Efficacy of gene-therapy based on adenovirus encoding granulocyte-macrophage colony-stimulating factor in drug-sensitive and drug-resistant experimental pulmonary tuberculosis

Francisco‐Cruz, Alejandro; Mata-Espinosa, Dulce; Ramos-Espinosa, Octavio; Marquina‐Castillo, Brenda; Estrada‐Parra, Sergio; Xing, Zhou; Hernández-Pando, Rogelio

doi:10.1016/j.tube.2016.05.015

Cited by 14 publications

(12 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, this finding verified previous reports that GM-CSF has antimycobacterial activity, as originally described by Denis et al ( 26 ). In addition, GM-CSF expression adenovirus therapy was recently shown to have some efficacy against both drug-sensitive and drug-resistant M. tuberculosis infection in mice ( 41 ). Furthermore, the GM-CSF −/− mouse is highly susceptible to M. tuberculosis infection, with a median survival time of 4 to 5 weeks ( 27 , 28 ).…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, clinical studies have found that the presence of anti-GM-CSF autoantibodies that block GM-CSF function are associated with susceptibility to both cryptococcal meningitis and pulmonary TB in otherwise healthy subjects ( 40 ), indicating that GM-CSF may also participate in host defense against infection in people. In contrast, immunotherapy that induces GM-CSF production was recently shown to be effective against both drug-resistant and drug-sensitive M. tuberculosis infection in mice ( 41 , 42 ).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Role of Granulocyte-Macrophage Colony-Stimulating Factor Production by T Cells duringMycobacterium tuberculosisInfection

Rothchild

Stowell

Goyal

et al. 2017

mBio

View full text Add to dashboard Cite

Mice deficient for granulocyte-macrophage colony-stimulating factor (GM-CSF−/−) are highly susceptible to infection with Mycobacterium tuberculosis, and clinical data have shown that anti-GM-CSF neutralizing antibodies can lead to increased susceptibility to tuberculosis in otherwise healthy people. GM-CSF activates human and murine macrophages to inhibit intracellular M. tuberculosis growth. We have previously shown that GM-CSF produced by iNKT cells inhibits growth of M. tuberculosis. However, the more general role of T cell-derived GM-CSF during infection has not been defined and how GM-CSF activates macrophages to inhibit bacterial growth is unknown. Here we demonstrate that, in addition to nonconventional T cells, conventional T cells also produce GM-CSF during M. tuberculosis infection. Early during infection, nonconventional iNKT cells and γδ T cells are the main source of GM-CSF, a role subsequently assumed by conventional CD4+ T cells as the infection progresses. M. tuberculosis-specific T cells producing GM-CSF are also detected in the peripheral blood of infected people. Under conditions where nonhematopoietic production of GM-CSF is deficient, T cell production of GM-CSF is protective and required for control of M. tuberculosis infection. However, GM-CSF is not required for T cell-mediated protection in settings where GM-CSF is produced by other cell types. Finally, using an in vitro macrophage infection model, we demonstrate that GM-CSF inhibition of M. tuberculosis growth requires the expression of peroxisome proliferator-activated receptor gamma (PPARγ). Thus, we identified GM-CSF production as a novel T cell effector function. These findings suggest that a strategy augmenting T cell production of GM-CSF could enhance host resistance against M. tuberculosis.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Role of Granulocyte-Macrophage Colony-Stimulating Factor Production by T Cells duringMycobacterium tuberculosisInfection

Rothchild

Stowell

Goyal

et al. 2017

mBio

View full text Add to dashboard Cite

show abstract

“…BALB/c mice (8 weeks of age, male) were anesthetized and inoculated intra-tracheally with 2.5x10 5 CFU of M. tuberculosis H37Rv in 100 µl of endotoxin-free sterile PBS.25 Thirty days after infection, each mouse (10 mice per group) received intra-peritoneal injections of 100 μl of 0.85% NaCl alone or with 2.5 μg of vesicle protein of S-EV or Mtb-EV, three times per week (as previously reported for other anti-tuberculosis treatments tested in this mouse model) 26,27. Mice were euthanized after 30 or 60 days of treatment.…”

Section: Methodsmentioning

confidence: 99%

<p>Extracellular vesicles released by J774A.1 macrophages reduce the bacterial load in macrophages and in an experimental mouse model of tuberculosis</p>

García-Martínez

Vázquez-Flores

Álvarez-Jiménez

et al. 2019

IJN

Self Cite

View full text Add to dashboard Cite

BackgroundTuberculosis is the leading cause of death by an infectious microorganism worldwide. Conventional treatment lasts at least six months and has adverse effects; therefore, it is important to find therapeutic alternatives that reduce the bacterial load and may reduce the treatment duration. The immune response against tuberculosis can be modulated by several mechanisms, including extracellular vesicles (EVs), which are nano-sized membrane-bound structures that constitute an efficient communication mechanism among immune cells.MethodsThe EVs released by the J774A.1 mouse macrophage cell line, both spontaneously (S-EV) and after infection with Mycobacterium tuberculosis H37Rv (Mtb-EV), were purified by ultra-centrifugation and size-exclusion chromatography. The size distribution and chemical composition of these EVs were evaluated, and their effect on the bacterial load and the production of cytokines was determined in both in vitro and in vivo models of M. tuberculosis infection.ResultsMtb-EV are larger than S-EV, they contain M. tuberculosis-specific antigens (not detected in EVs released from M. fortuitum-infected J774A.1 cells) and are rich in phosphatidylserine, present in their outer membrane layer. S-EV, but not Mtb-EV, reduced the bacterial load and the production of MCP-1 and TNF-α in M. tuberculosis-infected macrophages, and these effects were reversed when phosphatidylserine was blocked with annexin V. Both S-EV and Mtb-EV significantly reduced the lung bacterial load in mice infected with M. tuberculosis after 60 days of treatment, but they had no effect on survival or on the lung pneumonic area of these mice.ConclusionJ774A.1 macrophages infected with M. tuberculosis H37Rv released EVs that differed in size and phosphatidylserine content from spontaneously released EVs, and these EVs also had different biological effects: S-EV reduced the mycobacterial load and the cytokine production in vitro (through a phosphatidylserine-dependent mechanism), while both EVs reduced the lung bacterial load in vivo. These results are the basis for further experiments to evaluate whether EVs improve the efficiency of the conventional treatment for tuberculosis.

show abstract

“…Previous studies showed that GM-CSF exerts a host protective role during TB infection (202)(203)(204)(205)(240)(241)(242). It mediates the formation of granuloma and promotes bacterial clearance in the host (241), and induces classical activation of macrophage to M1 polarization state (242).…”

Section: Granulocyte-macrophage Colony-stimulating Factor (Gm-csf)mentioning

confidence: 99%

Understanding the Reciprocal Interplay Between Antibiotics and Host Immune System: How Can We Improve the Anti-Mycobacterial Activity of Current Drugs to Better Control Tuberculosis?

et al. 2021

View full text Add to dashboard Cite

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) infection, remains a global health threat despite recent advances and insights into host-pathogen interactions and the identification of diverse pathways that may be novel therapeutic targets for TB treatment. In addition, the emergence and spread of multidrug-resistant Mtb strains led to a low success rate of TB treatments. Thus, novel strategies involving the host immune system that boost the effectiveness of existing antibiotics have been recently suggested to better control TB. However, the lack of comprehensive understanding of the immunomodulatory effects of anti-TB drugs, including first-line drugs and newly introduced antibiotics, on bystander and effector immune cells curtailed the development of effective therapeutic strategies to combat Mtb infection. In this review, we focus on the influence of host immune-mediated stresses, such as lysosomal activation, metabolic changes, oxidative stress, mitochondrial damage, and immune mediators, on the activities of anti-TB drugs. In addition, we discuss how anti-TB drugs facilitate the generation of Mtb populations that are resistant to host immune response or disrupt host immunity. Thus, further understanding the interplay between anti-TB drugs and host immune responses may enhance effective host antimicrobial activities and prevent Mtb tolerance to antibiotic and immune attacks. Finally, this review highlights novel adjunctive therapeutic approaches against Mtb infection for better disease outcomes, shorter treatment duration, and improved treatment efficacy based on reciprocal interactions between current TB antibiotics and host immune cells.

show abstract

Efficacy of gene-therapy based on adenovirus encoding granulocyte-macrophage colony-stimulating factor in drug-sensitive and drug-resistant experimental pulmonary tuberculosis

Cited by 14 publications

References 35 publications

Role of Granulocyte-Macrophage Colony-Stimulating Factor Production by T Cells duringMycobacterium tuberculosisInfection

Role of Granulocyte-Macrophage Colony-Stimulating Factor Production by T Cells duringMycobacterium tuberculosisInfection

<p>Extracellular vesicles released by J774A.1 macrophages reduce the bacterial load in macrophages and in an experimental mouse model of tuberculosis</p>

Understanding the Reciprocal Interplay Between Antibiotics and Host Immune System: How Can We Improve the Anti-Mycobacterial Activity of Current Drugs to Better Control Tuberculosis?

Contact Info

Product

Resources

About