Host Directed Therapy for Chronic Tuberculosis via Intrapulmonary Delivery of Aerosolized Peptide Inhibitors Targeting the IL-10-STAT3 Pathway

Upadhyay, Rashmi; Sánchez-Hidalgo, Andrea; Wilusz, Carol J.; Lenaerts, Anne J.; Arab, Jennifer; Yeh, Joanna; Stefanisko, Karen; Tarasova, Nadya I.; Gonzalez-Juarrero, Mercedes

doi:10.1038/s41598-018-35023-0

Cited by 25 publications

(25 citation statements)

References 41 publications

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“…IL-10 and TGFβ are reported to be conducive to Mtb survival due to their inhibitory effect on pro-inflammatory cytokine production and T cell activation (Othieno et al, 1999). Furthermore, IL-10 is reported to inhibit autophagy in Mtb-infected macrophages (Upadhyay et al, 2018). Infected THP-PKR macrophages also produced lower levels of IL-1β and TNFα compared to control macrophages (Figures 3E,F), two cytokines that are critical for host resistance to Mtb due to their pro-inflammatory effects and their role in activating macrophage cell death (Flynn et al, 1995;Keane et al, 1997;Mayer-Barber et al, 2010;Jayaraman et al, 2013).…”

Section: Pkr Expression Alters the Immunological Profile Of Macrophages During Mycobacterium Tuberculosis Infectionmentioning

confidence: 99%

Protein Kinase R Restricts the Intracellular Survival of Mycobacterium tuberculosis by Promoting Selective Autophagy

et al. 2021

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Tuberculosis (TB) is a deadly infectious lung disease caused by the pathogenic bacterium Mycobacterium tuberculosis (Mtb). The identification of macrophage signaling proteins exploited by Mtb during infection will enable the development of alternative host-directed therapies (HDT) for TB. HDT strategies will boost host immunity to restrict the intracellular replication of Mtb and therefore hold promise to overcome antimicrobial resistance, a growing crisis in TB therapy. Protein Kinase R (PKR) is a key host sensor that functions in the cellular antiviral response. However, its role in defense against intracellular bacterial pathogens is not clearly defined. Herein, we demonstrate that expression and activation of PKR is upregulated in macrophages infected with Mtb. Immunological profiling of human THP-1 macrophages that overexpress PKR (THP-PKR) showed increased production of IP-10 and reduced production of IL-6, two cytokines that are reported to activate and inhibit IFNγ-dependent autophagy, respectively. Indeed, sustained expression and activation of PKR reduced the intracellular survival of Mtb, an effect that could be enhanced by IFNγ treatment. We further demonstrate that the enhanced anti-mycobacterial activity of THP-PKR macrophages is mediated by a mechanism dependent on selective autophagy, as indicated by increased levels of LC3B-II that colocalize with intracellular Mtb. Consistent with this mechanism, inhibition of autophagolysosome maturation with bafilomycin A1 abrogated the ability of THP-PKR macrophages to limit replication of Mtb, whereas pharmacological activation of autophagy enhanced the anti-mycobacterial effect of PKR overexpression. As such, PKR represents a novel and attractive host target for development of HDT for TB, and our data suggest value in the design of more specific and potent activators of PKR.

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Section: Pkr Expression Alters the Immunological Profile Of Macrophages During Mycobacterium Tuberculosis Infectionmentioning

confidence: 99%

Protein Kinase R Restricts the Intracellular Survival of Mycobacterium tuberculosis by Promoting Selective Autophagy

et al. 2021

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“…Our Lm infection studies in mice with NK cell-intrinsic STAT3 deficiency showed that preventing STAT3 activation in this cell population has a protective effect. Similarly, inhibition of either STAT3 or IL-10Rα was recently shown to reduce lung burdens in a model of chronic infection with Mycobacterium tuberculosis (62). While this study did not address which cell types were essential for the observed therapeutic effects, the phenotype observed suggests STAT3-dependent IL-10 production similarly contributes to susceptibility in the context of this important pulmonary bacterial pathogen and demonstrate the potential for therapeutic targeting of STAT3/IL-10/IL-10R.…”

Section: Discussionmentioning

confidence: 98%

NK Cell IL-10 Production Requires IL-15 and IL-10 Driven STAT3 Activation

et al. 2019

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Natural killer (NK) cells can produce IFNγ or IL-10 to regulate inflammation and immune responses but the factors driving NK cell IL-10 secretion are poorly-defined. Here, we identified NK cell-intrinsic STAT3 activation as vital for IL-10 production during both systemic Listeria monocytogenes (Lm) infection and following IL-15 cytokine/receptor complex (IL15C) treatment for experimental cerebral malaria (ECM). In both contexts, conditional Stat3 deficiency in NK cells abrogated production of IL-10. Initial NK cell STAT3 phosphorylation was driven by IL-15. During Lm infection, this required capture or presentation of IL-15 by NK cell IL-15Rα. Persistent STAT3 activation was required to drive measurable IL-10 secretion and required NK cell expression of IL-10Rα. Survival-promoting effects of IL-15C treatment in ECM were dependent on NK cell Stat3 while NK cell-intrinsic deficiency for Stat3, Il15ra, or Il10ra abrogated NK cell IL-10 production and increased resistance against Lm. NK cell Stat3 deficiency did not impact production of IFNγ, indicating the STAT3 activation initiated by IL-15 and amplified by IL-10 selectively drives the production of anti-inflammatory IL-10 by responding NK cells.

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“…Given its detrimental role during Tb, IL-10 is an attractive target for HDT. An HDT approach applying aerosolized peptide inhibitors targeting the IL-10R alpha chain had major beneficial effects on Mtb control in C57BL/6 mice (73). Future studies need to elucidate whether such treatment could also be applicable in situations of coinfection-induced disease exacerbation.…”

Section: Discussionmentioning

confidence: 99%

Blocking IL-10 receptor signaling ameliorates Mycobacterium tuberculosis infection during influenza-induced exacerbation

Ring¹,

Eggers²,

Behrends³

et al. 2019

JCI Insight

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Epidemiological findings indicate that coinfection with influenza viruses is associated with an increased risk of death in patients suffering from tuberculosis, but the underlying pathomechanisms are not well understood. In this study, we demonstrate that influenza A virus (IAV) coinfection rapidly impairs control of Mycobacterium tuberculosis ( Mtb ) in C57BL/6 mice. IAV coinfection was associated with significantly increased bacterial loads, reduced survival, and a substantial modulation of innate and adaptive immune defenses including an impaired onset and development of Mtb -specific CD4 + T cell responses and the accumulation of macrophages with increased arginase-1 production in the lungs. Our findings strongly indicate that IAV coinfection compromises the host’s ability to control Mtb infection via the production of IL-10, which was rapidly induced upon viral infection. The blockade of IL-10 receptor signaling reduced the bacterial load in coinfected mice to a level comparable to that in Mtb -only-infected animals. Taken together, our data suggest that IL-10 signaling constitutes a major pathway that enhances susceptibility to Mtb during concurrent IAV infection.

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Host Directed Therapy for Chronic Tuberculosis via Intrapulmonary Delivery of Aerosolized Peptide Inhibitors Targeting the IL-10-STAT3 Pathway

Cited by 25 publications

References 41 publications

Protein Kinase R Restricts the Intracellular Survival of Mycobacterium tuberculosis by Promoting Selective Autophagy

Protein Kinase R Restricts the Intracellular Survival of Mycobacterium tuberculosis by Promoting Selective Autophagy

NK Cell IL-10 Production Requires IL-15 and IL-10 Driven STAT3 Activation

Blocking IL-10 receptor signaling ameliorates Mycobacterium tuberculosis infection during influenza-induced exacerbation

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