scholarly journals Kallikrein 12 Regulates Innate Resistance of Murine Macrophages against Mycobacterium bovis Infection by Modulating Autophagy and Apoptosis

Cells ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 415 ◽  
Author(s):  
Naveed Sabir ◽  
Tariq Hussain ◽  
Yi Liao ◽  
Jie Wang ◽  
Yinjuan Song ◽  
...  
Keyword(s):  
Immune Response ◽  
Mycobacterium Bovis ◽  
Serine Proteases ◽  
New Paradigm ◽  
Murine Macrophages ◽  
Immune Response Regulation ◽  
The Difference

Mycobacterium bovis (M. bovis) is a member of the Mycobacterium tuberculosis (Mtb) complex causing bovine tuberculosis (TB) and imposing a high zoonotic threat to human health. Kallikreins (KLKs) belong to a subgroup of secreted serine proteases. As their role is established in various physiological and pathological processes, it is likely that KLKs expression may mediate a host immune response against the M. bovis infection. In the current study, we report in vivo and in vitro upregulation of KLK12 in the M. bovis infection. To define the role of KLK12 in immune response regulation of murine macrophages, we produced KLK12 knockdown bone marrow derived macrophages (BMDMs) by using siRNA transfection. Interestingly, the knockdown of KLK12 resulted in a significant downregulation of autophagy and apoptosis in M. bovis infected BMDMs. Furthermore, we demonstrated that this KLK12 mediated regulation of autophagy and apoptosis involves mTOR/AMPK/TSC2 and BAX/Bcl-2/Cytochrome c/Caspase 3 pathways, respectively. Similarly, inflammatory cytokines IL-1β, IL-6, IL-12 and TNF-α were significantly downregulated in KLK12 knockdown macrophages but the difference in IL-10 and IFN-β expression was non-significant. Taken together, these findings suggest that upregulation of KLK12 in M. bovis infected murine macrophages plays a substantial role in the protective immune response regulation by modulating autophagy, apoptosis and pro-inflammatory pathways. To our knowledge, this is the first report on expression and the role of KLK12 in the M. bovis infection and the data may contribute to a new paradigm for diagnosis and treatment of bovine TB.

scholarly journals Arginase Activity in Eisenia andrei Coelomocytes: Function in the Earthworm Innate Response

2021 ◽  
Vol 22 (7) ◽  
pp. 3687
Author(s):  
Joanna Homa ◽  
Alina Klosowska ◽  
Magdalena Chadzinska
Keyword(s):  
Immune Response ◽  
Wound Healing ◽  
Arginase Activity ◽  
Eisenia Andrei ◽  
Heavy Metals Ions ◽  
First Time ◽  
Important Marker

Arginase is the manganese metalloenzyme catalyzing the conversion of l-arginine to l-ornithine and urea. In vertebrates, arginase is involved in the immune response, tissue regeneration, and wound healing and is an important marker of alternative anti-inflammatory polarization of macrophages. In invertebrates, data concerning the role of arginase in these processes are very limited. Therefore, in the present study, we focused on the changes in arginase activity in the coelomocytes of Eisenia andrei. We studied the effects of lipopolysaccharide (LPS), hydrogen peroxide (H2O2), heavy metals ions (e.g., Mn2+), parasite infection, wound healing, and short-term fasting (5 days) on arginase activity. For the first time in earthworms, we described arginase activity in the coelomocytes and found that it can be up-regulated upon in vitro stimulation with LPS and H2O2 and in the presence of Mn2+ ions. Moreover, arginase activity was also up-regulated in animals in vivo infected with nematodes or experiencing segment amputation, but not in fasting earthworms. Furthermore, we confirmed that the activity of coelomocyte arginase can be suppressed by l-norvaline. Our studies strongly suggest that similarly to the vertebrates, also in the earthworms, coelomocyte arginase is an important element of the immune response and wound healing processes.

scholarly journals Influenza virus-specific CD4+ T helper type 2 T lymphocytes do not promote recovery from experimental virus infection.

1994 ◽  
Vol 180 (4) ◽  
pp. 1273-1282 ◽  
Author(s):  
M B Graham ◽  
V L Braciale ◽  
T J Braciale
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Lymphocytes ◽  
Cd4 T Cells ◽  
Primary Role ◽  
T Helper ◽  
Helper Type

T lymphocytes play a primary role in recovery from viral infections and in antiviral immunity. Although viral-specific CD8+ and CD4+ T cells have been shown to be able to lyse virally infected targets in vitro and promote recovery from lethal infection in vivo, the role of CD4+ T lymphocytes and their mechanism(s) of action in viral immunity are not well understood. The ability to further dissect the role that CD4+ T cells play in the immune response to a number of pathogens has been greatly enhanced by evidence for more extensive heterogeneity among the CD4+ T lymphocytes. To further examine the role of CD4+ T cells in the immune response to influenza infection, we have generated influenza virus-specific CD4+ T cell clones from influenza-primed BALB/c mice with differential cytokine secretion profiles that are defined as T helper type 1 (Th1) clones by the production of interleukin 2 (IL-2) and interferon gamma (IFN-gamma), or as Th2 clones by the production of IL-4, IL-5, and IL-10. Our studies have revealed that Th1 clones are cytolytic in vitro and protective against lethal challenge with virus in vivo, whereas Th2 clones are noncytolytic and not protective. Upon further evaluation of these clonal populations we have shown that not only are the Th2 clones nonprotective, but that pulmonary pathology is exacerbated as compared with control mice as evidenced by delayed viral clearance and massive pulmonary eosinophilia. These data suggest that virus-specific CD4+ T cells of the Th2 subset may not play a primary role in virus clearance and recovery and may lead to immune mediated potentiation of injury.

scholarly journals Dependence of Mycobacterium bovis BCG on Anaerobic Nitrate Reductase for Persistence Is Tissue Specific

2002 ◽  
Vol 70 (1) ◽  
pp. 286-291 ◽  
Author(s):  
Christian Fritz ◽  
Silvia Maass ◽  
Andreas Kreft ◽  
Franz-Christoph Bange
Keyword(s):  
Nitrate Reductase ◽  
Mycobacterium Bovis ◽  
Vaccine Development ◽  
Nitrate Respiration ◽  
Apparent Paradox ◽  
Tissue Specific ◽  
Deficient Mice

ABSTRACT Mycobacterium bovis BCG, the only presently available vaccine against tuberculosis, was obtained from virulent M. bovis after serial passages in vitro. The vaccine strain retained at least some of its original virulence, as it persists in immune-competent hosts and occasionally may cause fatal disease in immune-deficient hosts. Mycobacterial persistence in vivo is thought to depend on anaerobic metabolism, an apparent paradox since all mycobacteria are obligate aerobes. Here we report that M. bovis BCG lacking anaerobic nitrate reductase (NarGHJI), an enzyme essential for nitrate respiration, failed to persist in the lungs, liver, and kidneys of immune-competent (BALB/c) mice. In immune-deficient (SCID) mice, however, bacilli caused chronic infection despite disruption of narG, even if growth of the mutant was severely impaired in lungs, liver, and kidneys. Persistence and growth of BCG in the spleens of either mouse strain appeared largely unaffected by lack of anaerobic nitrate reductase, indicating that the role of the enzyme in pathogenesis is tissue specific. These data suggest first that anaerobic nitrate reduction is essential for metabolism of M. bovis BCG in immune-competent but not immune-deficient mice and second that its role in mycobacterial disease is tissue specific, both of which are observations with important implications for pathogenesis of mycobacteria and vaccine development.

Unravelling some mysteries of porcine respiratory and reproductive syndrome virus (PRRSV) infections: new insights from modelling studies

2009 ◽  
Vol 2009 ◽  
pp. 30-30
Author(s):  
A Doeschl-Wilson ◽  
I Kyriazakis ◽  
L Galina-Pantoja
Keyword(s):  
Immune Response ◽  
Host Immune Response ◽  
Growing Pigs ◽  
Modelling Studies ◽  
Porcine Respiratory ◽  
Insight Into

Porcine reproductive and respiratory syndrome (PRRS) is an endemic pig disease in most European countries, causing respiratory distress, fever and growth reductions in growing pigs and increased litter mortality in sows. The disease is characterised by exceptionally long-term viral persistence within the host, a weak innate host immune response and delayed adaptive host immune response, and large between animal variation in the immune response (Murtaugh et al., 2004). Although numerous in-vitro and in-vivo studies produced valid insight into the fine details of the virus dynamics and its interaction with the host’s immune response, several fundamental questions concerning the role of diverse immune components and host genetics remain unanswered. In this study mathematical models were developed to investigate the role of diverse processes caused by the virus or the immune response on the infection characteristics.

scholarly journals Immunomodulatory Effects of Adipose-Derived Stem Cells: Fact or Fiction?

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Angelo A. Leto Barone ◽  
Saami Khalifian ◽  
W. P. Andrew Lee ◽  
Gerald Brandacher
Keyword(s):  
Stem Cells ◽  
Immune Response ◽  
Clinical Trials ◽  
Immune System ◽  
Solid Organ ◽  
Adipose Derived Stem Cells ◽  
Adipose Derived Stromal Cells

Adipose-derived stromal cells (ASCs) are often referred to as adipose-derived stem cells due to their potential to undergo multilineage differentiation. Their promising role in tissue engineering and ability to modulate the immune system are the focus of extensive research. A number of clinical trials using ASCs are currently underway to better understand the role of such cell niche in enhancing or suppressing the immune response. If governable, such immunoregulatory role would find application in several conditions in which an immune response is present (i.e., autoimmune conditions) or feared (i.e., solid organ or reconstructive transplantation). Although allogeneic ASCs have been shown to prevent acute GvHD in both preclinical and clinical studies, their potential warrants further investigation. Well-designed and standardized clinical trials are necessary to prove the role of ASCs in the treatment of immune disorders or prevention of tissue rejection. In this paper we analyze the current literature on the role of ASCs in immunomodulationin vitroandin vivoand discuss their potential in regulating the immune system in the context of transplantation.

scholarly journals The Bacterial Second Messenger Cyclic di-GMP Regulates Brucella Pathogenesis and Leads to Altered Host Immune Response

2016 ◽  
Vol 84 (12) ◽  
pp. 3458-3470 ◽  
Author(s):  
Mike Khan ◽  
Jerome S. Harms ◽  
Fernanda M. Marim ◽  
Leah Armon ◽  
Cherisse L. Hall ◽  
...  
Keyword(s):  
Immune Response ◽  
Second Messenger ◽  
Host Immune Response ◽  
Vital Role ◽  
Host Cells ◽  
Content Type ◽  
Type Iv

Brucella species are facultative intracellular bacteria that cause brucellosis, a chronic debilitating disease significantly impacting global health and prosperity. Much remains to be learned about how Brucella spp. succeed in sabotaging immune host cells and how Brucella spp. respond to environmental challenges. Multiple types of bacteria employ the prokaryotic second messenger cyclic di-GMP (c-di-GMP) to coordinate responses to shifting environments. To determine the role of c-di-GMP in Brucella physiology and in shaping host- Brucella interactions, we utilized c-di-GMP regulatory enzyme deletion mutants. Our results show that a Δ bpdA phosphodiesterase mutant producing excess c-di-GMP displays marked attenuation in vitro and in vivo during later infections. Although c-di-GMP is known to stimulate the innate sensor STING, surprisingly, the Δ bpdA mutant induced a weaker host immune response than did wild-type Brucella or the low-c-di-GMP guanylate cyclase Δ cgsB mutant. Proteomics analysis revealed that c-di-GMP regulates several processes critical for virulence, including cell wall and biofilm formation, nutrient acquisition, and the type IV secretion system. Finally, Δ bpdA mutants exhibited altered morphology and were hypersensitive to nutrient-limiting conditions. In summary, our results indicate a vital role for c-di-GMP in allowing Brucella to successfully navigate stressful and shifting environments to establish intracellular infection.

scholarly journals Pivotal role of the B7:CD28 pathway in transplantation tolerance and tumor immunity

Blood ◽  
1994 ◽  
Vol 84 (10) ◽  
pp. 3261-3282 ◽  
Author(s):  
EC Guinan ◽  
JG Gribben ◽  
VA Boussiotis ◽  
GJ Freeman ◽  
LM Nadler
Keyword(s):  
Immune Response ◽  
Immune Function ◽  
Tumor Immunity ◽  
Clinical Applications ◽  
Pivotal Role ◽  
Transplantation Tolerance ◽  
Clinical Potential

The above story illustrates the translation of basic scientific discoveries to the clinic. In vitro and preclinical in vivo experimentation suggests that modulation of the B7:CD28 pathway will result in either amplification or suppression of the immune response. Considering the frequency with which diseases characterized by either inadequate or dysregulated immune function present to the practicing hematologist or oncologist, it is not difficult to envisage clinical applications for reagents that modulate this pathway. However, we still have much to learn about the function and clinical potential of this and other potentially redundant costimulatory pathways and therefore we suspect that this story will become considerably more complex over the next few years.

scholarly journals The Coxiella burnetii QpH1 plasmid is a virulence factor for colonizing bone marrow-derived murine macrophages

2020 ◽  
Author(s):  
Shengdong Luo ◽  
Zhihui Sun ◽  
Huahao Fan ◽  
Shanshan Lu ◽  
Yan Hu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Coxiella Burnetii ◽  
Virulence Factor ◽  
Critical Role ◽  
Murine Macrophages ◽  
Infection Models

AbstractCoxiella burnetii carries a large conserved plasmid or plasmid-like chromosomally integrated sequence of unknown function. Here we report the curing of QpH1 plasmid from C. burnetii Nine Mile phase II, the characterization of QpH1-deficient C. burnetii in in vitro and in vivo infection models, and the characterization of plasmid biology. A shuttle vector pQGK, which is composed of the CBUA0036-0039a region (predicted for QpH1 maintenance), an E. coli plasmid ori, eGFP and kanamycin resistance genes was constructed. The pQGK vector can be stably transformed into Nine Mile II and maintained at a similar low copy like QpH1. Importantly, transformation with pQGK cured the endogenous QpH1 due to plasmid incompatibility. Compared to a Nine Mile II transformant of a RSF1010-based vector, the pQGK transformant shows an identical one-step growth curve in axenic media, a similar growth curve in Buffalo green monkey kidney cells, an evident growth defect in macrophage-like THP-1 cells, and dramatically reduced ability of colonizing bone marrow-derived murine macrophages. In the SCID mouse infection model, the pQGK transformants caused a lesser extent of splenomegaly. Moreover, the plasmid biology was investigated by mutagenesis. We found CBUA0037-0039 are essential for plasmid maintenance, and CBUA0037-0038 account for plasmid compatibility. Taken together, our data suggest that QpH1 encodes factor(s) essential for colonizing murine macrophages, and to a lesser extent for colonizing human macrophages. This study highlights a critical role of QpH1 for C. burnetii persistence in rodents, and expands the toolkit for genetic studies in C. burnetii.Author summaryIt is postulated that C. burnetii recently evolved from an inherited symbiont of ticks by the acquisition of novel virulence factors. All C. burnetii isolates carry a large plasmid or have a chromosomally integrated plasmid-like sequence. The plasmid is a candidate virulence factor that contributes to C. burnetii evolution. Here we describe the construction of novel shuttle vectors that allow to make plasmid-deficient C. burnetii mutants. With this plasmid-curing approach, we characterized the role of the QpH1 plasmid in in vitro and in vivo C. burnetii infection models. We found that the plasmid plays a critical role for C. burnetii growth in macrophages, especially in murine macrophages, but not in axenic media and BGMK cells. Our work highlights an essential role of the plasmid for the acquisition of colonizing capability in rodents by C. burnetii. This study represents a major step toward unravelling the mystery of the C. burnetii cryptic plasmids.

Inflammation and Immune Response in Arrhythmogenic Cardiomyopathy: State-of-the-Art Review

Circulation ◽  
2021 ◽  
Vol 144 (20) ◽  
pp. 1646-1655
Author(s):  
Babken Asatryan ◽  
Angeliki Asimaki ◽  
Andrew P. Landstrom ◽  
Mohammed Y. Khanji ◽  
Katja E. Odening ◽  
...  
Keyword(s):  
Immune Response ◽  
Cardiac Myocyte ◽  
Clinical Investigation ◽  
Arrhythmogenic Right Ventricular Cardiomyopathy ◽  
Incomplete Penetrance ◽  
Arrhythmogenic Cardiomyopathy ◽  
Premature Ventricular Contractions

Arrhythmogenic cardiomyopathy (ACM) is a primary disease of the myocardium, predominantly caused by genetic defects in proteins of the cardiac intercalated disc, particularly, desmosomes. Transmission is mostly autosomal dominant with incomplete penetrance. ACM also has wide phenotype variability, ranging from premature ventricular contractions to sudden cardiac death and heart failure. Among other drivers and modulators of phenotype, inflammation in response to viral infection and immune triggers have been postulated to be an aggravator of cardiac myocyte damage and necrosis. This theory is supported by multiple pieces of evidence, including the presence of inflammatory infiltrates in more than two-thirds of ACM hearts, detection of different cardiotropic viruses in sporadic cases of ACM, the fact that patients with ACM often fulfill the histological criteria of active myocarditis, and the abundance of anti–desmoglein-2, antiheart, and anti-intercalated disk autoantibodies in patients with arrhythmogenic right ventricular cardiomyopathy. In keeping with the frequent familial occurrence of ACM, it has been proposed that, in addition to genetic predisposition to progressive myocardial damage, a heritable susceptibility to viral infections and immune reactions may explain familial clustering of ACM. Moreover, considerable in vitro and in vivo evidence implicates activated inflammatory signaling in ACM. Although the role of inflammation/immune response in ACM is not entirely clear, inflammation as a driver of phenotype and a potential target for mechanism-based therapy warrants further research. This review discusses the present evidence supporting the role of inflammatory and immune responses in ACM pathogenesis and proposes opportunities for translational and clinical investigation.

Neutral endopeptidase modulates neurotensin-induced airway contraction

1989 ◽  
Vol 66 (5) ◽  
pp. 2338-2343 ◽  
Author(s):  
T. D. Djokic ◽  
D. J. Dusser ◽  
D. B. Borson ◽  
J. A. Nadel
Keyword(s):  
Smooth Muscle ◽  
Serine Proteases ◽  
Neutral Endopeptidase ◽  
Smooth Muscle Contraction ◽  
Response Curves ◽  
Terminal Fragment ◽  
Carboxypeptidase N

To determine the role of endogenous neutral endopeptidase (NEP) (also called enkephalinase, EC 3.4.24.11) in regulating neurotensin-induced airway contraction, we used phosphoramidon, a specific NEP inhibitor, in the guinea pig. In studies in vitro, neurotensin and the COOH-terminal fragment neurotensin-(8–13) contracted strips of bronchial smooth muscle in a concentration-dependent fashion (P less than 0.001). In contrast, the NH2-terminal fragment neurotensin-(1–11) and the COOH-terminal fragment neurotensin-(12–13), the main fragments of neurotensin hydrolysis by NEP, had no effect. Phosphoramidon (10(-5) M) did not change resting tension but shifted the concentration-response curves to neurotensin to lower concentrations (P less than 0.001), whereas inhibitors of kininase II, aminopeptidases, serine proteases, and carboxypeptidase N were without effect. Removing the epithelium increased the contractile response to neurotensin (P less than 0.001), and phosphoramidon further increased the response to neurotensin in these tissues (P less than 0.001). Similar results were obtained in studies in vivo using aerosolized neurotensin and phosphoramidon. These results suggest that endogenous NEP in the airways modulates the effects of neurotensin on airway smooth muscle contraction by inactivating the peptide.

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