) are important in innate immune responses to various intracellular bacterial infections, including mycobacterial infections. It is generally recognized that reactive nitrogen intermediates play an effective role in host defense mechanisms against tuberculosis. In a murine model of tuberculosis, NO plays a crucial role in antimycobacterial activity; however, it is controversial whether NO is critically involved in host defense against Mycobacterium tuberculosis in humans. Here, we review the roles of NO in host defense against murine and human tuberculosis. We also discuss the specific roles of NO in the central nervous system and lung epithelial cells during mycobacterial infection. A greater understanding of these defense mechanisms in human tuberculosis will aid in the development of new strategies for the treatment of disease.
Autophagy is an intracellular catabolic process that is essential for a variety of cellular responses. Due to its role in the maintenance of biological homeostasis in conditions of stress, dysregulation or disruption of autophagy may be linked to human diseases such as inflammatory bowel disease (IBD). IBD is a complicated inflammatory colitis disorder; Crohn’s disease and ulcerative colitis are the principal types. Genetic studies have shown the clinical relevance of several autophagy-related genes (ATGs) in the pathogenesis of IBD. Additionally, recent studies using conditional knockout mice have led to a comprehensive understanding of ATGs that affect intestinal inflammation, Paneth cell abnormality and enteric pathogenic infection during colitis. In this review, we discuss the various ATGs involved in macroautophagy and selective autophagy, including ATG16L1, IRGM, LRRK2, ATG7, p62, optineurin and TFEB in the maintenance of intestinal homeostasis. Although advances have been made regarding the involvement of ATGs in maintaining intestinal homeostasis, determining the precise contribution of autophagy has remained elusive. Recent efforts based on direct targeting of ATGs and autophagy will further facilitate the development of new therapeutic opportunities for IBD.
Antimicrobial peptides/proteins are ancient and naturallyoccurring antibiotics in innate immune responses in a variety of organisms. Additionally, these peptides have been recognized as important signaling molecules in regulation of both innate and adaptive immunity. During mycobacterial infection, antimicrobial peptides including cathelicidin, defensin, and hepcidin have antimicrobial activities against mycobacteria, making them promising candidates for future drug development. Additionally, antimicrobial peptides act as immunomodulators in infectious and inflammatory conditions. Multiple crucial functions of cathelicidins in antimycobacterial immune defense have been characterized not only in terms of direct killing of mycobacteria but also as innate immune regulators, i.e., in secretion of cytokines and chemokines, and mediating autophagy activation. Defensin families are also important during mycobacterial infection and contribute to antimycobacterial defense and inhibition of mycobacterial growth both in vitro and in vivo. Hepcidin, although its role in mycobacterial infection has not yet been characterized, exerts antimycobacterial effects in activated macrophages. The present review focuses on recent efforts to elucidate the roles of host defense peptides in innate immunity to mycobacteria.
Mitochondria are inevitable sources for the generation of mitochondrial reactive oxygen species (mtROS) due to their fundamental roles in respiration. mtROS were reported to be bactericidal weapons with an innate effector function during infection. However, the controlled generation of mtROS is vital for the induction of efficient immune responses because excessive production of mtROS with mitochondrial damage leads to sustained inflammation, resulting in pathological outcomes such as sepsis. Here, we discuss the beneficial and detrimental roles of mtROS in the innate immune system during bacterial, viral, and fungal infections. Recent evidence suggests that several pathogens have evolved multiple strategies to modulate mtROS for their own benefit. We are just beginning to understand the mechanisms by which mtROS generation is regulated and how mtROS affect protective and pathological responses during infection. Several agents/small molecules that prevent the uncontrolled production of mtROS are known to be beneficial in the maintenance of tissue homeostasis during sepsis. mtROS-targeted approaches need to be incorporated into preventive and therapeutic strategies against a variety of infections.
SUMMARY This study investigated the profiles of IFN‐γ and its regulatory cytokines (IL‐12, IL‐18 and IL‐10) in response to a purified protein derivative (PPD) antigen in peripheral blood mononuclear cells (PBMC) from 18 HIV‐negative patients with multidrug‐resistant tuberculosis (MDRTB), and compared them with those from 19 healthy tuberculin reactors (HTR). ELISA results showed that following stimulation with PPD, IFN‐γ production was significantly reduced, whereas production of both IL‐18 and IL‐10 was significantly elevated in MDRTB patients compared with HTR. Three out of 18 patients with MDRTB of greater than 4 years duration showed significantly elevated IL‐12 p70 production, induced by in vitro PPD stimulation of their PBMC, when compared with data from HTR. However, when taken as a group, MDRTB patients were similar to HTR in their IL‐12 p70‐producing capacity. IL‐12 p70 protein paralleled IL‐12 p40 protein expression. In addition, the production of IL‐12 p40 was significantly correlated with IL‐10 in all patients, but was not correlated with IFN‐γ. Neutralization of IL‐10 increased IL‐12 p40 about twofold, but did not significantly alter IFN‐γ induction in MDRTB. IFN‐γ in MDRTB was highly correlated with lymphoproliferation and CD4 counts, but was not correlated with IL‐12, IL‐18 or IL‐10 production. Our findings suggest that patients with MDRTB have dysregulated IL‐12, IL‐18 and IL‐10 production during Mycobacterium tuberculosis infection, and the cytokine profiles are similar to those in patients with drug‐sensitive advanced TB previously reported in the literature. In addition, IL‐10 may not have a dominant role in defective IFN‐γ production in patients with MDRTB.
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