The macrophage marches on its phagosome: dynamic assays of phagosome function

Russell, David G.; VanderVen, Brian C.; Glennie, Sarah; Mwandumba, Henry C.; Heyderman, Robert S.

doi:10.1038/nri2591

Cited by 158 publications

(153 citation statements)

References 42 publications

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“…R-Mtb is highly adapted to life within macrophages, and it can modulate macrophage defenses and inhibit the processing of its Ags for the MHC class II pathway to promote its intracellular survival (32,33). In particular, metabolically active M. tuberculosis is endowed with the capacity to arrest phagosomal maturation (34)(35)(36)(37). To find a possible explanation for the increased Ag presentation capacity of D-Mtb-infected macrophages, we tested whether D-Mtb shares with R-Mtb the same ability to arrest phagosomal maturation (38).…”

Section: Discussionmentioning

confidence: 99%

Dormant Mycobacterium tuberculosis Fails To Block Phagosome Maturation and Shows Unexpected Capacity To Stimulate Specific Human T Lymphocytes

Mariotti

Pardini

Gagliardi

et al. 2013

The Journal of Immunology

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Dormancy is defined as a stable but reversible nonreplicating state of Mycobacterium tuberculosis. It is currently thought that dormant M. tuberculosis (D-Mtb) is responsible for latent tuberculosis (TB) infection. Recently, D-Mtb was also shown in sputa of patients with active TB, but the capacity of D-Mtb to stimulate specific immune responses was not investigated. We observed that purified protein derivative–specific human CD4+ T lymphocytes recognize mycobacterial Ags more efficiently when macrophages are infected with D-Mtb instead of replicating M. tuberculosis (R-Mtb). The different Ag recognition occurs even when the two forms of mycobacteria equally infect and stimulate macrophages, which secrete the same cytokine pattern and express MHC class I and II molecules at the same levels. However, D-Mtb but not R-Mtb colocalizes with mature phagolysosome marker LAMP-1 and with vacuolar proton ATPase in macrophages. D-Mtb, unlike R-Mtb, is unable to interfere with phagosome pH and does not inhibit the proteolytic efficiency of macrophages. We show that D-Mtb downmodulates the gene Rv3875 encoding for ESAT-6, which is required by R-Mtb to block phagosome maturation together with Rv3310 gene product SapM, previously shown to be downregulated in D-Mtb. Thus, our results indicate that D-Mtb cannot escape MHC class II Ag-processing pathway because it lacks the expression of genes required to block the phagosome maturation. Data suggest that switching to dormancy not only represents a mechanism of survival in latent TB infection, but also a M. tuberculosis strategy to modulate the immune response in different stages of TB.

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Section: Discussionmentioning

confidence: 99%

Dormant Mycobacterium tuberculosis Fails To Block Phagosome Maturation and Shows Unexpected Capacity To Stimulate Specific Human T Lymphocytes

Mariotti

Pardini

Gagliardi

et al. 2013

The Journal of Immunology

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“…The digestion of particulate matter and microbes by proteolysis following phagocytosis is required for both microbicidal activity and antigen presentation (13,14). Recently, we reported that AM phagosomal proteolysis function is impaired in asymptomatic HIV-infected ART-naive adults (6).…”

Section: Am Phagosomal Proteolysis Function Is Impaired In Hiv-infectmentioning

confidence: 99%

“…Phagosomal proteolysis in AM was measured using a flow cytometry-based reporter bead assay as described previously (6,13). The readout for the assay was Activity Index, which was calculated by first determining the ratio of median fluorescence intensity of the reporter over calibration flour at 10-minute and 240-minute time points, and then dividing the ratio at 240 minutes by ratio at 10 minutes.…”

Section: Measurement Of Am Phagosomal Proteolysismentioning

confidence: 99%

Asymptomatic HIV-infected Individuals on Antiretroviral Therapy Exhibit Impaired Lung CD4⁺T-Cell Responses to Mycobacteria

Jambo

Banda

Afran

et al. 2014

Am J Respir Crit Care Med

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Rationale: HIV-infected persons on antiretroviral therapy (ART) remain at higher risk of pulmonary tuberculosis (TB) than HIV-uninfected individuals. This increased susceptibility may be caused by impairment of alveolar macrophage (AM) function and/or mycobacteria-specific alveolar CD4 1 T-cell responses observed in HIV-infected ART-naive adults.Objectives: To determine whether ART was associated with improvement in both AM function, assessed by phagosomal proteolysis, and alveolar CD4 1 T-cell responses to Mycobacterium in HIV-infected individuals.Methods: Peripheral blood was drawn and bronchoalveolar lavage (BAL) performed on healthy, 35 HIV-uninfected, 25 HIV-infected ART-naive, and 50 HIV-infected ART-treated asymptomatic adults. Phagosomal proteolysis of AM was assessed with fluorogenic beads. Mycobacteria-specific CD4 1 T-cell responses were measured by intracellular cytokine staining.Measurements and Main Results: HIV-infected adults on ART exhibited lower plasma HIV viral load and higher blood CD4 1 T-cell count than ART-naive adults. AM proteolysis and total mycobacteria-specific Th1 CD4 1 T-cell responses in individuals on ART for greater than or equal to 4 years were similar to HIVuninfected control subjects but those on ART for less than 4 years had impaired responses. Total influenza-specific alveolar Th1 CD4 1 Tcell responses were intact in all individuals receiving ART. In contrast, BAL and blood mycobacteria-specific polyfunctional CD4 1 T-cell responses were impaired in adults on ART irrespective of duration.Conclusions: AM and mycobacteria-specific alveolar CD4 1 T-cell responses in HIV-infected adults on ART for less than 4 years are impaired and may partly explain the high risk of TB in HIV-infected individuals on ART. Strategies to augment ART to improve lung immune cell function and reduce the high incidence of TB in HIVinfected adults who initiate ART should be investigated.

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“…Macrophages, upon ingesting invading micro-organisms, have the primary function of killing bacteria through maturation of phagosomes as defined by their acidification (Russell et al, 2009;Vieira et al, 2002). The mature phagosome is also rich in proteolytic enzymes, ensuring effective degradation of internalized microbes (Kinchen and Ravichandran, 2008).…”

Section: Introductionmentioning

confidence: 99%

Role of phagosomal redox-sensitive trp channel TRPM2 in regulating bactericidal activity of macrophages

Kiya

Gong

et al. 2017

Journal of Cell Science

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Acidification of macrophage phagosomes serves an important bactericidal function. We show here that the redox-sensitive transient receptor potential (TRP) cation channel TRPM2 is expressed in the phagosomal membrane and regulates macrophage bactericidal activity through the activation of phagosomal acidification. Measurement of the TRPM2 current in phagosomes identified TRPM2 as a functional redox-sensitive cation channel localized in the phagosomal membrane. Simultaneous measurements of phagosomal Ca 2+ changes and phagosome acidification in macrophages undergoing phagocytosis demonstrated that TRPM2 was required to mediate the efflux of cations and for phagosomal acidification during the process of phagosome maturation. Acidification in phagosomes was significantly reduced in macrophages isolated from Trpm2 −/− mice as compared to wild type, and acidification was coupled to reduced bacterial clearance in Trpm2 −/− mice. Trpm2 +/+ macrophages treated with the vacuolar H + -ATPase inhibitor bafilomycin showed reduced bacterial clearance, similar to that in Trpm2 −/− macrophages. Direct activation of TRPM2 using adenosine diphosphate ribose (ADPR) induced both phagosomal acidification and bacterial killing. These data collectively demonstrate that TRPM2 regulates phagosomal acidification, and is essential for the bacterial killing function of macrophages.

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The macrophage marches on its phagosome: dynamic assays of phagosome function

Cited by 158 publications

References 42 publications

Dormant Mycobacterium tuberculosis Fails To Block Phagosome Maturation and Shows Unexpected Capacity To Stimulate Specific Human T Lymphocytes

Dormant Mycobacterium tuberculosis Fails To Block Phagosome Maturation and Shows Unexpected Capacity To Stimulate Specific Human T Lymphocytes

Asymptomatic HIV-infected Individuals on Antiretroviral Therapy Exhibit Impaired Lung CD4⁺T-Cell Responses to Mycobacteria

Role of phagosomal redox-sensitive trp channel TRPM2 in regulating bactericidal activity of macrophages

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The macrophage marches on its phagosome: dynamic assays of phagosome function

Cited by 158 publications

References 42 publications

Dormant Mycobacterium tuberculosis Fails To Block Phagosome Maturation and Shows Unexpected Capacity To Stimulate Specific Human T Lymphocytes

Dormant Mycobacterium tuberculosis Fails To Block Phagosome Maturation and Shows Unexpected Capacity To Stimulate Specific Human T Lymphocytes

Asymptomatic HIV-infected Individuals on Antiretroviral Therapy Exhibit Impaired Lung CD4+T-Cell Responses to Mycobacteria

Role of phagosomal redox-sensitive trp channel TRPM2 in regulating bactericidal activity of macrophages

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Asymptomatic HIV-infected Individuals on Antiretroviral Therapy Exhibit Impaired Lung CD4⁺T-Cell Responses to Mycobacteria