Vaccination with Recombinant Mycobacterium tuberculosis PknD Attenuates Bacterial Dissemination to the Brain in Guinea Pigs

The reduction of brain amyloid beta (Aβ) peptides by anti-Aβantibodies is one of the possible therapies for Alzheimer’s disease. We previously reported that the Aβpeptide vaccine including the T-cell epitope of diphtheria-tetanus combined toxoid (DT) induced anti-Aβantibodies, and the prior immunization with conventional DT vaccine enhanced the immunogenicity of the peptide. Cynomolgus monkeys were given the peptide vaccine subcutaneously in combination with the prior DT vaccination. Vaccination with a similar regimen was also performed on guinea pigs. The peptide vaccine induced anti-Aβantibodies in cynomolgus monkeys and guinea pigs without chemical adjuvants, and excessive immune responses were not observed. Those antibodies could preferentially recognize Aβ40, and Aβ42compared to Aβfibrils. The levels of serum anti-Aβantibodies and plasma Aβpeptides increased in both animals and decreased the brain Aβ40level of guinea pigs. The peptide vaccine could induce a similar binding profile of anti-Aβantibodies in cynomolgus monkeys and guinea pigs. The peptide vaccination could be expected to reduce the brain Aβpeptides and their toxic effects via clearance of Aβpeptides by generated antibodies.

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THE PATHOLOGIC EFFECTS OF STREPTOCOCCI FROM CASES OF POLIOMYELITIS AND OTHER SOURCES

Journal of Experimental Medicine ◽

10.1084/jem.25.4.557 ◽

1917 ◽

Vol 25 (4) ◽

pp. 557-580 ◽

Cited By ~ 25

Author(s):

Carroll G. Bull

Keyword(s):

Spinal Cord ◽

Guinea Pigs ◽

The Other ◽

Laboratory Animals ◽

Histological Changes ◽

Other Hand ◽

Brain And Spinal Cord ◽

The Brain

Streptococci cultivated from the tonsils of thirty-two cases of poliomyelitis were used to inoculate various laboratory animals. In no case was a condition induced resembling poliomyelitis clinically or pathologically in guinea pigs, dogs, cats, rabbits, or monkeys. On the other hand, a considerable percentage of the rabbits and a smaller percentage of some of the other animals developed lesions due to streptococci. These lesions consisted of meningitis, meningo-encephalitis, abscess of the brain, arthritis, tenosynovitis, myositis, abscess of the kidney, endocarditis, pericarditis, and neuritis. No distinction in the character or frequency of the lesions could be determined between the streptococci derived from poliomyelitic patients and from other sources. Streptococci isolated from the poliomyelitic brain and spinal cord of monkeys which succumbed to inoculation with the filtered virus failed to induce in monkeys any paralysis or the characteristic histological changes of poliomyelitis. These streptococci are regarded as secondary bacterial invaders of the nervous organs. Monkeys which have recovered from infection with streptococci derived from cases of poliomyelitis are not protected from infection with the filtered virus, and their blood does not neutralize the filtered virus in vitro. We have failed to detect any etiologic or pathologic relationship between streptococci and epidemic poliomyelitis in man or true experimental poliomyelitis in the monkey.

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Establishing Virulence Associated Polyphosphate Kinase 2 as a drug target for Mycobacterium tuberculosis

Scientific Reports ◽

10.1038/srep26900 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 13

Author(s):

Mamta Singh ◽

Prabhakar Tiwari ◽

Garima Arora ◽

Sakshi Agarwal ◽

Saqib Kidwai ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Mutant Strain ◽

Guinea Pigs ◽

High Throughput Screening ◽

Drug Target ◽

Wild Type Strain ◽

Wild Type ◽

Inorganic Polyphosphate ◽

Phosphate Donor ◽

Microbial Stress

Abstract Inorganic polyphosphate (PolyP) plays an essential role in microbial stress adaptation, virulence and drug tolerance. The genome of Mycobacterium tuberculosis encodes for two polyphosphate kinases (PPK-1, Rv2984 and PPK-2, Rv3232c) and polyphosphatases (ppx-1, Rv0496 and ppx-2, Rv1026) for maintenance of intracellular PolyP levels. Microbial polyphosphate kinases constitute a molecular mechanism, whereby microorganisms utilize PolyP as phosphate donor for synthesis of ATP. In the present study we have constructed ppk-2 mutant strain of M. tuberculosis and demonstrate that PPK-2 enzyme contributes to its ability to cause disease in guinea pigs. We observed that ppk-2 mutant strain infected guinea pigs had significantly reduced bacterial loads and tissue pathology in comparison to wild type infected guinea pigs at later stages of infection. We also report that in comparison to the wild type strain, ppk-2 mutant strain was more tolerant to isoniazid and impaired for survival in THP-1 macrophages. In the present study we have standardized a luciferase based assay system to identify chemical scaffolds that are non-cytotoxic and inhibit M. tuberculosis PPK-2 enzyme. To the best of our knowledge this is the first study demonstrating feasibility of high throughput screening to obtain small molecule PPK-2 inhibitors.

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Drug treatment combined with BCG vaccination reduces disease reactivation in guinea pigs infected with Mycobacterium tuberculosis

Vaccine ◽

10.1016/j.vaccine.2011.12.114 ◽

2012 ◽

Vol 30 (9) ◽

pp. 1572-1582 ◽

Cited By ~ 13

Author(s):

Shaobin Shang ◽

Crystal A. Shanley ◽

Megan L. Caraway ◽

Eileen A. Orme ◽

Marcela Henao-Tamayo ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Drug Treatment ◽

Guinea Pigs ◽

Bcg Vaccination ◽

Disease Reactivation

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Polyphosphate Deficiency in Mycobacterium tuberculosis Is Associated with Enhanced Drug Susceptibility and Impaired Growth in Guinea Pigs

Journal of Bacteriology ◽

10.1128/jb.00038-13 ◽

2013 ◽

Vol 195 (12) ◽

pp. 2839-2851 ◽

Cited By ~ 42

Author(s):

R. Singh ◽

M. Singh ◽

G. Arora ◽

S. Kumar ◽

P. Tiwari ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Guinea Pigs ◽

Drug Susceptibility

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Apurinic/Apyrimidinic Endonucleases of Mycobacterium tuberculosis Protect against DNA Damage but Are Dispensable for the Growth of the Pathogen in Guinea Pigs

PLoS ONE ◽

10.1371/journal.pone.0092035 ◽

2014 ◽

Vol 9 (5) ◽

pp. e92035 ◽

Cited By ~ 3

Author(s):

Rupangi Verma Puri ◽

P. Vineel Reddy ◽

Anil K. Tyagi

Keyword(s):

Dna Damage ◽

Mycobacterium Tuberculosis ◽

Guinea Pigs

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Mycobacterium of tuberculosis with defective cell wall, determined in the brain of the biological model with spongional changes

Reports of Vinnytsia National Medical University ◽

10.31393/reports-vnmedical-2019-23(1)-02 ◽

2019 ◽

Vol 23 (1) ◽

pp. 12-19

Author(s):

O.P. Lysenko ◽

V.V. Vlasenko ◽

H.K. Palii ◽

I.H. Vlasenko ◽

O.A. Nazarchuk

Keyword(s):

Central Nervous System ◽

Cell Wall ◽

Nervous System ◽

Mycobacterium Tuberculosis ◽

Brain Damage ◽

Molecular Genetic Study ◽

Central Nervous System Damage ◽

Infectious Dose ◽

Microbiological Methods ◽

The Brain

Mycobacterium tuberculosis is endowed with resistance to adverse factors and rapidly forms drug resistance. The aim is to study of the connection of tuberculosis infection and the development of brain damage with signs of spongymorphic changes. There were investigated canned 10% formalin fragments of the brain of 2 goats with signs of central nervous system damage by histological, microbiological methods. For microbiological examination, 3–5 years brain samples after were sowed on the MycСel DW nutrient medium with a growth stimulator. The molecular genetic study was performed using a polymerase chain reaction on a Molecular Imager GelDoc TM XR + (BioRad) device. The polypeptide profile was studied electrophoretically. In the goats, who died with symptoms of central nervous system damage, spongiform changes were detected in the brain. In the brain samples, DNA and mycobacterium tuberculosis with a defective cell wall have been detected, accumulation of mycobacterial antigens has been observed in the cells of the brain and in the intercellular space. Despite the fact that brain samples were in 10% formalin for 1 month, 3 years and 5 years, in all cases mycobacterium tuberculosis with a defective cell wall was isolated. Their viability was comparable to the infectiousness of prions. The isolation of mycobacterium tuberculosis with a defective cell wall from the brain did not differ in morphology and polypeptide composition from isolates from tuberculin, FLK-BLV, lymph nodes of cows, patients with tuberculosis. This indicates a high probability that mycobacterial infection, depending on the infectious dose, the characteristics of the strain and host genome, as well as the state of the immune system, can cause oncogenic action, cause active tuberculosis, brain damage, and the cardiovascular system.

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The effect of hyperoxia and hypoxia on free and bound γ-aminobutyric acid in mammalian brain

Canadian Journal of Biochemistry ◽

10.1139/o69-159 ◽

1969 ◽

Vol 47 (10) ◽

pp. 994-997 ◽

Cited By ~ 8

Author(s):

J. D. Wood ◽

W. J. Watson

Keyword(s):

Guinea Pigs ◽

Aminobutyric Acid ◽

Mammalian Brain ◽

Hypoxic Conditions ◽

Significant Change ◽

The Brain

In rats and guinea pigs exposed to hyperoxic conditions, the levels of both bound and free γ-aminobutyric acid in the brain were decreased, and under hypoxic conditions both were increased. A small but significant change in the proportion of γ-aminobutyric acid in the bound form was observed in the exposed animals. The significance of the findings is discussed.

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972. A Mycobacterium tuberculosis Secreted Lipid Triggers Cough Through a Neuronal Cough Receptor

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz359.074 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S33-S33

Author(s):

Paxton Cruz ◽

Cody Ruhl ◽

Michael Shiloh

Keyword(s):

Mycobacterium Tuberculosis ◽

Disease Transmission ◽

Guinea Pigs ◽

Cough Reflex ◽

Nociceptive Neurons ◽

Active Pulmonary Tuberculosis ◽

Neuronal Receptor ◽

Musculoskeletal Systems ◽

Cough Receptor

Abstract Background A hallmark symptom of active pulmonary tuberculosis vital for disease transmission is cough. The current paradigm for tuberculosis-related cough is that it results from airway damage or irritation. However, there is limited experimental data to support this theory, and whether Mycobacterium tuberculosis (Mtb) induces cough to facilitate its own transmission has not been explored. The cough reflex is a complex and coordinated event involving both the nervous and musculoskeletal systems initiated by particulate or chemical molecules activating nociceptive neurons, which sense pain or irritation. This activation induces a signaling cascade ultimately resulting in a cough. Respiratory nociceptive neurons innervate the airway of humans and most mammals and thus are poised to respond to noxious molecules to help protect the lung from damage. Because Mtb is a lung pathogen, cough is a primary mechanism of Mtb transmission, and respiratory nociceptive neurons activate cough, we hypothesized that Mtb produces molecules that stimulate cough thereby facilitating its spread from infected to uninfected individuals. We previously identified a cough molecule produced by Mtb, and in this work characterize its neuronal receptor using genetics, biochemistry, and pharmacology. Methods We used an in vitro neuronal activation bioassay to study Mtb cough-inducing molecules. We also used a biochemical assay to identify the cough receptor. Finally, we used gene silencing, biochemistry, and pharmacologic inhibition to validate and characterize the activity of the newly discovered cough receptor. Results We isolated a complex lipid produced by Mtb that activates nociceptive neurons. Both an organic Mtb extract and the purified molecule alone were sufficient to induce cough in a conscious guinea pig cough model and guinea pigs infected with wild-type Mtb cough much more frequently than guinea pigs infected with Mtb strains unable to produce nociceptive molecules. Using genetics, biochemistry, and pharmacology techniques, we identified and validated a cough receptor for the Mtb lipid expressed on nociceptive neurons. Conclusion We conclude that Mtb produces a molecule that activates nociceptive neurons and induces cough through a specific neuronal receptor. These findings have significant implications for our understanding of Mtb transmission. Disclosures All Authors: No reported Disclosures.

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