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    • 专利摘要:
    Mycobacterium chelonae strain and pharmaceutical, veterinary and food compositions containing it for the prevention and/or control of tuberculosis. The invention relates to a Mycobacterium chelonae CAR47 strain with deposit number DSM 33522 and to pharmaceutical, veterinary and food compositions comprising said inactivated strain, as well as its use for the prevention and/or control of tuberculosis. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2820312A1
    申请号:ES202030658
    申请日:2020-06-30
    公开日:2021-04-20
    发明作者:Llario Pedro Fernandez；Horrillo Rosario Cerrato；Jimenez Waldo L Garcia；Blanco Pilar Gonsalves；Santillana María Bravo；Manzano Verónica Arenas；REY Mª EUGENIA MORENO；Perez Davíd Risco
    申请人:Innovacion En Gestion Y Conservacion De Ungulados S L；
    IPC主号:
    专利说明:

    [0001] MYCOBACTERIUM CHELONAE STRAIN AND PHARMACEUTICAL, VETERINARY AND FOOD COMPOSITIONS CONTAINING IT FOR THE PREVENTION AND / OR
    [0003] TECHNICAL SECTOR
    [0005] The present invention belongs to the fields of the food industry, pharmaceutical and veterinary industry, more specifically to food, pharmaceutical or veterinary products comprising microorganisms for the prevention and / or control of tuberculosis.
    [0007] BACKGROUND OF THE INVENTION
    [0009] Tuberculosis is a chronic infectious disease caused by infection with Mycobacterium tuberculosis and other Mycobacterium species. It is the most important bacterial disease in developing countries, as well as a growing problem in developed parts of the world, with several million new cases each year. Although the infection can be asymptomatic for a considerable period of time (latency period), the clinical form mainly affects the respiratory system and results in fever and a non-productive cough. If left untreated, it often results in serious complications and death.
    [0011] Although tuberculosis can usually be controlled using prolonged antibiotic therapy, such treatment is not sufficient to prevent the spread of the disease. Infected individuals can remain asymptomatic, but contagious, for some time. Furthermore, although adherence to the treatment regimen is critical, it is difficult to control the patient's behavior. Some patients do not complete the course of treatment, which can lead to ineffective treatment and the development of drug resistance.
    [0013] BCG (Bacillus Calmette-Guérin), an attenuated strain of Mycobacterium bovis, has been used as a vaccine against tuberculosis since 1921. However, vaccination with BCG is not effective enough to stop the spread of this disease. BCG has proven its effectiveness in protecting against the appearance of the most serious cases of the disease, such as systemic spread in children or the development of meningitis. However, protection against respiratory disease is not as effective and therefore this facilitates the continued existence of patients who excrete the bacillus and spread the disease. Therefore, the control of excretion is essential for the interruption of the transmission of the disease.
    [0015] There are documents in the state of the art that describe vaccines for the treatment and / or prevention of tuberculosis that include peptide sequences from Mycobacterium species. However, the mycobacterial strains currently used in vaccines have several potential drawbacks: they are genetically unstable, ineffective in certain geographic areas, and the protection conferred on a vaccinated individual diminishes over time.
    [0017] Other treatments for tuberculosis have been developed based primarily on other live, attenuated strains of mycobacteria or on bacterial subunits. An example is document WO2013186409A1, which describes the use of inactivated mycobacteria, specifically selected from Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium africanum, and Mycobacterium microti, Mycobacterium bovis BCG, Mycobacterium fortuitum and Mycobacterium kansasii, administered in the prevention of tuberculosis orally according to a regimen of administration of multiple doses (at least 5), administered with a reduced time interval between them (not greater than 5 days), so that it induces a tolerant response against infection by the bacillus tuberculosis.
    [0019] However, compositions that include mycobacteria such as Mycobacterium chelonae and that are effective in the control and / or prevention of tuberculosis have not been found in the state of the art described.
    [0021] DESCRIPTION OF THE INVENTION
    [0023] The present invention relates to the strain Mycobacterium chelonae CAR47 with deposit number DSM 33522 and to compositions comprising said inactivated strain, as well as its use for the prevention and / or control of tuberculosis.
    [0025] Mycobacterium chelonae strain CAR47 with deposit number DSM 33522 modulates the immune response against pathogenic mycobacteria and helps control the spread of the illness. All this makes the strain of the present invention a bacterial strain of potential interest for use as medicine and food.
    [0027] Within the scope of this document, the reference to the strain of the invention will be made indistinctly as: Mycobacterium chelonae strain CAR47 (DSM 33522), Mycobacterium chelonae strain CAR47, strain CAR47 (DSM 33522) or strain CAR47.
    [0029] In a first aspect, the present invention relates to a mycobacterium strain, specifically Mycobacterium chelonae CAR47 deposited at the Leibniz Institute DSMZ-German collection of microorganisms and cell cultures with deposit number DSM 33522.
    [0031] In the present invention, the sequence of the genomic deoxyribonucleic acid (hereinafter, DNA) of the strain Mycobacterium chelonae CAR47 is SEQ ID NO: 1.
    [0033] In a second aspect, the present invention relates to a composition comprising the inactivated Mycobacterium chelonae strain CAR47. By inactivated mycobacteria, also called dead mycobacteria, are understood those mycobacteria that have undergone a physical or chemical treatment that transforms the living mycobacterium into a form incapable of replication. In the present invention, the Mycobacterium chelonae strain CAR47 is inactivated by heat treatment at 80 ° C for 60 minutes.
    [0035] In a preferred embodiment, the composition has an inactivated strain concentration of between 102-103 colony forming units (CFU) per gram or milliliter of final composition.
    [0037] In a third aspect, the present invention relates to a pharmaceutical composition, comprising the inactivated Mycobacterium chelonae strain CAR47 (DSM 33522). Preferably said composition will additionally comprise at least one pharmaceutically acceptable carrier and / or excipient.
    [0039] Additionally, the present invention also relates to a veterinary composition, comprising the inactivated Mycobacterium chelonae strain CAR47 (DSM 33522). Preferably said composition will additionally comprise at least one veterinarily acceptable carrier and / or excipient.
    [0040] The term "excipient" refers to that material that, included in the pharmaceutical and veterinary forms, is added to the active principles or their associations to serve as a vehicle, enable their preparation and stability, modify their organoleptic properties or determine the physicochemical properties of the drug and its bioavailability.
    [0042] The "pharmaceutically acceptable" excipient must allow the activity of the compounds of the pharmaceutical composition, that is, it must be compatible with said components.
    [0044] The "veterinarily acceptable" excipient must allow the activity of the compounds of the veterinary composition, that is, be compatible with said components.
    [0046] The "vehicle" or carrier is preferably an inert substance. The function of the vehicle is to facilitate the incorporation of other compounds, to allow a better dosage and administration or to give consistency and shape to the pharmaceutical and veterinary composition. Therefore, the vehicle is a substance that is used in the medicine to dilute any of the components of the pharmaceutical or veterinary composition of the present invention to a certain volume or weight; or that even without diluting said components it is capable of allowing a better dosage and administration or giving consistency and shape to the medicine.
    [0048] A pharmaceutical or veterinary composition should be understood as the composition that comprises one or more drugs (chemically active substance that exerts its effect on the body), presented for industrial or clinical use and intended for use in people or animals, endowed with properties that They allow the best pharmacological effect of their components in order to prevent, alleviate or improve the state of health of sick people or sick animals, or to modify physiological states.
    [0050] The pharmaceutical or veterinary composition can be presented in any clinically permitted form of administration and in a therapeutically effective amount.
    [0052] The preferred form of administration is a form adapted for oral administration. The form adapted for oral administration is selected from the list which includes, but is not limited to, drops, syrup, herbal tea, elixir, suspension, extemporaneous suspension, drinkable vial, tablet, capsule, granule, seal, pill, tablet, lozenge, troche. or lyophilized.
    [0053] Another aspect of the invention relates to the veterinary composition of the present invention for use in animals, specifically in ruminants and swine. Preferably cows, goats and deer in ruminants, and pigs and wild boar in suids.
    [0055] Another aspect of the present invention refers to the fact that the composition can also be a food composition, comprising the inactivated Mycobacterium chelonae strain CAR47 (DSM 33522), such as a food, a supplement, a nutraceutical or a paraprobiotic.
    [0057] The term "food composition" of the present invention refers to that food that, regardless of providing nutrients to the subject who takes it, beneficially affects one or more functions of the body, so that it provides a better state of health and well-being. As a consequence, said food composition can be intended for the prevention and / or treatment of a disease or of the factor causing a disease. Therefore, the term "food composition" of the present invention can be used synonymously with functional food or food for specific nutritional purposes or medicinal food.
    [0059] The term "supplement", synonymous with any of the terms "dietary supplement", "nutritional supplement"; or "food supplement" is a "food ingredient" intended to supplement the diet. Some examples of dietary supplements are, but are not limited to, vitamins, minerals, botanicals, amino acids, and food components such as enzymes and glandular extracts. They are not presented as substitutes for a conventional food or as a single component of a meal or of the nutritional diet but as a complement to the diet.
    [0061] The term "nutraceutical" as used in the present invention refers to highly concentrated bioactive natural substances that, although they are present in food, are processed to eliminate the excess and leave the beneficial part. Being concentrated and in higher doses than natural food, they have a favorable effect on health much greater than that of food as it occurs in nature.
    [0063] The term "paraprobiotic" as used in the present invention refers to non-viable microbial cells or cell extracts which, administered in adequate amounts, they can confer a benefit to the health of the host.
    [0065] In another aspect, the present invention relates to the Mycobacterium chelonae strain CAR47 (DSM 33522), a pharmaceutical composition of the present invention or a veterinary composition of the present invention for use as a medicine.
    [0067] In another aspect, the present invention relates to the Mycobacterium chelonae strain CAR47 (DSM 33522), a pharmaceutical composition of the present invention or a veterinary composition of the present invention for use in the prevention and / or control of tuberculosis.
    [0069] In another aspect, the present invention refers to the Mycobacterium chelonae strain CAR47 (DSM 33522), a pharmaceutical composition of the present invention or a veterinary composition of the present invention for the manufacture of a drug for the prevention and / or control of tuberculosis .
    [0071] In a final aspect, the present invention refers to a method for the prevention and / or control of tuberculosis that comprises administering Mycobacterium chelonae CAR47 (DSM 33522) of the present invention, a pharmaceutical composition of the present invention or a veterinary composition of the present invention in a subject in need.
    [0073] The term "prevention" as understood in the present invention consists of preventing the onset of the disease, that is, preventing the disease or pathological condition from occurring in a subject, in particular, when said subject is predisposed to the condition. pathological.
    [0075] The term "control" as understood in the present invention refers to the fact that in those individuals who are exposed and are infected, the disease does not progress, and this is achieved thanks to the modulation of the immune response when the individual is exposed to the tuberculous bacillus, and this response prevents it from spreading through the body and passing into the active phase of tuberculosis.
    [0077] In a final aspect, the present invention relates to the use of the Mycobacterium chelonae strain CAR47 (DSM 33522) for the preparation of a food composition or food.
    [0078] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as those commonly understood by a person skilled in the field of the invention.
    [0080] Throughout the description and claims the word "comprise" and its variants are not intended to exclude other technical characteristics, additives, components or steps. For those skilled in the art, other objects, advantages and characteristics of the invention will emerge partly from the description and partly from the practice of the invention. The following examples and figures are provided by way of illustration, and are not intended to be limiting of the present invention.
    [0082] FREE TEXT OF THE SEQUENCE LIST
    [0083] The free text that appears in the sequence list is provided below.
    [0085] SEQ ID NO: 1
    [0086] Genome of the strain Mycobacterium chelonae CAR47 with deposit number DSM 33522.
    [0087] In relation to the sequence, the positions 1054763-1054783 and 2007279-2007280 that includes an "n", can be any base (a, g, c or t).
    [0089] BRIEF DESCRIPTION OF THE FIGURES
    [0091] Figure 1. Relationship between the amount of M. marinum DNA, ZN positive bacilli and% of total involvement in the control and supplemented group.
    [0093] Figure 2. Expression of pro-inflammatory cytokines in the control and supplemented group . A moderate expression of pro-inflammatory cytokines was observed in the supplemented group, which is related to the type of lesions and a lower percentage of involvement in the supplemented group compared to the control group.
    [0095] DEPOSIT OF MICROORGANISMS UNDER THE BUDAPEST TREATY
    [0097] The microorganism object of the present invention, Mycobacterium chelonae CAR47, has been deposited on May 8, 2020 by INNOVACION EN GESTION Y CONSERVACION DE UNGULADOS SL (INGULADOS) at the Leibniz Institute DSMZ German collection of microorganisms and cell cultures, located at Inhoffenstrasse 7B, 38124, Braunschweig (Germany), with deposit number DSM 33522.
    [0099] EXAMPLES
    [0101] The purposes of the examples listed below serve to illustrate the invention, without thereby limiting the scope of the invention.
    [0103] Example 1: Isolation, identification and characterization of the strain
    [0105] For the isolation of the strain, different ecological areas were selected in which the epidemiological history of tuberculosis was known in the 10 years prior to the study, and three of them were selected with the following common characteristics:
    [0106] • High density of wild boar (90 wild boar / hectare).
    [0107] • Prevalence of tuberculosis caused by Mycobacterium bovis that did not exceed 5%.
    [0108] • Generalized disease patterns had not been observed.
    [0110] In the hunting actions carried out on these farms, a complete and regulated macroscopic inspection of the killed animals was carried out, analyzing the different organs and tissues that may be affected by the disease:
    [0111] - Lymph nodes of the head (mandibular, retropharyngeal).
    [0112] - Lungs and lymph nodes of the respiratory tract (tracheobronchial and mediastinal).
    [0113] - Liver.
    [0114] - Spleen.
    [0115] - Mesenteric lymph nodes.
    [0117] Retropharyngeal or submandibular lymph nodes were sampled from animals with only localized lesions or reactive lymph nodes for subsequent laboratory analysis.
    [0119] The following table shows the animals inspected in each of the hunting actions and the samples collected:
    [0120] Table 1. Total number of animals inspected, with macroscopic lesions compatible with tuberculosis (TB) detected and samples collected for analysis in the laboratory.
    [0125] Subsequently, in the laboratory, a detailed macroscopic analysis of each of the samples was carried out after serial cross-sections were performed. Next, the macroscopic description of the pathological findings was carried out.
    [0127] The terminology used to classify the lesions was as follows:
    [0128] - "Non-reactive" lymph node: The lymph node has a normal appearance and size.
    [0129] - "Slightly reactive" lymph node: The lymph node is slightly enlarged.
    [0130] - "Reactive" lymph node: The lymph node shows an increase in size and on section a hyperplasia of the marrow is observed, which is sometimes edematous.
    [0131] - Lymph node with a lesion compatible with tuberculosis of the “proliferative” type: A lesion compatible with tuberculosis is observed, which may be formed by one or multiple granulomas, but which are well defined and mostly have central calcification.
    [0132] - Lymph node with lesion compatible with tuberculosis of the “exudative” type: Lesions of a larger size than those previously described are observed, characterized by having abundant caseous tissue and poor delimitation.
    [0134] The microbiological isolation was carried out from the lymph nodes considered as "slightly reactive" or "reactive", following the protocol described by García-Jiménez et al., 2015 with some modifications:
    [0135] First, the samples were dissected removing the connective tissue and fat. They were then chopped and suspended in a solution of 10 ml of 0.2% albumin. This solution helps bind free fatty acids that can be toxic to the growth of mycobacteria. This solution was then added to a "stomacher" bag for homogenization of the tissue for 4 minutes.
    [0137] The next step consisted in the decontamination of the samples, since the mandibular lymph nodes act as "filter" organs, in which a great variety of microbial agents can concentrate. Due to the slow growth of mycobacteria, this measure is essential to avoid that other faster growing bacteria make it difficult to isolate Cetylpyridinium chloride 0.75% was used as a decontaminating solution (Corner and Trajstman, 1988).
    [0139] After 30 min decontamination, the solution was centrifuged discarding the supernatant. Finally, the sediment was used for cultivation in Lowenstein-Jensen medium with pyruvate and without glycerol, which was incubated at 37 ° C for 1 to 8 weeks under aerobic conditions. The tubes were checked weekly.
    [0141] Of the 95 samples inspected and processed in the laboratory, growth of colonies compatible with mycobacteria was obtained in 19 samples, which were identified by Zielh-Neelsen staining and molecular methods (Wilton and Cousins, 1992). After the analysis of the 19 isolates, the following results were obtained:
    [0142] - Two isolates belonging to the CMTB ( Mycobacterium tuberculosis complex). - Two isolates identified as NTM (non-tuberculous mycobacteria).
    [0143] - 14 isolates that were not mycobacteria.
    [0145] In the two strains identified as MNT, complete genome sequencing was performed with the following results:
    [0146] • CEPA ALT 10: genome analysis generated a 2145 Mbp sample. Analysis of similar sequences in the NCBI database resulted in 95% identity to the strain Mycobacterium chelonae CCUG 47445, complete genome (NZ_CP007220.1). This strain is not the object of protection of the present invention.
    [0148] • CEPA CAR47: genome analysis generated a 1942Mbp sample. Analysis of similar sequences in the NCBI database resulted in 96% identity with the strain Mycobacterium chelonae CCUG 47445, complete genome (NZ_CP007220.1).
    [0149] Mycobacterium chelonae is phylogenetically within the genus Mycobacterium, five clades within this genus have recently been identified. M. chelonae is classified in the clade “Abscessus-Chelonae” as a fast growing Mycobacterium , but phylogenetically separated from the clade “Tuberculosis-Simiae” and “Fortuitum-Vaccae” (Gupta et al 2018), which indicates that it is a mycobacterium phylogenetically separated from the Mycobacterium tuberculosis Complex, where the tuberculosis-producing strains are found in man and animals (clade “Tuberculosis-Simiae ').
    [0151] For the following tests, the strain CAR47 (DSM 33522) object of the present invention was used. The DNA sequence of the Mycobacterium chelonae CAR47 strain is SEQ ID NO: 1.
    [0153] Example 2: Modulation of the immune response against tuberculosis in an in vivo model using the strain CAR47 (DSM 33522)
    [0155] To evaluate whether the strain CAR47 (DSM 33522) could have a positive effect on the control of tuberculosis in animals, oral supplements were developed from said strain and subsequently an experimental infection was carried out in the zebrafish model. ( Danio rerio ) with Mycobacerium marinum . This model is widely used for toxicological studies, as well as for safety and efficacy for the evaluation of new substances. In this case, the effect of the supplement on the control of tuberculous lesions and the immune system of adult zebrafish of the wild type line infected with Mycobacterium marinum was evaluated.
    [0157] - Evaluation of the Safety of the two food supplements
    [0159] The supplements were made by culture and heat inactivation of strain CAR47 (DSM 33522). The supplements had a concentration of 102 CFU / ml, and were heat inactivated at 80 ° C for 60 minutes. Sterility control was carried out by culture in general and enriched media at 37 ° C for 48-72h to check the effect of inactivation.
    [0161] For the safety test of the supplements, adult zebrafish (Danio rerio ) of the wild type stock were administered the compounds by immersion for 15 days. On First, the fish were acclimatized for 24 hours in the new experimental tanks, 6 fish per tank distributed according to the study groups (Control Group, Supplemented Group). To administer the compound daily, 2 buckets of 500 ml of water from the fish tanks were prepared and 5 ml of the corresponding supplement were added:
    [0162] > Cuvette 1: supplement 1- CONTROL
    [0163] > Cuvette 2: supplement 2- CAR47
    [0165] The fish were then placed in the trays where they were kept for 30 minutes. Once this time had elapsed, they were returned to the fish tanks of origin and fed normally.
    [0167] As a result, no toxicity symptoms were observed in any of the fish in this study throughout the 15 days of experimentation, so the supplements are considered safe.
    [0169] - Experimentation on an animal model of adult zebrafish (Danio rerio ) of the wild type lineage
    [0171] The day before the start of the experiment, the groups of adult fish (6 to 9 months) were prepared. The total number of animals used for each experiment was 12 and two experimental groups were formed:
    [0172] • Control group: commercial food (n = 6)
    [0173] • Supplement group: commercial food Supplement (n = 6)
    [0175] The tests described in this experimental design were carried out in triplicate, using a total of 36 adult fish.
    [0177] The administration schedule that was followed is a daily dose (half an hour of immersion) of the supplement for two weeks, during which the evolution of the adults will be monitored.
    [0179] Once the supplementation period was over, infection with Mycobacterium marinum strain ATCC 927 was carried out. The inoculum was prepared from a pure culture of the strain and adjusted to 106 CFU / mL.
    [0180] The fish were anesthetized with tricaine (MS-222 Sigma-Aldrich) for 10 min and a 10 µl volume of the adjusted inoculum was injected using Hamilton syringes (Hamilton Company). After the injection, the fish were placed in recovery water and once their condition was verified, they were returned to the fish tank of origin.
    [0182] The monitoring of the fish was carried out every day, for 2-3 weeks, noting the symptoms that were observed and the casualties. The dead specimens were removed and reserved for later performing the established analyzes using histopathology and RT-PCR techniques.
    [0184] - Analysis performed
    [0186] -Histological study: 4 sections were made to each of the fish, two sections were stained with Hematoxylin-Eosin (H / E) to study the presence and type of granulomas throughout the organism, and two sections with Ziehl's stain- Neelsen (Z / N) to more easily detect bacteria and granulomas formed around it.
    [0188] - Gene expression study: A battery of RT-PCR was carried out to analyze the expression levels of 5 genes that encode pro-inflammatory cytokines: IFN- y , TNF-a, IL-6, IL-10 and iNOS. Likewise, the expression of 16S rRNA was studied to determine M. marinum and D. rerio actb1 to carry out the standardization of the technique.
    [0190] - Study of the amount of DNA of M. marinum: it was calculated from the standard line made with the DNA extracted from a pure culture of M. marinum, in a concentration range of 10 ng to 0.001ng / pL and converted to colony forming units (CFU).
    [0192] - CCEA approval
    [0194] This experimental procedure was approved by an Ethical Committee for Animal Experimentation (Code 101-18). All the personnel involved in it have the necessary training and experience to carry out the proposed procedures.
    [0196] - Results
    [0197] Regarding the survival of the zebrafish in the test, the fish were euthanized 15 days post-infection and the control group was compared with the group treated prior to infection with the supplement of the present invention.
    [0199] Overall, a survival of 61.11% was observed in the control group, compared to 66.67% in the group treated with the supplement of the present invention.
    [0201] The results of the histological study indicate that there are no significant differences in terms of the number of total granulomas per group, but a lower% of affectation and ZN positive bacilli are observed in the supplemented group, as well as a higher ratio of type I and II granulomas. , which indicates greater control of the infection (García-Jiménez et al., 2013b) (Table 1). Figure 1 shows the relationship between the amount of M. marinum DNA found, as well as ZN positive bacilli and% of total involvement in the control and supplemented group.
    [0203] Table 1. General histological evaluation
    [0205]
    [0208] Regarding the expression of cytokines, a moderate expression of pro-inflammatory cytokines (IFN- y , TNF-a, IL-6, IL-10 and iNOS) was observed in the supplemented group, which is related to the type of lesions observed and the lower percentage of affectation in the supplemented group with respect to the control group (Figure 2)
    [0210] In conclusion, when faced with a tuberculosis infection in the zebrafish model, the previous administration of the supplement comprising the CAR47 strain induces a moderate expression of pro-inflammatory cytokines. Therefore, the application of the supplement contributes to the control of diseases such as tuberculosis through a modulation of the inflammatory response that helps control the spread of the disease.
    [0211] BIBLIOGRAPHY
    [0213] - García-Jiménez W. L., J. M. Benítez-Medina, P. Fernández-Llario, J. A. Abecia, A.
    [0214] García-Sánchez, R. Martínez, D. Risco, A. Ortiz-Peláez, F. J. Salguero, N. H. Smith, L. Gómez and J. Hermoso de Mendoza. 2013a. Comparative Pathology of the Natural infections by Mycobacterium bovis and by Mycobacterium caprae in Wild Boar (Sus scrofa). Transboundary and Emerging Diseases, 60: 102-109.
    [0216] - García-Jiménez W. L., F. J. Salguero, P. Fernández-Llario, R. Martínez, D. Risco, J. Gough, A. Ortiz-Peláez, J. Hermoso-de-Mendoza and L. Gómez. 2013b. Immunopathology of granulomas produced by Mycobacterium bovis in naturally infected wild boar. Veterinary Immunology and Immunopathology, 156: 54-63.
    [0218] - García-Jiménez WL, JM Benítez-Medina, R. Martínez, J. Carranza, R. Cerrato, A. García-Sánchez, D. Risco, JC Moreno, M. Sequeda, L. Gómez, P. Fernández-Llario and J. Hermoso-de-Mendoza. 2015. Non-tuberculous mycobacteria in wild boar (Sus scrofa) from southern Spain: Epidemiological, clinical and diagnostic concerns. Transboundary and Emerging Diseases, 62: 72-80.
    [0220] - Radhey S. Gupta, Brian Lo and Jeen Son. 2018. Phylogenomics and Comparative Genomic Studies Robustly Support Division of the Genus Mycobacterium into an Emended Genus Mycobacterium and Four Novel Genera. Frontiers in Microbiology.
    [0221] - Corner L. A. and A. C. Trajstman. 1988. An evaluation of 1-hexadecylpyridinium chloride as a decontaminant in the primary isolation of Mycobacterium bovis from bovine lesions. Veterinary Microbiology, 18: 127-134.
    [0223] - Wilton, S., and D. Cousins. (1992) Detection and Identification of Multiple Mycobacterial Pathogens by DNA Amplification in a Single Tube. PCR Methods and Applications 1: 269-73.
    [0225] - Radhey S. Gupta, Brian Lo and Jeen Son. 2018. Phylogenomics and Comparative Genomic Studies Robustly Support Division of the Genus Mycobacterium into an Emended Genus Mycobacterium and Four Novel Genera. Frontiers in Microbiology.
    权利要求:
    Claims (14)
    [1]
    1. Mycobacterium chelonae strain CAR47 deposited at the Leibniz Institute DSMZ-German collection of microorganisms and cell cultures with deposit number DSM 33522.
    [2]
    2. Composition comprising the Mycobacterium chelonae strain CAR47 (DSM 33522) according to claim 1 inactivated.
    [3]
    Composition according to claim 2, wherein said composition has a concentration of the inactivated strain of between 102-103 colony forming units (CFU) per gram or milliliter of final composition.
    [4]
    Composition according to claim 2, wherein said composition is a pharmaceutical composition.
    [5]
    Composition according to claim 2, wherein said composition is a veterinary composition.
    [6]
    Composition according to claim 4 or 5, characterized in that said pharmaceutical or veterinary composition additionally comprises at least one pharmaceutical or veterinarily acceptable carrier and / or excipient.
    [7]
    Composition according to any of claims 4 or 5, wherein said pharmaceutical or veterinary composition is presented in a form adapted for oral administration.
    [8]
    8. Veterinary composition according to claim 5, for use in animals.
    [9]
    9. Veterinary composition according to claim 8, wherein said animals are selected from the group comprising ruminants and suids.
    [10]
    Composition according to claim 2, wherein said composition is a food composition.
    [11]
    Composition according to claim 10, wherein the food composition is selected from a food, a supplement, a nutraceutical or a paraprobiotic.
    [12]
    A strain according to claim 1 or composition according to any one of claims 2 to 9, for use as a medicine.
    [13]
    13. Strain or composition for use according to claim 11, for the prevention and / or control of tuberculosis.
    [14]
    14. Use of the strain according to claim 1, or of the composition according to claim 2, for the preparation of a food.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    NZ562036A|2001-07-26|2009-07-31|Agres Ltd|Immunogenic compositions wherein the immunogenic components are dispersed throughout a lipid matirx|
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