Biology subjects

Foreman, T. W.

Publications and source records attributed to Foreman, T. W..

5 recordsLinked to original sources

bioRxiv2025

PU.1 Shapes Host Epigenetic Responses to Mycobacterium tuberculosis and Represents a Target for Host Directed Therapy

Mycobacterium tuberculosis (Mtb) infection induces widespread epigenetic changes in monocytes and macrophages. To characterize the critical factor responsible for Mtb-induced epigenetic responses, we performed an integrative analyses of chromatin modification (H3K27ac), transcription factor binding, and gene expression in human monocytes and macrophages. Our data identified PU.1 (SPI1) as a key transcriptional regulator to be upregulated and bound to gene promoters in response to Mtb. PU.1 enrichment was associated with enhanced proinflammatory and anti-apoptotic gene programs. PU.1 expression was also elevated in the lung tissues from Mtb-infected macaques and tuberculosis patients. PU.1 knockdown enhanced human macrophage apoptosis, dampened inflammation and reduced bacterial survival, suggesting its functional role in supporting Mtb infection. Pharmacological inhibition of PU.1 replicated the effects of knockdown, restricting Mtb growth without cytotoxicity. These findings identify PU.1 as a central node in the host epigenetic response to Mtb and a candidate for host-directed therapeutic targeting in tuberculosis.

immunology↗

bioRxiv2022

IL-10 suppresses T cell expansion while promoting tissue-resident memory cell formation during SARS-CoV-2 infection in rhesus macaques

The pro- and anti-inflammatory pathways that determine the balance of inflammation and viral control during SARS-CoV-2 infection are not well understood. Here we examine the roles of IFN{gamma} and IL-10 in regulating inflammation, immune cell responses and viral replication during SARS-CoV-2 infection of rhesus macaques. IFN{gamma} blockade tended to decrease lung inflammation based on 18FDG-PET/CT imaging but had no major impact on innate lymphocytes, neutralizing antibodies, or antigen-specific T cells. In contrast, IL-10 blockade transiently increased lung inflammation and enhanced accumulation of virus-specific T cells in the lower airways. However, IL-10 blockade also inhibited the differentiation of virus-specific T cells into airway CD69+CD103+ TRM cells. While virus-specific T cells were undetectable in the nasal mucosa of all groups, IL-10 blockade similarly reduced the frequency of total TRM cells in the nasal mucosa. Neither cytokine blockade substantially affected viral load and infection ultimately resolved. Thus, in the macaque model of mild COVID-19, the pro- and anti-inflammatory effects of IFN{gamma} and IL-10 have no major role in control of viral replication. However, IL-10 has a key role in suppressing the accumulation of SARS-CoV-2-specific T cells in the lower airways, while also promoting TRM at respiratory mucosal surfaces.

immunology↗

bioRxiv2022

Mild SARS-CoV-2 infection in rhesus macaques is associated with viral control prior to antigen-specific T cell responses in tissues

SARS-CoV-2 primarily replicates in mucosal sites, and more information is needed about immune responses in infected tissues. We used rhesus macaques to model protective primary immune responses in tissues during mild COVID-19. Viral RNA levels were highest on days 1-2 post-infection and fell precipitously thereafter. 18F-fluorodeoxyglucose (FDG)-avid lung abnormalities and interferon (IFN)-activated myeloid cells in the bronchoalveolar lavage (BAL) were found on days [~]3-4. Virus-specific effector CD8 and CD4 T cells were detectable in the BAL and lung tissue on days [~]7-10, after viral RNA, lung inflammation, and IFN-activated myeloid cells had declined. Notably, SARS-CoV-2-specific T cells were not detectable in the nasal turbinates, salivary glands, and tonsils on day 10 post-infection. Thus, SARS-CoV-2 replication wanes in the lungs prior to T cell responses, and in the nasal and oral mucosa despite the apparent lack of Ag-specific T cells, suggesting that innate immunity efficiently restricts viral replication during mild COVID-19. ONE SENTENCE SUMMARYSARS-CoV-2 infection leads to mild, focal lung inflammation, and type I IFN activated myeloid cells that mostly resolve prior to the influx of virus-specific effector T cells or antibody responses in rhesus macaques.

immunology↗

bioRxiv2021

CD4 T cells are rapidly depleted from tuberculosis granulomas following acute SIV co-infection

The HIV-mediated decline in circulating CD4 T cells correlates with increased the risk of active tuberculosis (TB)1-4. However, HIV/Mycobacterium tuberculosis (Mtb) co-infected individuals also have an increased incidence of TB prior to loss of CD4 T cells in blood3,5, raising the possibility that HIV co-infection leads to disruption of CD4 T cell responses at the site of lung infection before they are observed systemically. Here we used a rhesus macaque model of SIV/Mtb co-infection to study the early effects of acute SIV infection on CD4 T cells in pulmonary Mtb granulomas. Two weeks after SIV co-infection CD4 T cells were dramatically depleted from granulomas, before significant bacterial outgrowth, disease reactivation as measured by PET-CT imaging, or CD4 T cell loss in blood, airways, and lymph nodes. Mtb-specific CD4 T cells, CCR5-expressing, in granulomas were preferentially depleted by SIV infection. Moreover, CD4 T cells were preferentially depleted from the granuloma core and lymphocyte cuff relative to B cell-rich regions, and live imaging of granuloma explants showed that SIV co-infection reduced T cell motility. Thus, Mtb-specific CD4 T cells in pulmonary granulomas may be decimated before many patients even experience the first symptoms of acute HIV infection.

immunology↗

bioRxiv2020

PD-1 blockade exacerbates Mycobacterium tuberculosis infection in rhesus macaques

Boosting immune cell function by targeting the co-inhibitory receptor PD-1 may have applications in the treatment of chronic infections. Here we examine the role of PD-1 during Mycobacterium tuberculosis (Mtb) infection of rhesus macaques. Animals treated with PD-1 mAb developed worse disease and higher granuloma bacterial loads compared to isotype control treated monkeys. PD-1 blockade increased the number and functionality of granuloma Mtb-specific CD8 T cells. In contrast, Mtb-specific CD4 T cells in PD-1 treated macaques were not increased in number or function in granulomas, upregulated high levels of CTLA-4 and exhibited reduced intralesional trafficking in live imaging studies. In granulomas of PD-1 treated animals, multiple pro-inflammatory cytokines were elevated, and more cytokines correlated with bacterial loads, leading to the identification of a role for caspase 1 in the exacerbation of tuberculosis after PD-1 blockade. Lastly, increased Mtb bacterial loads after PD-1 blockade were found to associate with the composition of the intestinal microbiota prior to infection in individual macaques. Therefore, PD-1-mediated co-inhibition is required for control of Mtb infection in macaques, perhaps due to its role in dampening detrimental inflammation as well as allowing for normal CD4 T cell responses.

immunology↗