PP2Ac Modulates AMPK-Mediated Induction of Autophagy in Mycobacterium bovis—Infected Macrophages

Mycobacterium bovis (M. bovis) is the causative agent of bovine tuberculosis in cattle population across the world. Human beings are at equal risk of developing tuberculosis beside a wide range of M. bovis infections in animal species. Autophagic sequestration and degradation of intracellular pathogens is a major innate immune defense mechanism adopted by host cells for the control of intracellular infections. It has been reported previously that the catalytic subunit of protein phosphatase 2A (PP2Ac) is crucial for regulating AMP-activated protein kinase (AMPK)-mediated autophagic signaling pathways, yet its role in tuberculosis is still unclear. Here, we demonstrated that M. bovis infection increased PP2Ac expression in murine macrophages, while nilotinib a tyrosine kinase inhibitor (TKI) significantly suppressed PP2Ac expression. In addition, we observed that TKI-induced AMPK activation was dependent on PP2Ac regulation, indicating the contributory role of PP2Ac towards autophagy induction. Furthermore, we found that the activation of AMPK signaling is vital for the regulating autophagy during M. bovis infection. Finally, the transient inhibition of PP2Ac expression enhanced the inhibitory effect of TKI-nilotinib on intracellular survival and multiplication of M. bovis in macrophages by regulating the host’s immune responses. Based on these observations, we suggest that PP2Ac should be exploited as a promising molecular target to intervene in host–pathogen interactions for the development of new therapeutic strategies towards the control of M. bovis infections in humans and animals.

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Inhibition of Type I Interferon Signaling abrogates Early Mycobacterium bovis Infection

10.21203/rs.2.14196/v1 ◽

2019 ◽

Author(s):

Jie Wang ◽

Tariq Hussain ◽

Kai Zhang ◽

Yi Liao ◽

Jiao Yao ◽

...

Keyword(s):

Mycobacterium Bovis ◽

Bacterial Count ◽

Immune Defense ◽

Type I ◽

Type I Ifn ◽

Human Beings ◽

Inflammatory Reactions ◽

Regulatory Pathways ◽

Type I Ifns

Abstract Background: Mycobacterium bovis (M. bovis) is the central causative agent of bovine tuberculosis; however, it also caused serious infection in human beings. Type I IFNs is a key factor in reducing viral multiplication and modulate host immune defense against viral infection. However, the regulatory pathways of type I IFN signaling during Mycobactrium bovis (M. bovis) infection are not yet fully explored. Here, we investigate the role of type I IFN signaling on the pathogenesis of M. bovis infection in mice. Methods: C57BL/6 mice were treated with IFNAR1-blocking antibody or Isotype control 24 hour before M. bovis infection. After 21 and 84 days of infection mice were sacrificed, for analysis of type I IFN signaling on the pathogenesis of M. bovis. qRT-PCR and ELISA was performed to detect the expression of type I IFNs and relative gene. M. bovis induced lung lesions and viable bacterial count was assessed by conducting histopathology and CFU assay. Results: We observed an abundant expression of type I IFNs in the blood serum and lung tissues of M. bovis infected mice. In vivo blockade of type I IFN signaling reduced the recruitment of neutrophils to the lung tissue, mediate the activation of macrophages toward a pro-inflammatory profile and regulate the inflammatory cytokine production; however, no impact on T cell recruitment and activation in the early acute phase of infection was observed. Additionally, blocking of type I IFN signaling reduces bacterial burden in infected mice than untreated infected mice. Conclusions: Altogether, our results reveal that type I IFN mediates a balance between infection-mediated inflammatory reactions and pathogen’s control mechanism of the host during M. bovis infection. Thus, modulating type I IFN signaling could be exploited as therapeutic strategies against a large repertoire of inflammatory disorders, including tuberculosis.

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Insights into the Gryllus bimaculatus Immune-Related Transcriptomic Profiling to Combat Naturally Invading Pathogens

Journal of Fungi ◽

10.3390/jof6040232 ◽

2020 ◽

Vol 6 (4) ◽

pp. 232 ◽

Cited By ~ 1

Author(s):

Abid Hussain ◽

Muhammad Waqar Ali ◽

Ahmed Mohammed AlJabr ◽

Saad Naser AL-Kahtani

Keyword(s):

Defense Mechanism ◽

Immune Defense ◽

Cdna Libraries ◽

Gryllus Bimaculatus ◽

Illumina Hiseq ◽

Field Crickets ◽

Wide Range ◽

Illumina Hiseq Platform ◽

Immune Related Genes ◽

First Time

Natural pathogen pressure is an important factor that shapes the host immune defense mechanism. The current study primarily aimed to explore the molecular basis of the natural immune defense mechanism of a sporadic pest, Gryllus bimaculatus, during swarming by constructing cDNA libraries of the female mid-gut, male mid-gut, testes, and ovaries. The Illumina HiSeq platform generated an average of 7.9 G, 11.77 G, 10.07 G, and 10.07 G bases of outputs from the male mid-gut, female mid-gut, testes, and ovaries and libraries, respectively. The transcriptome of two-spotted field crickets was assembled into 233,172 UniGenes, which yielded approximately 163.58 million reads. On the other hand, there were 43,055 genes in common that were shared among all the biological samples. Gene Ontology analysis successfully annotated 492 immune-related genes, which comprised mainly Pattern Recognition Receptors (62 genes), Signal modulators (57 genes), Signal transduction (214 genes), Effectors (36 genes), and another immune-related 123 genes. In summary, the identified wide range of immune-related genes from G. bimaculatus indicates the existence of a sophisticated and specialized broad spectrum immune mechanism against invading pathogens, which provides, for the first time, insights into the molecular mechanism of disease resistance among two-spotted field crickets.

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Plant Antimicrobial Peptides as Potential Anticancer Agents

BioMed Research International ◽

10.1155/2015/735087 ◽

2015 ◽

Vol 2015 ◽

pp. 1-11 ◽

Cited By ~ 51

Author(s):

Jaquelina Julia Guzmán-Rodríguez ◽

Alejandra Ochoa-Zarzosa ◽

Rodolfo López-Gómez ◽

Joel E. López-Meza

Keyword(s):

Antimicrobial Peptides ◽

Anticancer Agents ◽

Pathogenic Bacteria ◽

Defense Mechanism ◽

Immune Defense ◽

Innate Immune ◽

High Morbidity ◽

Anticancer Activities ◽

Innate Immune Defense ◽

Wide Range

Antimicrobial peptides (AMPs) are part of the innate immune defense mechanism of many organisms and are promising candidates to treat infections caused by pathogenic bacteria to animals and humans. AMPs also display anticancer activities because of their ability to inactivate a wide range of cancer cells. Cancer remains a cause of high morbidity and mortality worldwide. Therefore, the development of methods for its control is desirable. Attractive alternatives include plant AMP thionins, defensins, and cyclotides, which have anticancer activities. Here, we provide an overview of plant AMPs anticancer activities, with an emphasis on their mode of action, their selectivity, and their efficacy.

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Characterization of the chorismate mutase effector (SsCm1) from Sclerotinia sclerotiorum

10.32747/2015.7600027.bard ◽

2015 ◽

Author(s):

Martin B. Dickman ◽

Oded Yarden

Keyword(s):

Secondary Metabolites ◽

Sclerotinia Sclerotiorum ◽

Plant Cell Wall ◽

Defense Mechanism ◽

Critical Role ◽

Host Tissue ◽

Chorismate Mutase ◽

Host Cells ◽

Fungal Virulence ◽

Wide Range

Sclerotinia sclerotiorum is a filamentous fungus (mold) that causes plant disease. It has an extremely wide range of hosts (>400 species) and causes considerable damage (annual multimillion dollar losses) in economically important crops. It has proven difficult to control (culturally or chemically) and host resistance to this fungus has generally been inadequate. It is believed that this fungus occurs in almost every country. Virulence of this aggressive pathogen is bolstered by a wide array of plant cell wall degrading enzymes and various compounds (secondary metabolites) produced by the fungus. It is well established that plant pathogenic fungi secrete proteins and small molecules that interact with host cells and play a critical role in disease development. Such secreted proteins have been collectively designated as “effectors”. Plant resistance against some pathogens can be mediated by recognition of such effectors. Alternatively, effectors can interfere with plant defense. Some such effectors are recognized by the host plant and can culminate in a programmed cell death (PCD) resistant response. During the course of this study, we analyzed an effector in Sclerotiniasclerotiorum. This specific effector, SsCM1 is the protein chorismatemutase, which is an enzyme involved in a pathway which is important in the production of important amino acids, such a Tryptophan. We have characterized the Sclerotiniaeffector, SsCM1, and have shown that inactivation of Sscm1 does not affect fungal vegetative growth, development or production of oxalic acid (one of this fungus’ secondary metabolites associated with disease) production. However, yhis does result in reduced fungal virulence. We show that, unexpectedly, the SsCM1 protein translocates to the host chloroplast, and demonstrated that this process is required for full fungal virulence. We have also determined that the fungal SsCM1 protein can interact with similar proteins produced by the host. In addition, we have shown that the fungal SsCM1 is able to suppress at least some of the effects imposed by reactive oxygen species which are produced as a defense mechanism by the host. Last, but not least, the results of our studies have provided evidence contradicting the current dogma on at least some of the mechanist aspects of how this pathogen infects the host. Contrary to previousons, indicating that this pathogen kills its host by use of metabolites and enzymes that degrade the host tissue (a process called necrotrophy), we now know that at least in the early phases of infection, the fungus interacts with live host tissue (a phenomenon known as biotrophy). Taken together, the results of our studies provide novel insights concerning the mechanistic aspects of Sclerotinia-host interactions. We hope this information will be used to interfere with the disease cycle in a manner that will protect plants from this devastating fungus.

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THE DEMONSTRATION OF ONE-STEP GROWTH CURVES OF INFLUENZA VIRUSES THROUGH THE BLOCKING EFFECT OF IRRADIATED VIRUS ON FURTHER INFECTION

Journal of Experimental Medicine ◽

10.1084/jem.86.5.423 ◽

1947 ◽

Vol 86 (5) ◽

pp. 423-437 ◽

Cited By ~ 37

Author(s):

Werner Henle ◽

Gertrude Henle ◽

Evelyn B. Rosenberg

Keyword(s):

Growth Curves ◽

Allantoic Fluid ◽

Inhibitory Effect ◽

Influenza Viruses ◽

Host Cells ◽

Susceptible Host ◽

Interference Phenomenon ◽

Wide Range ◽

One Step ◽

Heterologous Virus

After allantoic injection of chick embryos with a known amount of influenza virus, the process of adsorption of the agent onto host cells and infection of them can be interrupted at a given time by the administration of large quantities of heterologous virus inactivated by irradiation. A sudden great increase in the amount of free virus in the allantoic fluid occurring after 6 hours in the case of the PR8 strain, and 9 hours in that of the Lee strain, indicates that the untreated virus associated with the host cells has multiplied. The length of the period preliminary to this increase remains the same even though the concentration of the original inoculum is varied over a wide range. Since administration of the irradiated virus leaves no susceptible host cells, because of the interference phenomenon, and further adsorption of active virus is minimized or entirely prevented, practically the entire new increment of virus can be found in the allantoic fluid and assayed; for every ID50 adsorbed about 50 ID50 are released. Homologous irradiated virus, on the other hand, when injected after infection of the allantoic sac, reduces the yield of virus to a more or less considerable extent. Some inhibitory effect can still be observed when the homologous irradiated virus is given several hours after infection. This effect is linked to the virus particle and destroyed by prolonged irradiation.

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Nilotinib: A Tyrosine Kinase Inhibitor Mediates Resistance to Intracellular Mycobacterium Via Regulating Autophagy

Cells ◽

10.3390/cells8050506 ◽

2019 ◽

Vol 8 (5) ◽

pp. 506 ◽

Cited By ~ 7

Author(s):

Tariq Hussain ◽

Deming Zhao ◽

Syed Zahid Ali Shah ◽

Naveed Sabir ◽

Jie Wang ◽

...

Keyword(s):

Immune Responses ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Bacterial Infections ◽

Defense Mechanism ◽

Kinase Inhibitor ◽

Mycobacterium Avium Subspecies Paratuberculosis ◽

Immune Defense ◽

Innate Immune

Nilotinib, a tyrosine kinase inhibitor, has been studied extensively in various tumor models; however, no information exists about the pharmacological action of nilotinib in bacterial infections. Mycobacterium bovis (M. bovis) and Mycobacterium avium subspecies paratuberculosis (MAP) are the etiological agents of bovine tuberculosis and Johne’s disease, respectively. Although M. bovis and MAP cause distinct tissue tropism, both of them infect, reside, and replicate in mononuclear phagocytic cells of the infected host. Autophagy is an innate immune defense mechanism for the control of intracellular bacteria, regulated by diverse signaling pathways. Here we demonstrated that nilotinib significantly inhibited the intracellular survival and growth of M. bovis and MAP in macrophages by modulating host immune responses. We showed that nilotinib induced autophagic degradation of intracellular mycobacterium occurred via the inhibition of PI3k/Akt/mTOR axis mediated by abelson (c-ABL) tyrosine kinase. In addition, we observed that nilotinib promoted ubiquitin accumulation around M. bovis through activation of E3 ubiquitin ligase parkin. From in-vivo experiments, we found that nilotinib effectively controlled M. bovis growth and survival through enhanced parkin activity in infected mice. Altogether, our data showed that nilotinib regulates protective innate immune responses against intracellular mycobacterium, both in-vitro and in-vivo, and can be exploited as a novel therapeutic remedy for the control of M. bovis and MAP infections.

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Oxidative and Non-Oxidative Antimicrobial Activities of the Granzymes

Frontiers in Immunology ◽

10.3389/fimmu.2021.750512 ◽

2021 ◽

Vol 12 ◽

Author(s):

Marilyne Lavergne ◽

Maria Andrea Hernández-Castañeda ◽

Pierre-Yves Mantel ◽

Denis Martinvalet ◽

Michael Walch

Keyword(s):

Reactive Oxygen Species ◽

Defense Mechanism ◽

Reactive Oxygen ◽

Antimicrobial Activities ◽

Immune Defense ◽

Host Cells ◽

Microbial Pathogens ◽

Parasitic Infections ◽

Intracellular Pathogens ◽

Oxygen Species

Cell-mediated cytotoxicity is an essential immune defense mechanism to fight against viral, bacterial or parasitic infections. Upon recognition of an infected target cell, killer lymphocytes form an immunological synapse to release the content of their cytotoxic granules. Cytotoxic granules of humans contain two membrane-disrupting proteins, perforin and granulysin, as well as a homologous family of five death-inducing serine proteases, the granzymes. The granzymes, after delivery into infected host cells by the membrane disrupting proteins, may contribute to the clearance of microbial pathogens through different mechanisms. The granzymes can induce host cell apoptosis, which deprives intracellular pathogens of their protective niche, therefore limiting their replication. However, many obligate intracellular pathogens have evolved mechanisms to inhibit programed cells death. To overcome these limitations, the granzymes can exert non-cytolytic antimicrobial activities by directly degrading microbial substrates or hijacked host proteins crucial for the replication or survival of the pathogens. The granzymes may also attack factors that mediate microbial virulence, therefore directly affecting their pathogenicity. Many mechanisms applied by the granzymes to eliminate infected cells and microbial pathogens rely on the induction of reactive oxygen species. These reactive oxygen species may be directly cytotoxic or enhance death programs triggered by the granzymes. Here, in the light of the latest advances, we review the antimicrobial activities of the granzymes in regards to their cytolytic and non-cytolytic activities to inhibit pathogen replication and invasion. We also discuss how reactive oxygen species contribute to the various antimicrobial mechanisms exerted by the granzymes.

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Vacuole and Mitochondria Patch (vCLAMP) Protein Vam6 Is Involved in Maintenance of Mitochondrial and Vacuolar Functions under Oxidative Stress in Candida albicans

Antioxidants ◽

10.3390/antiox10010136 ◽

2021 ◽

Vol 10 (1) ◽

pp. 136

Author(s):

Xiaolong Mao ◽

Li Yang ◽

Yingzheng Liu ◽

Congcong Ma ◽

Tianyu Ma ◽

...

Keyword(s):

Oxidative Stress ◽

Candida Albicans ◽

Fungal Pathogens ◽

Critical Role ◽

Immune Defense ◽

Host Cells ◽

Human Beings ◽

H2o2 Treatment ◽

System Maintenance

Candida albicans is one of the most common opportunistic fungal pathogens in human beings. When infecting host cells, C. albicans is often exposed to oxidative stress from the host immune defense system. Maintenance of mitochondrial and vacuolar functions is crucial for its resistance to oxidative stress. However, the role of vacuole and mitochondria patchs (vCLAMPs) in cellular oxidative stress resistance and in the maintenance of organelle functions remains to be elucidated. Herein, the function of the vCLAMP protein Vam6 in response to oxidative stress was explored. The results showed that the vam6∆/∆ mutant exhibited obvious mitochondrial swelling, mtDNA damage, reduced activity of antioxidant enzymes, and abnormal vacuolar morphology under H2O2 treatment, indicating its important role in maintaining the structures and functions of both mitochondria and vacuoles under oxidative stress. Further studies showed that deletion of VAM6 attenuated hyphal development under oxidative stress. Moreover, loss of Vam6 obviously affected host tissue invasion and virulence of C. albicans. Taken together, this paper reveals the critical role of vCLAMPs in response to oxidative stress in C. albicans.

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Impact of Environmental Degradation on Human Health

International Research Journal of Management IT and Social Sciences ◽

10.21744/irjmis.v3i1.82 ◽

2016 ◽

Vol 3 (1) ◽

pp. 1 ◽

Cited By ~ 2

Author(s):

_______ Archana ◽

Charu Datta ◽

Pratibha Tiwari

Keyword(s):

Environmental Degradation ◽

Human Population ◽

Environmental Problems ◽

Population Increase ◽

Human Beings ◽

The People ◽

Wide Range ◽

Different Types ◽

Economic Institute ◽

Day By Day

Degradation of environment is one of the most serious challenges before the mankind in today’s world. Mankind has been facing a wide range of problem arising out of the degradation of environment. Not only the areas under human inhabitation, but the areas of the planet without human population have also been suffering from these problems. As the population increase day by day, the amenities are not improved simultaneously. With the advancement of science and technologies the needs of human beings has been changing rapidly. As a result different types of environmental problems have been rising. Environmental degradation is a wide- reaching problem and it is likely to influence the health of human population is great. It may be defined the deterioration of the environment through depletion of resources such as air, water, and soil. The destruction of ecosystem and extinction of wildlife. Environmental degradation has occurred due to the recent activities in the field of socio-economic, institute and technology. Poverty still remains a problem as the root of several environmental problems to create awareness among the people about the ill effect of environmental pollution. In the whole research it is clear that all factors of environmental degradation may be reduced through- Framing the new laws on environmental degradation, Environment friend policy, Controlling all the ways and means of noise, air, soil and water pollution, Through growing more and more trees and by adapting the proper sanitation policy.

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P1, P5-Bis-(5′-adenosyl)pentaphosphate: Is this Adenylate Kinase Inhibitor Substrate for Mitochondrial Processes?

Zeitschrift für Naturforschung C ◽

10.1515/znc-1977-9-1021 ◽

1977 ◽

Vol 32 (9-10) ◽

pp. 786-791 ◽

Cited By ~ 1

Author(s):

Josef Köhrle ◽

Joachim Lüstorff ◽

Eckhard Schlimme

Keyword(s):

Adenylate Kinase ◽

Kinase Inhibitor ◽

Adenine Nucleotide ◽

Nucleoside Diphosphate Kinase ◽

Liver Mitochondria ◽

Inhibitory Effect ◽

Rat Liver Mitochondria ◽

Intermembrane Space ◽

Rabbit Muscle ◽

Inner Mitochondrial Membrane

Abstract 1. P1, P5-Bis-(5′-adenosyl)pentaphosphate (Ap5A) inhibits “soluble” adenylate kinase even when this enzyme is an integral part of the complete mitochondrion. The Ki is 10-5м , i. e. about two orders of magnitude higher than the inhibitor constants determined for the purified adenylate kinase of rabbit muscle and an enzyme preparation separated from the mitochondrial intermembrane space. The weaker inhibitory effect is due to a lower accessibility of the enzyme.2. As to be expected Ap5A which is of the “multisubstrate analogue”-type does not affect mito chondrial nucleoside diphosphate kinase.3. Though Ap5A owns the structural elements of both ATP and ADP it is not a substrate of the adenine nucleotide carrier, i.e. neither it is exchanged across the inner mitochondrial membrane nor specifically bound.4. Ap5A is not metabolized by rat liver mitochondria.

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