Mycobacterium bovis induces mitophagy to suppress host xenophagy for its intracellular survival

Abstract Background Mycobacterium bovis persistently survives in macrophages by developing multiple strategies to evade host immune responses, and the early induction of interferon-β (IFN-β) is one of these critical strategies. The mitochondrial transcription factor A (TFAM) plays a vital role in mitochondrial DNA (mtDNA) metabolism and has been suggested to influence IFN-β production in response to viral infection. However, its role in the production of IFN-β by M. bovis has not been elucidated. Methods In the current study, we investigated the role of TFAM in the production of IFN-β in M. bovis–infected macrophages. Results We found that knockdown of TFAM expression significantly reduced M. bovis–induced IFN-β production, mtDNA copy numbers and cytosolic mtDNA were increased in murine macrophages with M. bovis infection, cytosolic mtDNA contributed to IFN-β production, and TFAM was required for the increase in mtDNA copy numbers induced by M. bovis. We also observed that TFAM affected the intracellular survival of M. bovis. Conclusions Our results suggest that TFAM plays an essential role in M. bovis–induced IFN-β production by regulating mtDNA copy numbers. This might be a new strategy adopted by M. bovis for its intracellular survival.

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Supervivencia intracelular de cepas de Mycobacterium bovis de alta y baja frecuencia probado en un modelo de macrófagos bovinos

Revista Mexicana de Ciencias Pecuarias ◽

10.22319/rmcp.v12i2.5542 ◽

2021 ◽

Vol 12 (2) ◽

pp. 487-502

Author(s):

Alejandro Nava-Vargas ◽

Feliciano Milián-Suazo ◽

Germinal Jorge Cantó-Alarcón ◽

José A. Gutiérrez-Pabello

Keyword(s):

Mycobacterium Bovis ◽

Bovine Tuberculosis ◽

High Frequency ◽

Low Frequency ◽

Intracellular Survival ◽

Strain Identification ◽

Cattle Population ◽

Intracellular Growth ◽

Colony Forming Units ◽

Significant Difference

Bovine tuberculosis is a disease caused by Mycobacterium bovis that affects cattle and other species, including humans. Mycobacterium bovis resides mainly in macrophages, so bacilli survival within macrophages is related to virulence. Isolation and strain identification are important for disease control. However, little is known about virulence of the circulating strains in cattle populations. Therefore, the aim of this study was to compare the intracellular survival of Mycobacterium bovis strains with high and low frequency genotypes in cattle in Mexico. Four high frequency genotypes and four low frequency genotypes were identified and subjected to intracellular survival assays in bovine macrophages. Results showed that the phagocytosis proportion was approximately 63 % for all strains. There were no significant differences in the average Colony Forming Units (CFUs) in phagocytosis and survival between the high and low frequency groups; however, when the CFU average of phagocytosis was compared with the survival, significant differences were found in both groups. In intracellular growth, a significant difference was observed between low and high frequency strains, and between low frequency strains. Finally, the intracellular growth average of the groups was analyzed showing no significant difference. These results suggest that the frequency of the genotype in cattle population is not related to the intracellular survival and the virulence of the M. bovis strains.

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Intracellular survival of virulent Mycobacterium bovis and M. bovis BCG in ferret macrophages

Veterinary Microbiology ◽

10.1016/s0378-1135(99)00011-5 ◽

1999 ◽

Vol 66 (3) ◽

pp. 235-243 ◽

Cited By ~ 6

Author(s):

M.L Cross ◽

F.E Aldwell ◽

J.F.T Griffin ◽

C.G Mackintosh

Keyword(s):

Mycobacterium Bovis ◽

Intracellular Survival

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Intracellular survival of Brucella abortus, Mycobacterium bovis BCG, Salmonella dublin, and Salmonella typhimurium in macrophages from cattle genetically resistant to Brucella abortus

Veterinary Immunology and Immunopathology ◽

10.1016/0165-2427(95)05492-8 ◽

1996 ◽

Vol 50 (1-2) ◽

pp. 55-65 ◽

Cited By ~ 44

Author(s):

T. Qureshi ◽

J.W. Templeton ◽

L.G. Adams

Keyword(s):

Salmonella Typhimurium ◽

Mycobacterium Bovis ◽

Brucella Abortus ◽

Intracellular Survival ◽

Mycobacterium Bovis Bcg ◽

Salmonella Dublin

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Dissecting the Mycobacterium bovis BCG Response to Macrophage Infection to Help Prioritize Targets for Anti-Tuberculosis Drug and Vaccine Discovery

Vaccines ◽

10.3390/vaccines10010113 ◽

2022 ◽

Vol 10 (1) ◽

pp. 113

Author(s):

Jamie Medley ◽

Aaron Goff ◽

Paulo J. G. Bettencourt ◽

Madelaine Dare ◽

Liam Cole ◽

...

Keyword(s):

Mycobacterium Bovis ◽

Iron Homeostasis ◽

Vaccine Development ◽

Gene Families ◽

Intracellular Survival ◽

Macrophage Infection ◽

Mycobacterium Bovis Bcg ◽

Macrophage Phagocytosis ◽

Upregulated Genes ◽

Novel Drug

New strategies are required to reduce the worldwide burden of tuberculosis. Intracellular survival and replication of Mycobacterium tuberculosis after macrophage phagocytosis is a fundamental step in the complex host–pathogen interactions that lead to granuloma formation and disease. Greater understanding of how the bacterium survives and thrives in these environments will inform novel drug and vaccine discovery programs. Here, we use in-depth RNA sequencing of Mycobacterium bovis BCG from human THP-1 macrophages to describe the mycobacterial adaptations to the intracellular environment. We identify 329 significantly differentially regulated genes, highlighting cholesterol catabolism, the methylcitrate cycle and iron homeostasis as important for mycobacteria inside macrophages. Examination of multi-functional gene families revealed that 35 PE/PPE genes and five cytochrome P450 genes were upregulated 24 h after infection, highlighting pathways of potential significance. Comparison of the intracellular transcriptome to gene essentiality and immunogenicity studies identified 15 potential targets that are both required for intracellular survival and induced on infection, and eight upregulated genes that have been demonstrated to be immunogenic in TB patients. Further insight into these new and established targets will support drug and vaccine development efforts.

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