is 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,
and
were once thought to be closely related, although it was later suggested that
might be related to
In this study, the complete genome of
was sequenced using a combination of PacBio and Illumina sequencing. Phylogenomic analyses confirmed that
is a distinct species within the
complex (MAC). The
genome 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
has undergone genome reduction. An error-prone repair homologue of the DNA polymerase III α-subunit was found to be nonfunctional in
, which might contribute to pseudogene formation due to the accumulation of mutations in nonessential genes.
has retained the functionality of several genes thought to influence virulence among members of the MAC.
seems 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.
could 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.
can be cultivated
only under specific conditions and even then with difficulty. Elucidating the metabolic (in)capabilities of
will help develop suitable axenic media and facilitate genetic studies.
Summary
Murine leprosy is a natural disease of the mouse, the most popular model animal used in biomedical research; the disease is caused by Mycobacterium lepraemurium (MLM), a successful parasite ...of macrophages. The aim of the study was to test the hypothesis that MLM survives within macrophages because it highly resists the toxic effects of the reactive oxygen intermediaries produced by these cells in response to infection by the microorganism. MLM cells were incubated in the presence of horseradish peroxidase (HRPO)–H2O2–halide for several periods of time. The peroxidative effect of this system was investigated by assessing the changes occurred in (a) lipid composition; (b) viability; and (c) infectivity of the microorganism. Changes in the lipid composition of peroxidated‐ vs. intact‐MLM were analysed by thin layer chromatography. The effect of the peroxidative system on the viability and infectivity of MLM was measured by the alamar blue reduction assay and by its ability to produce an infection in the mouse, respectively. Peroxidation of MLM produced drastic changes in the lipid envelope of the microorganism, killed the bacteria and abolished their ability to produce an in vivo infection in the mouse. In vitro, MLM is highly susceptible to the noxious effects of the HRPO–H2O2–halide system. Although the lipid envelope of MLM might protect the microorganism from the peroxidative substances produced at ‘physiological’ concentrations in vivo, the success of MLM as a parasite of macrophages might rather obey for other reasons. The ability of MLM to enter macrophages without triggering these cells’ oxidative response and the lack of granular MPO in mature macrophages might better explain its success as an intracellular parasite of these cells.
Murine leprosy, caused by Mycobacterium lepraemurium (MLM), is a chronic disease that closely resembles human leprosy. Even though this disease does not directly involve the nervous system, we ...investigated a possible effect on working memory during this chronic infection in Balb/c mice. We evaluated alterations in the dorsal region of the hippocampus and measured peripheral levels of cytokines at 40, 80, and 120 days post-infection. To evaluate working memory, we used the T-maze while a morphometric analysis was conducted in the hippocampus regions CA1, CA2, CA3, and dentate gyrus (DG) to measure morphological changes. In addition, a neurochemical analysis was performed by HPLC. Our results show that, at 40 days post-infection, there was an increase in the bacillary load in the liver and spleen associated to increased levels of IL-4, working memory deterioration, and changes in hippocampal morphology, including degeneration in the four subregions analyzed. Also, we found a decrease in neurotransmitter levels at the same time of infection. Although MLM does not directly infect the nervous system, these findings suggest a possible functional link between the immune system and the central nervous system.
Abstract Background 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. Experimental Under the hypothesis that transforming macrophages into peroxidase-positive (PO+ ) cells, these cells would be able to kill Mycobacterium tuberculosis , in this study, mature macrophages were loaded with exogenous peroxidase and were tested for their capacity to kill the Mycobacterium in the presence or in the absence of hydrogen peroxide. Results It was found that PO-loaded macrophages eagerly ingest M. tuberculosis , but do not show a significant mycobactericidal activity on this microorganism despite that it is highly susceptible to the Klebanoff system in vitro . Failure of PO-loaded macrophages to kill M. tuberculosis may obey either to an inappropriate location of the exogenous PO in these cells or more likely, to the presence of efficient detoxifying mechanisms in the bacteria. On the contrary, MPO-loaded or unloaded macrophages efficiently killed Listeria monocytogenes. Conclusion The lack of granular MPO in mature macrophages, and the predilection of mycobacteria to infect these cells are two situations that favor the development of tuberculosis and related diseases, such as leprosy and Buruli ulcer.
•Low expression of IL-6 and TNF-α correlates with IκBNS and BCL-3 in uterus.•IκBNS and BCL-3 are expressed in uterus.•IκBNS and BCL-3 control the expression of IL-6 and TNF-α in murine uterus.
The ...dynamic regulation of NF-κB activity in the uterus maintains a favorable environment of cytokines necessary to prepare for pregnancy throughout the estrous cycle. Recently, the mechanisms that directly regulate the NF-κB transcriptional activity in different tissues are of growing interest. IκBNS and BCL-3 are negative nuclear regulators of NF-κB activity that regulate IL-6 and TNF-α transcription, respectively. Both cytokines have been described as important factors in the remodeling of uterus for blastocyst implantation. In this work we analyzed in ICR mice the mRNA expression and protein production profile of IL-6, TNF-α, and their correspondent negative transcription regulators IκBNS or BCL-3 using real-time PCR, western blot and immunochemistry. We found that the expression of TNF-α and IL-6 was oscillatory along the estrous cycle, and its low expression coincided with the presence of BCL-3 and IκBNS, and vice versa, when the presence of the regulators was subtle, the expression of TNF-α and IL-6 was exacerbated. When we compared the production of TNF-α and IL-6 in the different estrous stages relating with diestrus we found that at estrus there is an important increase of the cytokines (p<0.05) decreasing at metestrus to reach the basal expression at diestrus. In the immunochemistry analysis we found that at diestrus BCL-3 is distributed all over the tissue with a barely detected TNF-α, but on the contrary, at estrus the expression of BCL-3 is not detected with TNF-α clearly observable along the tissue; the same phenomenon occur in the analysis of IκBNS and IL-6. With that evidence we suggest that the expression of TNF-α and IL-6 might be regulated through NF-κB nuclear regulators BCL-3 and IκBNS in the uterus of mice as has been demonstrated in other systems.
Resident alveolar macrophages, dendritic cells, and immigrating neutrophils (NEU) are the first cells to contact
in the lung. These cells, and additional lymphoid cells in the developing granuloma, ...release a series of components that may concentrate in the serum and affect disease progression.
The aim of this study was to investigate the effect of the serum from tuberculosis (TB) patients and their household contacts (HHC) on the nuclear morphology of NEU.
NEU from healthy (HLT) people were incubated with sera from patients with active pulmonary TB, their HHC, and unrelated people. Changes in the nuclear morphology of NEU were analyzed by light and electron microscopy.
Sera from patients with TB induced changes in the nuclear morphology of NEU that included pyknosis, swelling, apoptosis, and netosis in some cases. Sera from some HHC induced similar changes, while sera from HLT people had no significant effects. Bacteria did not appear to participate in this phenomenon because bacteremia is not a recognized feature of nonmiliary TB, and because sera from patients that induced nuclear changes maintained their effect after filtration through 0.22 µm membranes. Neither anti-mycobacterial antibodies, TNFα, IL-6, IFNγ, or IL-8 participated in the phenomenon. In contrast, soluble mycobacterial antigens were likely candidates, as small quantities of soluble
antigens added to the sera of HLT people led to the induction of nuclear changes in NEU in a dose-dependent manner.
These results might help to detect subclinical TB within HHC, thus leading to a recommendation of prophylactic treatment.
Objectives To determine phagocytic capacity of PMN leukocytes in workers occupationally exposed to benzene. Method Cross-sectional study that included 54 workers of a paint manufacture company in ...Mexico City; exposure to benzene was determined through S-phenylmercapturic acid (SPMA) presence in urine. The PMN phagocytic capacity analysis included three parameters: 1) nitro-blue tetrazolium (NBT) reduction, 2) hydrogen peroxide (H2O2) production, and 3) cell adhesion (CAD) Results In the whole of workers included in the study, NBT reduction = 0.419 ± 0.075, H2O2 production = 6.7 ± 1.4 ng, and CAD = 58.3 ± 6.2 μg. SPMA was identified in all workers although 24 of them are not in occupationally exposure to organic solvents (2.3 ± 0.81 μmol/mol creatinine), while the remaining 30 handle these substances (3.2 ± 1.8, p = 0.02). Among these exposure groups, there were not statistically differences in any of the parameters analysed. Although the simple regression analysis of these parameters with the concentration of SPMA identified in urine, a decrease was observed in NBT reduction (β= -0.009, R2= 0.01), in H2O2 production (β= -0.16, R2= 0.02), and in CAD (β= -0.53, R2= 0.01), none was statistically significant (p ≥ 0.05) Conclusions PMN phagocytic capacity in the workers studied seems to be intact. Attract attention the consistently decrease of the three parameters in relation to the concentration of SPMA identified in urine even when there was no statistical significance. Some limitations do not allow a more complete analysis, so it is encouraged to make further studies.
Discoid lupus erythematosus (DLE) is a cutaneous autoimmune inflammatory disease in which the role of conventional dendritic cells (cDCs) in skin damage has not been evaluated.
To evaluate the ...involvement of cDCs in DLE pathogenesis.
Skin biopsies from 42 patients with DLE were embedded in paraffin or placed in culture. The dermis was separated and cell suspensions were characterized by flow cytometry.
We found an increase in cDCs with inflammatory characteristics in the skin of DLE patients, compared with control skins. Interestingly, cDCs from the DLE patients expressed low levels of the inhibitory molecule PD-L1 and showed a high expression of CCR6, which correlated with disease activity. Increased cellular death was observed in the skin of DLE patients compared with control skin and remarkably we found that damage-associated molecular patterns could be responsible for CCR6 expression on cDCs in the skin.
Our results indicate the presence of pathogenic CCR6+ cDCs in the skin lesions of DLE patients, which could result from in situ phenotypic changes.
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