The Voltage-Dependent Anion Channels (VDAC) of Mycobacterium avium phagosome are associated with bacterial survival and lipid export in macrophages

Danelishvili, Lia; Chinison, Jessica J.; Pham, Tuan Anh; Gupta, Rashmi; Bermudez, Luiz E.

doi:10.1038/s41598-017-06700-3

Cited by 11 publications

(6 citation statements)

References 68 publications

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“…More recently, host cell VDACs have been reported to interact with intracellular pathogens. VDAC was identified as a component of the Mycobacterium avium phagosome membrane and was used by the bacterium for the transport of mycobacterial lipids into the cytoplasm via an interaction with mmpL4 (mycobacterial membrane protein large 4) lipoproteins (71). During infection with E.…”

Section: Discussionmentioning

confidence: 99%

Microsporidia Interact with Host Cell Mitochondria via Voltage-Dependent Anion Channels Using Sporoplasm Surface Protein 1

Han

et al. 2019

mBio

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Microsporidia are opportunistic intracellular pathogens that can infect a wide variety of hosts ranging from invertebrates to vertebrates. During invasion, the microsporidian polar tube pushes into the host cell, creating a protective microenvironment, the invasion synapse, into which the sporoplasm extrudes. Within the synapse, the sporoplasm then invades the host cell, forming a parasitophorous vacuole (PV). Using a proteomic approach, we identified Encephalitozoon hellem sporoplasm surface protein 1 (EhSSP1), which localized to the surface of extruded sporoplasms. EhSSP1 was also found to interact with polar tube protein 4 (PTP4). Recombinant EhSSP1 (rEhSSP1) bound to human foreskin fibroblasts, and both anti-EhSSP1 and rEhSSP1 caused decreased levels of host cell invasion, suggesting that interaction of SSP1 with the host cell was involved in invasion. Coimmunoprecipitation (Co-IP) followed by proteomic analysis identified host cell voltage-dependent anion channels (VDACs) as EhSSP1 interacting proteins. Yeast two-hybrid assays demonstrated that EhSSP1 was able to interact with VDAC1, VDAC2, and VDAC3. rEhSSP1 colocalized with the host mitochondria which were associated with microsporidian PVs in infected cells. Transmission electron microscopy revealed that the outer mitochondrial membrane interacted with meronts and the PV membrane, mitochondria clustered around meronts, and the VDACs were concentrated at the interface of mitochondria and parasite. Knockdown of VDAC1, VDAC2, and VDAC3 in host cells resulted in significant decreases in the number and size of the PVs and a decrease in mitochondrial PV association. The interaction of EhSSP1 with VDAC probably plays an important part in energy acquisition by microsporidia via its role in the association of mitochondria with the PV. IMPORTANCE Microsporidia are important opportunistic human pathogens in immune-suppressed individuals, such as those with HIV/AIDS and recipients of organ transplants. The sporoplasm is critical for establishing microsporidian infection. Despite the biological importance of this structure for transmission, there is limited information about its structure and composition that could be targeted for therapeutic intervention. Here, we identified a novel E. hellem sporoplasm surface protein, EhSSP1, and demonstrated that it can bind to host cell mitochondria via host VDAC. Our data strongly suggest that the interaction between SSP1 and VDAC is important for the association of mitochondria with the parasitophorous vacuole during microsporidian infection. In addition, binding of SSP1 to the host cell is associated with the final steps of invasion in the invasion synapse.

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Section: Discussionmentioning

confidence: 99%

Microsporidia Interact with Host Cell Mitochondria via Voltage-Dependent Anion Channels Using Sporoplasm Surface Protein 1

Han

et al. 2019

mBio

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“…Top enriched candidates from fatty acid metabolism and synthesis were FadD5 ( Table 1 ; ratio milk 4 °C/M7H9: 122.9; milk 37 °C/M7H9: 103.1), which may serve to recycle mycolic acids for the long-term survival of the tubercle bacilli [ 64 ], MmpL4_1 and LipN. MmpL4_1 ( Table 1 ; ratio milk 4 °C/M7H9 and milk 37 °C/M7H9: infinite) is important for virulence of mycobacteria through secretion of specific lipids and participates in export of mycobacterium cell wall components to the bacterial surface [ 65 , 66 ]. LipN ( Table 1 ; ratio milk 4 °C/M7H9: 6.0; milk 37 °C/M7H9: 5.9) is a fatty acid degradation lipase/esterase that was shown to be significantly upregulated in MAP shed in cow feces [ 61 ].…”

Section: Discussionmentioning

confidence: 99%

Mycobacterium avium subsp. paratuberculosis Proteome Changes Profoundly in Milk

Kleinwort¹,

Hobmaier²,

Mayer

et al. 2021

Metabolites

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Mycobacterium avium subspecies paratuberculosis (MAP) are detectable viable in milk and other dairy products. The molecular mechanisms allowing the adaptation of MAP in these products are still poorly understood. To obtain information about respective adaptation of MAP in milk, we differentially analyzed the proteomes of MAP cultivated for 48 h in either milk at 37 °C or 4 °C or Middlebrook 7H9 broth as a control. From a total of 2197 MAP proteins identified, 242 proteins were at least fivefold higher in abundance in milk. MAP responded to the nutritional shortage in milk with upregulation of 32% of proteins with function in metabolism and 17% in fatty acid metabolism/synthesis. Additionally, MAP upregulated clusters of 19% proteins with roles in stress responses and immune evasion, 19% in transcription/translation, and 13% in bacterial cell wall synthesis. Dut, MmpL4_1, and RecA were only detected in MAP incubated in milk, pointing to very important roles of these proteins for MAP coping with a stressful environment. Dut is essential and plays an exclusive role for growth, MmpL4_1 for virulence through secretion of specific lipids, and RecA for SOS response of mycobacteria. Further, 35 candidates with stable expression in all conditions were detected, which could serve as targets for detection. Data are available via ProteomeXchange with identifier PXD027444.

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“…In addition to the pivotal roles of mitochondria in cellular metabolism ( Ramond et al, 2019 ), in macrophages VDACs appear to play a more negative role during infection, being crucial for bacterial growth and survival within phagosomes. The channels were reported to colocalize and interact with bacterial proteins and aid bacterial lipid translocation ( Danelishvili et al, 2017 ).…”

Section: Further Macrophage Ion Channelsmentioning

confidence: 99%

The contribution of ion channels to shaping macrophage behaviour

2022

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The expanding roles of macrophages in physiological and pathophysiological mechanisms now include normal tissue homeostasis, tissue repair and regeneration, including neuronal tissue; initiation, progression, and resolution of the inflammatory response and a diverse array of anti-microbial activities. Two hallmarks of macrophage activity which appear to be fundamental to their diverse cellular functionalities are cellular plasticity and phenotypic heterogeneity. Macrophage plasticity allows these cells to take on a broad spectrum of differing cellular phenotypes in response to local and possibly previous encountered environmental signals. Cellular plasticity also contributes to tissue- and stimulus-dependent macrophage heterogeneity, which manifests itself as different macrophage phenotypes being found at different tissue locations and/or after different cell stimuli. Together, plasticity and heterogeneity align macrophage phenotypes to their required local cellular functions and prevent inappropriate activation of the cell, which could lead to pathology. To execute the appropriate function, which must be regulated at the qualitative, quantitative, spatial and temporal levels, macrophages constantly monitor intracellular and extracellular parameters to initiate and control the appropriate cell signaling cascades. The sensors and signaling mechanisms which control macrophages are the focus of a considerable amount of research. Ion channels regulate the flow of ions between cellular membranes and are critical to cell signaling mechanisms in a variety of cellular functions. It is therefore surprising that the role of ion channels in the macrophage biology has been relatively overlooked. In this review we provide a summary of ion channel research in macrophages. We begin by giving a narrative-based explanation of the membrane potential and its importance in cell biology. We then report on research implicating different ion channel families in macrophage functions. Finally, we highlight some areas of ion channel research in macrophages which need to be addressed, future possible developments in this field and therapeutic potential.

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The Voltage-Dependent Anion Channels (VDAC) of Mycobacterium avium phagosome are associated with bacterial survival and lipid export in macrophages

Cited by 11 publications

References 68 publications

Microsporidia Interact with Host Cell Mitochondria via Voltage-Dependent Anion Channels Using Sporoplasm Surface Protein 1

Microsporidia Interact with Host Cell Mitochondria via Voltage-Dependent Anion Channels Using Sporoplasm Surface Protein 1

Mycobacterium avium subsp. paratuberculosis Proteome Changes Profoundly in Milk

The contribution of ion channels to shaping macrophage behaviour

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