Mycoplasma bovis delay in apoptosis of macrophages is accompanied by increased expression of anti-apoptotic genes, reduced cytochrome C translocation and inhibition of DNA fragmentation

Maina, Teresia; Prysliak, Tracy; Perez-Casal, José

doi:10.1016/j.vetimm.2018.12.004

Cited by 15 publications

(10 citation statements)

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“…Responses to M. bovis infection differed among host cells. For example, M. bovis can inhibit peripheral blood mononuclear cell proliferation (van der Merwe et al, 2010) and induce apoptosis in various bovine cells, including lymphocytes (Vanden Bush and Rosenbusch, 2002), embryonic turbinate cells (Josi et al, 2018), and neutrophils (Jimbo et al, 2017), as well as delay apoptosis in macrophages (Maina et al, 2019). In a previous study, 2 M. bovis strains did not induce apoptosis and cytotoxicity in bovine mammary epithelial cells (bMEC) at multiplicities of infection (MOI) ranging from 1:1.3 to 1:9 (Josi et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Mycoplasma bovis-generated reactive oxygen species and induced apoptosis in bovine mammary epithelial cell cultures

Liu

Zhou

et al. 2020

Journal of Dairy Science

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Mycoplasma bovis is an important cause of bovine mastitis in China and worldwide. We hypothesized that M. bovis damages bovine mammary epithelial cells (bMEC), with the degree of damage varying among field isolates. Our objective was to evaluate 2 novel sequence type (ST) field strains of M. bovis (ST172 and ST173) for their ability to induce oxidative stress, cytotoxicity, pathomorphological changes, and apoptosis in bMEC, as a model for pathogenesis of M. bovis-induced bovine mastitis. Cytotoxicity (as indicated by release of lactate dehydrogenase, LDH) from bMEC depended on multiplicity of infection (MOI), with a high MOI (1:1,000) being required to induce cytotoxicity. Morphological changes in bMEC, including shrinkage, loss of cell integrity, and heavy staining (hematoxylin and eosin) of cytoplasm were apparent 24 h after infection with ST172 or ST173 M. bovis, with more severe changes being induced by the latter strain. Adhesion and invasion assays both had curvilinear patterns, peaking 12 h after infection with MOI of 1:1,000. Both production of reactive oxygen species (ROS) and proportion of apoptotic cells increased with time after infection. Increased Bax/Bcl-2 ratios and activation of caspase-3 implied involvement of mitochondria-dependent pathways of apoptosis. Furthermore, intracellular ROS generation, apoptosis, and cleaved caspase-3 were mitigated by N-acetyl-l-cysteine, a ROS scavenger. Both interleukin (IL)-1β and IL-6 were significantly upregulated by ST172 and ST173 M. bovis, with little change in expression of tumor necrosis factor-α. One ST173 M. bovis isolate had the greatest cytotoxicity of all of our field isolates, with the highest LDH release, adhesion, invasion, ROS production, and apoptosis. In conclusion, our hypothesis was supported: M. bovis damaged bMEC by generating ROS and initiating a mitochondria-dependent pathway of apoptosis, with the degree of damage varying among field isolates. This study provided new knowledge regarding pathogenesis of M. bovis-induced bovine mastitis.

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Section: Introductionmentioning

confidence: 99%

Mycoplasma bovis-generated reactive oxygen species and induced apoptosis in bovine mammary epithelial cell cultures

Liu

Zhou

et al. 2020

Journal of Dairy Science

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“…However, we still lack information about its mechanism of attenuation and protective immune response. In recent years, apoptosis inhibition by different bacteria has been suggested as a mechanism of survival by allowing the pathogen to replicate and disseminate in the host ( Maina et al, 2019 ). Here, we show the difference in the modulation of apoptosis and survival in BoMac cells by M. bovis P1 and P150.…”

Section: Discussionmentioning

confidence: 99%

“…We anticipated that M. bovis virulent strain P1 might interfere with the expression of CHOP protein during the pathogen-induced ER stress because CHOP is the major proapoptotic transcription factor activated by UPR. This could be one of the reasons for the M. bovis -infected cells’ delayed apoptosis ( Maina et al, 2019 ). To learn more about the role of CHOP in apoptosis in M. bovis P150 infection, we used siRNA against the CHOP gene to reduce apoptosis while also decreasing intracellular survival.…”

Section: Discussionmentioning

confidence: 99%

“…M. bovis has been shown to delay apoptosis in bovine monocytes in vitro , extending bacterial viability and facilitating bacterial dissemination ( Mulongo et al, 2014 ). M. bovis may also suppress the intrinsic apoptotic pathway in bovine macrophage BoMac cells ( Maina et al, 2019 ). However, M. bovis of varying virulence has been observed to modulate PBMC proliferation, apoptosis, and survival in distinct ways ( Suleman et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

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The attenuated Mycoplasma bovis strain promotes apoptosis of bovine macrophages by upregulation of CHOP expression

Zhang

Lu²,

Jin³

et al. 2022

Front. Microbiol.

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Mycoplasma bovis (M. bovis) is one of the major pathogens in the bovine respiratory disease complex, which includes pneumonia, mastitis, and arthritis and causes a great economic loss in the cattle industry. In China, a live-attenuated vaccine strain M. bovis P150 was obtained by a continuous culture of the wild-type strain M. bovis HB0801 (P1) in vitro for 150 passages. Using the infected bovine macrophage cell line BoMac, this work attempted to investigate the mechanism of P150 attenuation and protective immune response. To begin, we show that M. bovis P150 effectively triggered cytotoxicity and apoptosis in BoMac, although with lower intracellular survival than P1. The transcriptomes of BoMac after infection with M. bovis strains P1 and P150 were sequenced, and bioinformatic analysis identified 233 differentially expressed genes (DEGs), with 185 upregulated and 48 downregulated. Further Gene Ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analyses revealed that the majority of the DEGs were linked to CHOP complex, MAP kinase phosphatase activity and were involved in the IL-17 signaling pathway in immune response, MAPK signaling pathway in signal transduction, and p53 signaling pathway in cell growth and death. Among them, the level of C/EBP homologous protein (CHOP) was significantly upregulated in P150-infected BoMac compared to P1-infected cells at different time points, along with its upstream and downstream genes phosphorylated-PERK, phosphorylated-EIF2α, ATF4, and GADD45A increased in the PERK-dependent ER stress response. The role of CHOP in apoptosis was further verified by M. bovis-induced siCHOP knockdown in BoMac cells. The results showed that CHOP knockdown enhanced P150-induced apoptosis and dramatically increased the M. bovis P1 and P150 intracellular survival, particularly for P150. These data suggest that P150 infection upregulates CHOP expression, which can increase apoptosis and mediate a crosstalk between ER stress and apoptosis during infection, and hence, contribute to high cytotoxicity and low intracellular survival.

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“…Bacterial pathogens also have the ability to survive and manipulate intracellular mechanisms of host cells to escape the immune system. A recent study showed that Mycoplasma bovis has the ability to inhibit the apoptosis of infected bovine alveolar macrophages by increasing the expression of several anti-apoptotic genes ( Maina et al, 2019 ). Necroptosis is a programmed form of inflammatory cell death (necrosis) that actively causes cell death of infected cells or the propagation of danger signals to stimulate the immune system.…”

Section: Discussionmentioning

confidence: 99%

Integrated Network Analysis to Identify Key Modules and Potential Hub Genes Involved in Bovine Respiratory Disease: A Systems Biology Approach

et al. 2021

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Background: Bovine respiratory disease (BRD) is the most common disease in the beef and dairy cattle industry. BRD is a multifactorial disease resulting from the interaction between environmental stressors and infectious agents. However, the molecular mechanisms underlying BRD are not fully understood yet. Therefore, this study aimed to use a systems biology approach to systematically evaluate this disorder to better understand the molecular mechanisms responsible for BRD.Methods: Previously published RNA-seq data from whole blood of 18 healthy and 25 BRD samples were downloaded from the Gene Expression Omnibus (GEO) and then analyzed. Next, two distinct methods of weighted gene coexpression network analysis (WGCNA), i.e., module–trait relationships (MTRs) and module preservation (MP) analysis were used to identify significant highly correlated modules with clinical traits of BRD and non-preserved modules between healthy and BRD samples, respectively. After identifying respective modules by the two mentioned methods of WGCNA, functional enrichment analysis was performed to extract the modules that are biologically related to BRD. Gene coexpression networks based on the hub genes from the candidate modules were then integrated with protein–protein interaction (PPI) networks to identify hub–hub genes and potential transcription factors (TFs).Results: Four significant highly correlated modules with clinical traits of BRD as well as 29 non-preserved modules were identified by MTRs and MP methods, respectively. Among them, two significant highly correlated modules (identified by MTRs) and six nonpreserved modules (identified by MP) were biologically associated with immune response, pulmonary inflammation, and pathogenesis of BRD. After aggregation of gene coexpression networks based on the hub genes with PPI networks, a total of 307 hub–hub genes were identified in the eight candidate modules. Interestingly, most of these hub–hub genes were reported to play an important role in the immune response and BRD pathogenesis. Among the eight candidate modules, the turquoise (identified by MTRs) and purple (identified by MP) modules were highly biologically enriched in BRD. Moreover, STAT1, STAT2, STAT3, IRF7, and IRF9 TFs were suggested to play an important role in the immune system during BRD by regulating the coexpressed genes of these modules. Additionally, a gene set containing several hub–hub genes was identified in the eight candidate modules, such as TLR2, TLR4, IL10, SOCS3, GZMB, ANXA1, ANXA5, PTEN, SGK1, IFI6, ISG15, MX1, MX2, OAS2, IFIH1, DDX58, DHX58, RSAD2, IFI44, IFI44L, EIF2AK2, ISG20, IFIT5, IFITM3, OAS1Y, HERC5, and PRF1, which are potentially critical during infection with agents of bovine respiratory disease complex (BRDC).Conclusion: This study not only helps us to better understand the molecular mechanisms responsible for BRD but also suggested eight candidate modules along with several promising hub–hub genes as diagnosis biomarkers and therapeutic targets for BRD.

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Mycoplasma bovis delay in apoptosis of macrophages is accompanied by increased expression of anti-apoptotic genes, reduced cytochrome C translocation and inhibition of DNA fragmentation

Cited by 15 publications

References 65 publications

Mycoplasma bovis-generated reactive oxygen species and induced apoptosis in bovine mammary epithelial cell cultures

Mycoplasma bovis-generated reactive oxygen species and induced apoptosis in bovine mammary epithelial cell cultures

The attenuated Mycoplasma bovis strain promotes apoptosis of bovine macrophages by upregulation of CHOP expression

Integrated Network Analysis to Identify Key Modules and Potential Hub Genes Involved in Bovine Respiratory Disease: A Systems Biology Approach

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