Immunotherapeutic effects of recombinant adenovirus encoding interleukin 12 in experimental pulmonary tuberculosis

Mata-Espinosa, Dulce; Francisco‐Cruz, Alejandro; Marquina‐Castillo, Brenda; Barrios-Payán, Jorge; Ramos-Espinosa, Octavio; Bini, Estela Isabel; Xing, Zhou; Hernández-Pando, Rogelio

doi:10.1111/sji.12743

Cited by 14 publications

(15 citation statements)

References 42 publications

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“…Modulating T‐cell responses to restore immunity can be mediated by vaccination or T‐cell cytokine therapies. Administration of IL‐12 141 or IL‐24 142 or blocking Th2 cytokine IL‐4, 131 promotes Th1 responses with lasting IFN‐γ production that may be preferred over IFN‐γ administration. Which of these strategies is (most) efficacious and which patients benefit most from this therapy remains to be addressed.…”

Section: Personalized and Combinatorial Hdtmentioning

confidence: 99%

“…Administration of IFNγ also reduced Mav growth in murine macrophages,137 and improved clinical outcome (ie, decreased respiratory symptoms and mortality) in several but not all Mav-infected individuals,[138][139][140] suggesting potential of IFNγ as HDT in both Mtb and Mav infections. In vivo administration of IL-12, a key cytokine that drives Th1 skewing, enhanced IFNγ and TNFα responses and significantly reduced bacterial burden in an acute mouse TB model 141. Similarly, restoring IL-24 expression in a mouse TB model enhanced Th1-responses and IFNγ production, with concomitant improved survival and reduced bacterial loads 142.…”

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confidence: 99%

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Host‐directed therapy to combat mycobacterial infections*

Kilinç

Saris

Ottenhoff

et al. 2021

Immunological Reviews

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Section: Personalized and Combinatorial Hdtmentioning

confidence: 99%

mentioning

confidence: 99%

Host‐directed therapy to combat mycobacterial infections*

Kilinç

Saris

Ottenhoff

et al. 2021

Immunological Reviews

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“…The M1 phase induces the expression of several genes through IFN-γ such as IL-1β, IL-12, TNF-α, and iNOS/NOS2 (inducible NO synthase), the products of which result in bacterial clearance. For instance, TNF-α signaling results in apoptosis; IL-1β signaling results in ROS generation, IL-12 is a determiner of protective immunity against Mtb (Mata-Espinosa et al, 2019 ) which is produced by macrophages upon interaction with Mtb antigens. The secreted IL-12 signals through the JAK-STAT pathway to induce IFN-γ that in turn switches on various antimicrobial defenses.…”

Section: Mycobacterium Tuberculosis Infection Reallocates MImentioning

confidence: 99%

Mycobacterial Control of Host Mitochondria: Bioenergetic and Metabolic Changes Shaping Cell Fate and Infection Outcome

Mohareer

Medikonda

Vadankula

et al. 2020

Front. Cell. Infect. Microbiol.

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Mitochondria, are undoubtedly critical organelle of a eukaryotic cell, which provide energy and offer a platform for most of the cellular signaling pathways that decide cell fate. The role of mitochondria in immune-metabolism is now emerging as a crucial process governing several pathological states, including infection, cancer, and diabetes. Mitochondria have therefore been a vulnerable target for several bacterial and viral pathogens to control host machinery for their survival, replication, and dissemination. Mycobacterium tuberculosis, a highly successful human pathogen, persists inside alveolar macrophages at the primary infection site, applying several strategies to circumvent macrophage defenses, including control of host mitochondria. The infection perse and specific mycobacterial factors that enter the host mitochondrial milieu perturb mitochondrial dynamics and function by disturbing mitochondrial membrane potential, shifting bioenergetics parameters such as ATP and ROS, orienting the host cell fate and thereby infection outcome. In the present review, we attempt to integrate the available information and emerging dogmas to get a holistic view of Mycobacterium tuberculosis infection visa -vis mycobacterial factors that target host mitochondria and changes therein in terms of morphology, dynamics, proteomic, and bioenergetic alterations that lead to a differential cell fate and immune response determining the disease outcome. We also discuss critical host factors and processes that are overturned by Mycobacterium tuberculosis, such as cAMP-mediated signaling, redox homeostasis, and lipid droplet formation. Further, we also present alternate dogmas as well as the gaps and limitations in understanding some of the present research areas, which can be further explored by understanding some critical processes during Mycobacterium tuberculosis infection and the reasons thereof. Toward the end, we propose to have a set of guidelines for pursuing investigations to maintain uniformity in terms of early and late phase, MOI of infection, infection duration and incubation periods, the strain of mycobacteria, passage numbers, and so on, which all work as probable variables toward different readouts. Such a setup would, therefore, help in the smooth integration of information across laboratories toward a better understanding of the disease and possibilities of host-directed therapy.

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“…Similarly, Mata-Espinosa et al. demonstrated that intranasal administration of a genetically engineered adenoviral vector expressing mouse IL-12 during Mtb infection resulted in a significant reduction in pulmonary bacterial loads ( Mata-Espinosa et al., 2019 ). However, the effects of IL-12 supplementation during antibiotic treatment of Mtb-infected mice to the best of our knowledge have never been investigated.…”

Section: Resultsmentioning

confidence: 99%

“…Elıás-Loṕez et al found that oral administration of extracts of transgenic tomatoes expressing recombinant murine IL-12 resulted in increased levels of the cytokine in the circulation and bronchoalveolar space of Mtb-infected mice, consequently improving the control of bacterial replication by the animals (Elias-Lopez et al, 2008). Similarly, Mata-Espinosa et al demonstrated that intranasal administration of a genetically engineered adenoviral vector expressing mouse IL-12 during Mtb infection resulted in a significant reduction in pulmonary bacterial loads (Mata-Espinosa et al, 2019). However, the effects of IL-12 supplementation during antibiotic treatment of Mtbinfected mice to the best of our knowledge have never been investigated.…”

Section: Strategies Aimed At Boosting Th1mentioning

confidence: 99%

Enhancement of CD4+ T Cell Function as a Strategy for Improving Antibiotic Therapy Efficacy in Tuberculosis: Does It Work?

Costa

Amaral

Namasivayam

et al. 2021

Front. Cell. Infect. Microbiol.

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Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) remains a major public health problem worldwide due in part to the lack of an effective vaccine and to the lengthy course of antibiotic treatment required for successful cure. Combined immuno/chemotherapeutic intervention represents a major strategy for developing more effective therapies against this important pathogen. Because of the major role of CD4+ T cells in containing Mtb infection, augmentation of bacterial specific CD4+ T cell responses has been considered as an approach in achieving this aim. Here we present new data from our own research aimed at determining whether boosting CD4+ T cell responses can promote antibiotic clearance. In these studies, we first characterized the impact of antibiotic treatment of infected mice on Th1 responses to major Mtb antigens and then performed experiments aimed at sustaining CD4+ T cell responsiveness during antibiotic treatment. These included IL-12 infusion, immunization with ESAT-6 and Ag85B immunodominant peptides and adoptive transfer of Th1-polarized CD4+ T cells specific for ESAT-6 or Ag85B during the initial month of chemotherapy. These approaches failed to enhance antibiotic clearance of Mtb, indicating that boosting Th1 responses to immunogenic Mtb antigens highly expressed by actively dividing bacteria is not an effective strategy to be used in the initial phase of antibiotic treatment, perhaps because replicating organisms are the first to be eliminated by the drugs. These results are discussed in the context of previously published findings addressing this concept along with possible alternate approaches for harnessing Th1 immunity as an adjunct to chemotherapy.

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Immunotherapeutic effects of recombinant adenovirus encoding interleukin 12 in experimental pulmonary tuberculosis

Cited by 14 publications

References 42 publications

Host‐directed therapy to combat mycobacterial infections*

Host‐directed therapy to combat mycobacterial infections*

Mycobacterial Control of Host Mitochondria: Bioenergetic and Metabolic Changes Shaping Cell Fate and Infection Outcome

Enhancement of CD4+ T Cell Function as a Strategy for Improving Antibiotic Therapy Efficacy in Tuberculosis: Does It Work?

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