In vivo inhibition of tryptophan catabolism reorganizes the tuberculoma and augments immune-mediated control of<i>Mycobacterium tuberculosis</i>

Gautam, Uma S.; Foreman, Taylor W.; Bucşan, Allison N.; Veatch, Ashley V.; Álvarez, Xavier; Adékambi, Toïdi; Golden, Nadia; Gentry, Kaylee M.; Doyle-Meyers, Lara A.; Russell‐Lodrigue, Kasi; Didier, Peter J.; Blanchard, James; Kousoulas, Konstantin G.; Lackner, Andrew A.; Kalman, Daniel; Rengarajan, Jyothi; Khader, Shabaana A.; Kaushal, Deepak; Mehra, Smriti

doi:10.1073/pnas.1711373114

Cited by 161 publications

(211 citation statements)

References 73 publications

(151 reference statements)

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“…In non-human primates (NHP), T cells accumulate in the lymphocyte cuff surrounding the granuloma, but are present in lesser numbers in the central granuloma core where Mtb-infected cells reside. Inhibition of tryptophan metabolism has been shown to promote T cell re-localization to the center of the granuloma and decrease bacterial burdens (Gautam et al, 2017). These observations underscore the importance of T cell effector responses occurring in the right location, as well as reveal the likely presence of inhibitory mechanisms within the granuloma to modulate optimal T cell function.…”

Section: Introductionmentioning

confidence: 80%

TGFβ restricts T cell function and bacterial control within the tuberculous granuloma

Gern¹,

Adams²,

Plumlee³

et al. 2019

Preprint

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Interferon gamma (IFNɣ) produced by CD4 T cells is required for immune containment ofMycobacterium tuberculosis (Mtb) infection. Despite this, IFNɣ plays a minor role in CD4 T cellmediated immunity within the lung. In this study, we use a recently-developed murine model of physiologic Mtb infection coupled with advanced quantitative imaging to demonstrate that IFNɣ production by Mtb-specific T cells is rapidly extinguished within the granuloma, but not in unaffected areas of the lung. This is mediated via localized immunosuppression through cellintrinsic TGFβ signaling in effector T helper 1 cells within the granuloma, and blockade of TGFβ signaling in T cells results in improved immune cell function and decreased pulmonary bacterial burden. These findings uncover a potent immunosuppressive mechanism associated with Mtb infection and provide potential targets for host-directed therapy.

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Section: Introductionmentioning

confidence: 80%

TGFβ restricts T cell function and bacterial control within the tuberculous granuloma

Gern¹,

Adams²,

Plumlee³

et al. 2019

Preprint

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“…Cellular composition in BAL samples and peripheral blood 11, 12 at necropsy showed markedly altered immune cell responses in the lung compartment following infection of macaques. In healthy lungs, BAL is predominantly comprised of alveolar macrophages (AMs) 13 but respiratory tract infections result in the influx of other immune cells.…”

Section: Mainmentioning

confidence: 99%

SARS-CoV-2 infection leads to acute infection with dynamic cellular and inflammatory flux in the lung that varies across nonhuman primate species

Singh

Ganatra

Singh

et al. 2020

Preprint

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SummaryThere are no known cures or vaccines for COVID-19, the defining pandemic of this era. Animal models are essential to fast track new interventions and nonhuman primate (NHP) models of other infectious diseases have proven extremely valuable. Here we compare SARS-CoV-2 infection in three species of experimentally infected NHPs (rhesus macaques, baboons, and marmosets). During the first 3 days, macaques developed clinical signatures of viral infection and systemic inflammation, coupled with early evidence of viral replication and mild-to-moderate interstitial and alveolar pneumonitis, as well as extra-pulmonary pathologies. Cone-beam CT scans showed evidence of moderate pneumonia, which progressed over 3 days. Longitudinal studies showed that while both young and old macaques developed early signs of COVID-19, both groups recovered within a two-week period. Recovery was characterized by low-levels of viral persistence in the lung, suggesting mechanisms by which individuals with compromised immune systems may be susceptible to prolonged and progressive COVID-19. The lung compartment contained a complex early inflammatory milieu with an influx of innate and adaptive immune cells, particularly interstitial macrophages, neutrophils and plasmacytoid dendritic cells, and a prominent Type I-interferon response. While macaques developed moderate disease, baboons exhibited prolonged shedding of virus and extensive pathology following infection; and marmosets demonstrated a milder form of infection. These results showcase in critical detail, the robust early cellular immune responses to SARS-CoV-2 infection, which are not sterilizing and likely impact development of antibody responses. Thus, various NHP genera recapitulate heterogeneous progression of COVID-19. Rhesus macaques and baboons develop different, quantifiable disease attributes making them immediately available essential models to test new vaccines and therapies.

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“…Since CD4 T cells must directly recognize and contact infected cells to control intracellular M. tuberculosis (Srivastava and Ernst, 2013), the architecture of TB granulomas may limit the efficacy of T cells in TB. One promising finding is that in M. tuberculosis -infected rhesus macaques, inhibition of indoleamine-2,3-dioxygenase (IDO; a tryptophan-catalyzing enzyme whose products can modulate T cell differentiation and activation) at the onset of the adaptive immune response resulted in enhanced T cell responses, positioning more T cells in the central regions of granulomas, and reducing the number of bacteria in lesions (Gautam et al, 2018). If IDO inhibition is effective when administered after establishment of granulomas, this may be a promising adjunct to TB chemotherapy or vaccination.…”

Section: Mechanisms Of T Cell Evasion In Tbmentioning

confidence: 99%

Mechanisms of M. tuberculosis Immune Evasion as Challenges to TB Vaccine Design

Ernst

2018

Cell Host & Microbe

104

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Tuberculosis (TB) is a large global health problem, in part because of the long period of coevolution of the pathogen, Mycobacterium tuberculosis, and its human host. A major factor that sustains the global epidemic of TB is the lack of a sufficiently effective vaccine. While basic mechanisms of immunity that protect against TB have been identified, attempts to improve immunity to TB by vaccination have been disappointing. This Review discusses the mechanisms used by M. tuberculosis to evade innate and adaptive immunity and that likely limit the efficacy of vaccines developed to date. Despite multiple mechanisms of immune evasion, recent trials have indicated that effective TB vaccines remain an attainable goal. This Review discusses how knowledge from other systems can inform improvements on current vaccine approaches.

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In vivo inhibition of tryptophan catabolism reorganizes the tuberculoma and augments immune-mediated control ofMycobacterium tuberculosis

Cited by 161 publications

References 73 publications

TGFβ restricts T cell function and bacterial control within the tuberculous granuloma

TGFβ restricts T cell function and bacterial control within the tuberculous granuloma

SARS-CoV-2 infection leads to acute infection with dynamic cellular and inflammatory flux in the lung that varies across nonhuman primate species

Mechanisms of M. tuberculosis Immune Evasion as Challenges to TB Vaccine Design

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