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Although no precise moment or unique event marks its birth, neuroimmunoendocrinology arguably shares a great deal of history with other medical and biologic disciplines. It originated from empirical observations and suppositions that failed to prevail upon the existing axioms. Despite the widespread resistance to embracing novel ideas, the seeming defeats inspired visionary researchers. Those pioneers managed to systematize the emerging knowledge and were able to contribute to science with real foundations. In consequence, new concepts and ideas arose in physiology, anatomy, endocrinology and early immunology. Together, they gave rise to a budding approach on the integration between the nervous, immune and endocrine systems. Then, neuroimmunoendocrinology emerged as a discipline integrating an intricate system with multidirectional functions and interactions that allow for responding to internal and external threats. Such response is mediated by cytokines, hormones and neurotransmitters, involved in different physiologic mechanisms of the organism homeostasis. Neuroimmunoendocrinology is no longer an area of scientific skepticism; on the contrary, it has cemented its position as a biomedical discipline worldwide for the past 70 years. Now, it offers a better understanding of pathologic processes. Neuroimmunoendocrinology is has established its place as a biomedical discipline worldwide in the past 70 years.

In 2004, a novel mechanism of cellular death, called ‘NETosis’, was described in neutrophils. This mechanism, different from necrosis and apoptosis, is characterized by the release of chromatin webs admixed with microbicidal granular proteins and peptides (NETs). NETs trap and kill a variety of microorganisms. Diverse microorganisms, including Mycobacterium tuberculosis, are NET inducers in vitro. The aim of this study was to examine whether M. tuberculosiscan also induce NETs in vivoand if the NETs are bactericidal to the microorganism. Guinea pigs were intradermally inoculated with M. tuberculosisH37Rv, and the production of NETs was investigated at several time points thereafter. NETs were detected as early as 30 min post-inoculation and were clearly evident by 4 h post-inoculation. NETs produced in vivocontained DNA, myeloperoxidase, elastase, histones, ROS and acid-fast bacilli. Viable and heat-killed M. tuberculosis, as well as Mycobacterium bovisBCG were efficient NET inducers, as were unilamellar liposomes prepared with lipids from M. tuberculosis. In vitro,guinea pig neutrophils also produced NETs in response to M. tuberculosis. However, neither the in vivonor the in vitro-produced NETs were able to kill M. tuberculosis.Nevertheless, in vivo, neutrophils might propitiate recruitment and activation of more efficient microbicidal cells.

Myeloperoxidase (MPO), in the presence of hydrogen peroxide and a halide represent an efficient microbicidal mechanism of phagocytic cells. MPO is abundant in neutrophils which also respond to infection by producing large amounts of reactive oxygen species (ROS). MPO, ROS and halide constitute a very toxic antimicrobial system (called the Klebanoff system or KS). Resting mature macrophages do not contain granular MPO and thus are unable to kill pathogenic mycobacteria and some other microorganisms by this system.

The acid-acting proteinase, cathepsin D (EC 3.4.4.23), was purified from extracts of homogenized rabbit lung and beef lung by autolysis at acid pH, acetone and ammonium sulfate fractionation, column chromatography, and isoelectric focusing. Four isoenzymes were obtained from each source. With acid hemoglobin as the substrate, the proteinase from rabbit lung had a pH optimum of 3.0 and that from beef lung had a pH optimum of 3.6. Their activity was not affected by thiol reagents or by Fe2+, Mn2+, or Mg2+. One isoenzyme from rabbit lung was used to immunize a goat, and one from beef lung was used to immunize a rabbit. In immunoelectrophoresis, each resulting antiserum formed a single precipitin line with its homologous enzyme. They cross-reacted with the other three isoenzymes from the same species, but not with any isoenzyme from the other species. At high concentrations, each antiserum completely inhibited the proteolytic activity of its homologous enzyme. The antiserum against rabbit lung cathepsin D also inhibited the proteolytic activity of rabbit peritoneal and pulmonary macrophages. In limited quantities, this antiserum has now been made commercially available and is being used with labeled antibody techniques to identify under a microscope the presence of cathepsin D in macrophages and to study its role in the pathogenesis of tuberculosis.

ABSTRACTMycobacterium lepraemuriumis the causative agent of murine leprosy, a chronic, granulomatous disease similar to human leprosy. Due to the similar clinical manifestations of human and murine leprosy and the difficulty of growing both bacilli axenically, Mycobacterium lepraeand M. lepraemuriumwere once thought to be closely related, although it was later suggested that M. lepraemuriummight be related to Mycobacterium avium. In this study, the complete genome of M. lepraemuriumwas sequenced using a combination of PacBio and Illumina sequencing. Phylogenomic analyses confirmed that M. lepraemuriumis a distinct species within the M. aviumcomplex (MAC). The M. lepraemuriumgenome is 4.05 Mb in length, which is considerably smaller than other MAC genomes, and it comprises 2,682 functional genes and 1,139 pseudogenes, which indicates that M. lepraemuriumhas undergone genome reduction. An error-prone repair homologue of the DNA polymerase III α-subunit was found to be nonfunctional in M. lepraemurium, which might contribute to pseudogene formation due to the accumulation of mutations in nonessential genes. M. lepraemuriumhas retained the functionality of several genes thought to influence virulence among members of the MAC.IMPORTANCEMycobacterium lepraemuriumseems to be evolving toward a minimal set of genes required for an obligatory intracellular lifestyle within its host, a niche seldom adopted by most mycobacteria, as they are free-living. M. lepraemuriumcould be used as a model to elucidate functions of genes shared with other members of the MAC. Its reduced gene set can be exploited for studying the essentiality of genes in related pathogenic species, which might lead to discovery of common virulence factors or clarify host-pathogen interactions. M. lepraemuriumcan be cultivated in vitroonly under specific conditions and even then with difficulty. Elucidating the metabolic (in)capabilities of M. lepraemuriumwill help develop suitable axenic media and facilitate genetic studies.