Fc-FcgR interactions shift alveolar macrophage metabolism to promote Mycobacterium tuberculosis restriction in mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE198064 | GEO | 2023/05/31
REPOSITORIES: GEO
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Project description:Novel vaccination and therapeutic strategies are urgently needed to mitigate the tuberculosis (TB) epidemic. While extensive efforts have focused on potentiating cell-mediated immunity to control Mycobacterium tuberculosis (Mtb) infection, less effort has been invested in exploiting the humoral immune system to combat Mtb. Emerging data point to a role for antibodies in microbial control of Mtb, however the precise mechanism(s) of this control remain incompletely understood. Here we took an antibody Fc-engineering approach to determine whether Fc-modifications could improve the ability of antibodies to restrict Mtb, and to define Fc-mediated mechanism(s) antibodies leverage for this restriction. Using an antibody specific to the capsular polysaccharide α-glucan, we engineer a panel of Fc variants to augment or dampen select antibody effector functions, rationally building antibodies with enhanced capacity to promote Mtb restriction in a human whole blood model of infection. Surprisingly, restrictive Fc-engineered antibodies drive Mtb control in a neutrophil, not monocyte, dependent manner. Using single cell RNA sequencing, we show that restrictive antibodies promote neutrophil survival and expression of cell intrinsic antimicrobial programs. These data provide a roadmap for exploiting Fc-engineered antibodies as a novel class of TB therapeutics able to harness the protective functions of neutrophils to achieve disease control.
2024-07-01 | GSE271079 | GEO
Project description:Fc-FcgR interactions shift alveolar macrophage metabolism to promote Mycobacterium tuberculosis restriction in mice
| PRJNA813556 | ENA
Project description:Mtb appears to have developed specialized biomolecular infrastructure to survive and persist within granulomas, where it is subjected to a diverse set of stress conditions. One of these stress conditions is hypoxia. We hypothesized that host cell response is radically altered with hypoxia stressed Mtb and designed in-vitro experiments to study this phenomenon. Hypoxia-stressed as well as aerobically grown Mtb were used to infect rhesus macaque bone marrow derived macrophages (Rh-BMDMs) and the host global transcriptional response compared. Using 4 x44 k Agilent arrays specific for rhesus macaque genome, we tested in biological duplicate the effect of aerogically grown Mtb on rhesus macaque BMDMs and compared this to the corresponding effect of the hypoxia-conditioned Mtb on rhesus macaque BMDMs
2013-05-22 | E-GEOD-47163 | biostudies-arrayexpress
Project description:Mtb appears to have developed specialized biomolecular infrastructure to survive and persist within granulomas, where it is subjected to a diverse set of stress conditions. One of these stress conditions is hypoxia. We hypothesized that host cell response is radically altered with hypoxia stressed Mtb and designed in-vitro experiments to study this phenomenon. Hypoxia-stressed as well as aerobically grown Mtb were used to infect rhesus macaque bone marrow derived macrophages (Rh-BMDMs) and the host global transcriptional response compared.
2013-05-22 | GSE47163 | GEO
Project description:Mounting evidence indicates that antibodies can contribute towards control of tuberculosis (TB). However, the underlying mechanisms of humoral immune protection and whether antibodies can be exploited in therapeutic strategies to combat TB are relatively understudied. Here we engineered the receptor-binding Fc (fragment crystallizable) region of an antibody recognizing the Mycobacterium tuberculosis (Mtb) capsule, to define antibody Fc-mediated mechanism(s) of Mtb restriction. We generated 52 Fc variants that either promote or inhibit specific antibody effector functions, rationally building antibodies with enhanced capacity to promote Mtb restriction in a human whole-blood model of infection. While there is likely no singular Fc profile that universally drives control of Mtb, here we found that several Fc-engineered antibodies drove Mtb restriction in a neutrophil-dependent manner. Single-cell RNA sequencing analysis showed that a restrictive Fc-engineered antibody promoted neutrophil survival and expression of cell-intrinsic antimicrobial programs. These data show the potential of Fc-engineered antibodies as therapeutics able to harness the protective functions of neutrophils to promote control of TB.
| S-EPMC11371646 | biostudies-literature
Project description:The aim of this study was to measure the immune response of alveolar macrophages (AMs) to intracellular Mtb infection in vivo. We characterized the transcriptional profile of murine Mtb-infected AMs after aerosol infection by sorting cells from bronchoalveolar lavage fluid and performing low-input RNA-sequencing. To determine the effect of the transcription factor Nrf2 on this response we also measured the transcriptional profiles of AMs from mice lacking Nrf2.
2019-06-12 | GSE125287 | GEO
Project description:Crosstalk between autophagy, host cell death, and inflammatory host responses to bacterial pathogens enables effective innate immune responses that limit bacterial growth while reducing coincidental host damage. Mycobacterium tuberculosis thwarts innate immune defense mechanisms in alveolar macrophages (AMs) during the initial stages of infection and in recruited bone marrow-derived cells during later stages of infection. How protective inflammatory responses are achieved during Mycobacterium tuberculosis (Mtb) infection and the differences in these responses in macrophage subtypes are obscure. Here, we discovered that the autophagy receptor Tax1bp1 plays a critical role in enhancing inflammatory cytokine production and promoting the susceptibility of mice to infection with Mtb. These results were surprising because Tax1bp1 instead restricts Mtb growth during infection of bone marrow-derived macrophages (BMDMs), as we previously showed (Budzik et al. 2020), and terminates cytokine production in response to cytokine stimulation or viral infection. Tax1bp1 also leads to increases in bacterial growth and inflammatory responses during infection of mice with Listeria monocytogenes, an intracellular pathogen that is not effectively targeted to canonical autophagy. In contrast to its role in restricting Mtb growth in BMDMs, Tax1bp1 promotes Mtb growth in AMs, neutrophils, and recruited monocyte-derived cells from the bone marrow. In Mtb-infected AMs, Tax1bp1 enhances necrosis and inflammatory cytokine synthesis while restraining apoptosis, changing the mode of host cell death to favor Mtb replication. Similar to Tax1bp1-deficiency in AMs, the expression of phosphosite-deficient Tax1bp1 restricts Mtb growth. Together, these results show that Tax1bp1 plays a crucial role in linking the regulation of autophagy, cell death, and pro-inflammatory host responses to augment susceptibility to bacterial infection.
2025-02-12 | GSE280399 | GEO
Project description:Alveolar macrophages (AMs) and recruited monocyte-derived macrophages (MDMs) mediate early lung immune responses to Mycobacterium tuberculosis (Mtb). Using paired human AMs and MDMs from 6 healthy volunteers, we investigated transcriptional profiles in responses to Mtb. We found 681 genes that were Mtb-dependent in AMs compared to MDMs, 107 that were induced in both cell types but in different directions, and 4538 that were Mtb-dependent in MDMs but not AMs (FDR < 0.05). We found that IFNA Response and IFNG Response were the top two gene sets selectively induced in Mtb-infected AM. Thus, a second experiment utilized MDMs treated with IFNA1, IFNA8, IFNE, or IFNL1 found that IFNA8 modulated Mtb-induced pro-inflammatory cytokines and, compared to other interferons,stimulated unique transcriptional profiles.
2024-03-20 | GSE236156 | GEO
Project description:Mycobacterium tuberculosis (Mtb) infects alveolar macrophages (AMs) causing pulmonary tuberculosis (PTB), the more frequent form of the disease. Less frequently, Mtb disseminates to many other organs and tissues resulting in different extrapulmonary forms of TB. Nevertheless, very few studies have addressed the global mRNA response of human AMs, in particular from humans with the active form of the disease. Strikingly, almost no studies have addressed the response to infection with Mtb by human extrapulmonary macrophages.
2020-05-12 | GSE139825 | GEO
Project description:A cell-based phenotypic screen for inhibitors of biofilm formation in Mycobacterium tuberculosis (Mtb) identified the small molecule TCA1, which has bactericidal activity against both drug susceptible and drug resistant Mtb, and synergizes with rifampicin (RIF) or isoniazid (INH) in sterilization of Mtb in vitro. In addition, TCA1 has bactericidal activity against non-replicating Mtb in vitro and is efficacious in acute and chronic Mtb infection mouse models, both alone and in combination with INH or RIF. Transcriptional analysis revealed that TCA1 down-regulates genes known to be involved in Mtb dormancy and drug tolerance. Mutagenesis and affinity-based methods identified DprE1 and MoeW, enzymes involved in cell wall and molybdenum cofactor biosynthesis, respectively, as the targets responsible for TCA1M-bM-^@M-^Ys activity. These in vitro and in vivo results indicate that TCA1functions by a novel mechanism and suggest that it may be the first product of a promising new approach for the development of anti-tuberculosis drugs. Transcriptional profile of TCA1-treated cells relative to DMSO-treated control. Three biological replicates, third is a dye flip.
2013-05-24 | E-GEOD-42151 | biostudies-arrayexpress