About

Investigating the roles of alveolar macrophages as innate immune sentinels during Mycobacterium tuberculosis infection and regulators of inflammation at the airway-tissue interface. Alveolar macrophages are the most abundant tissue-resident immune cell in the lung. By studying alveolar macrophage biology, we are interested in uncovering mechanisms of innate immunity and inflammatory regulation in the lung in order to identify novel therapeutic targets and strategies. Our focus is on the innate immune response to Mycobacterium tuberculosis, combining immunology, microbiology, and systems biology approaches.

Research topics

• Medicine
• Internal medicine
• Biology
• Immunology
• Genetics
• Computational biology
• Bioinformatics
• Intensive care medicine
• Microbiology
• Virology
• Pathology

Selected publications

• Shared and distinct responses of human and murine alveolar macrophages and monocyte-derived macrophages to <i>Mycobacterium tuberculosis</i>

  ImmunoHorizons · 2025-10-09 · 1 citations

  articleOpen access

  Macrophages are important sites of bacterial replication and host immune responses during Mycobacterium tuberculosis (Mtb) infection with distinct roles for alveolar macrophages (AMs) early in infection and monocyte-derived macrophages (MDMs) later in disease. Here, we leverage data from human and mouse models to perform a cross-species analysis of macrophage responses to Mtb. Overall, we find that both subsets of human and murine macrophages mount a strong interferon response to Mtb infection. However, AMs across both species do not generate as strong a pro-inflammatory response as human MDMs or murine bone marrow-derived macrophages (BMDMs), as characterized by TNFA signaling and inflammatory response pathways. Interestingly, AMs from mice that were previously vaccinated with BCG (scBCG) or from a model of contained TB (coMtb) had more similar responses to human AMs than control mice. We also identify species-specific pathways altered by infection differently in mouse and human macrophages, including cholesterol homeostasis. Lastly, to investigate downstream effects of the macrophage interferon responses, we examine expression of interleukin (IL)-10, an immunosuppressive cytokine induced by Type I Interferons, and c-Maf, a transcription factor required for myeloid IL-10 expression. We find that c-Maf and IL-10 have significantly lower expression in AMs compared to MDMs in both humans and mice, suggesting one possible mechanism by which AMs mount a stronger interferon response following Mtb infection. Overall, these results highlight the dynamics of innate myeloid responses throughout Mtb infection and the benefit of a combined analysis across species to reveal conserved and unique responses.

  PublisherDOI

• NRF2 inhibition of alveolar macrophage MHC II expression during <i>Mycobacterium tuberculosis</i> infection

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-17 · 2 citations

  preprintOpen accessSenior authorCorresponding

  SUMMARY During Mycobacterium tuberculosis (Mtb) infection, infected alveolar macrophages (AMs) initially up-regulate a NRF2 regulated cell-protective program, which is detrimental to host control and impedes AM activation, including MHC II expression. MHC II is critical for CD4 + T cell activation and host immunity during Mtb infection. We hypothesized that NRF2 regulates the MHC II pathway and AM antigen presentation to T cells. We found that NRF2 inhibits MHC II, but not MHC I, specifically in AMs, following Mtb infection in vitro and in vivo . NRF2 dampens Ciita and H2-Ab1 gene expression in uninfected AMs, and MHC II inhibition by NRF2 is retained following innate stimuli and IFNγ exposure. NRF2 expression in Mtb-infected AMs impedes their ability to activate ESAT6-specific CD4 + T cells. Thus, although NRF2 expression enhances cell-protective functions, it has the unexpected consequence of limiting innate-adaptive crosstalk, which can impair CD4+ T cell activation and host immunity during Mtb infection. HIGHLIGHTS NRF2 inhibits MHC II on AMs, but not DCs, MDMs, or PMNs, during Mtb infection NRF2 inhibits Ciita and H2-Ab1 and total MHC II protein in AMs, but not in BMDMs NRF2 blockade of AM MHC II is retained following PAMP and IFNγ stimulation NRF2 impedes the activation of antigen-specific CD4 + T cells by Ams

  PublisherOA PDFDOI

• Shared and distinct responses of human and murine alveolar macrophages and monocyte-derived macrophages to <i>Mycobacterium tuberculosis</i>

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-03-05 · 2 citations

  preprintOpen accessCorresponding

  (Mtb) infection with distinct roles for alveolar macrophages (AMs) early in infection and monocyte-derived (MDMs) during later stages of disease. Here, we leverage data from human and mouse models to perform a cross-species analysis of macrophage responses to Mtb infection. Overall, we find that both subsets of human and murine macrophages mount a strong interferon response to Mtb infection. However, AM across both species do not generate as strong a pro-inflammatory response as human MDMs or murine bone marrow-derived macrophages (BMDMs), as characterized by TNFA signaling and inflammatory response pathways. Interestingly, AMs from mice that were previously vaccinated with BCG (scBCG) or from a model of contained TB (coMtb) had Mtb responses that were more similar to human AMs than control mice. We also identify species-specific pathways altered by infection differently in mouse and human macrophages, specifically in pathways related to cholesterol in AMs as well as MYC targets and Hedgehog signaling in MDMs/BMDMs. Lastly, to investigate downstream effects of the macrophage interferon responses, we examine macrophage expression of IL-10, an immunosuppressive cytokine induced by Type I Interferons, and c-Maf, a transcription factor required for IL-10 expression in myeloid cells. We find that c-Maf and IL-10 have significantly lower expression in AMs compared to MDMs in both humans and mice, suggesting one possible mechanism by which AMs mount a stronger interferon response following Mtb infection. Overall, these results highlight the dynamics of innate myeloid responses over the course of Mtb infection and the benefit of a combined analysis across species to reveal conserved and unique responses.

  PublisherOA PDFDOI

• Absence of c-Maf and IL-10 enables type I IFN enhancement of innate responses to LPS in alveolar macrophages

  The Journal of Immunology · 2025-03-01 · 5 citations

  articleOpen accessSenior author

  Alveolar macrophages (AMs) are lung-resident myeloid cells and airway sentinels for inhaled pathogens and environmental particles. While AMs can be highly inflammatory in response to respiratory viruses, they do not mount proinflammatory responses to all airborne pathogens. For example, we previously showed that AMs fail to mount a robust proinflammatory response to Mycobacterium tuberculosis. Here, we address this discrepancy by investigating the capacity of murine AMs for direct innate immune sensing, using LPS as a model. Use of LPS-coated fluorescent beads enabled us to distinguish between directly exposed and bystander cells to measure transcriptional responses, by RNA-sequencing after cell sorting, and cytokine responses, by flow cytometry. We find that AMs have decreased proinflammatory responses to low-dose LPS compared to other macrophage types (bone marrow-derived macrophages, peritoneal macrophages), as measured by TNF, IL-6, Ifnb, and Ifit3. The reduced response to low-dose LPS correlates with minimal TLR4 and CD14 surface expression, despite sufficient internal expression of TLR4. We also find that AMs do not produce IL-10 in response to a variety of stimuli due to low expression of the transcription factor c-Maf, while exogenous c-Maf expression restores IL-10 production in AMs. Lastly, we show that lack of IL-10 enables type I IFN enhancement of AM responses to LPS. Overall, we demonstrate AMs have a cell-intrinsic hyporesponsiveness to LPS, which makes them uniquely tolerant to low-dose exposure. Regulation of AM innate responses by distinct CD14, c-Maf, and IL-10 expression patterns has important implications for both respiratory infections and environmental airborne exposures.

  PublisherOA PDFDOI

• Trehalose dimycolate inhibits phagosome maturation and promotes intracellular <i>Mycobacterium tuberculosis</i> growth via noncanonical SNARE interactions

  Proceedings of the National Academy of Sciences · 2025-05-12 · 11 citations

  articleOpen access

  Mycobacterial cell envelopes are rich in unusual lipids and glycans that play key roles during infection and vaccination. The most abundant envelope glycolipid is trehalose dimycolate (TDM). TDM compromises the host response to mycobacterial species via multiple mechanisms, including inhibition of phagosome maturation. The molecular mechanism by which TDM inhibits phagosome maturation has been elusive. We find that a clickable, photoaffinity TDM probe recapitulates key phenotypes of native TDM in macrophage host cells and binds several host Soluble N-ethylmaleimide-Sensitive Factor Attachment Proteins Receptor (SNARE) proteins, including Vesicle Transport through Interaction with t-SNAREs 1B (VTI1B), Syntaxin 8 (STX8), and Vesicle-Associated Membrane Protein 2 (VAMP2). VTI1B and STX8 normally promote endosome fusion by forming a complex with VAMP8. However, in the presence of Mycobacterium tuberculosis , VTI1B and STX8 complex with VAMP2, which in turn decreases VAMP8 binding. VAMP2 acts together with mycolate structure to inhibit phagosome maturation and promotes intracellular M. tuberculosis replication. Thus one mechanism by which TDM constrains the innate immune response to M. tuberculosis is via noncanonical SNARE complexation.

  PublisherDOI

• Editorial: Rising stars in tuberculosis

  Frontiers in Tuberculosis · 2025-07-01

  editorialOpen access

  MDR-TB is a significant global health challenge due to its complex treatment, high cost, and severe health outcomes. Understanding the mechanisms of drug resistance and addressing the factors contributing to its development are crucial for controlling the spread of MDR-TB. In Sverdlovsk Oblast in Russia, MDR-TB is a considerable problem. Genetic patterns were used to study transmission dynamics of MDR-TB cases by Umpeleva et al (1) (https://www.frontiersin.org/journals/tuberculosis/articles/10.3389/ftubr.2025.1406536 /abstract). The study found that a significant proportion of M. tuberculosis isolates had unique genetic patterns, suggesting minimal recent transmission. The presence of mutations in gyrA/B genes, associated with fluoroquinolone resistance, was more common in isolates with unique patterns, indicating that these mutations may have developed in already drug-resistant strains due to inadequate chemotherapy regimens but had not yet circulated widely, which could be due to biological fitness costs related to these mutations. Investigating the gyrA/B mutations may provide insights into how M. tuberculosis adapts to drug resistance and maintains its transmissibility.M. tuberculosis infection can be transmitted to the fetus via hematogenous spread from the placenta to the umbilical vein or through the aspiration or ingestion of infected amniotic fluid. Congenital TB is a relatively rare condition compared to other forms of TB but carries a high mortality rate. The incidence of congenital TB is higher in regions with high prevalence, such as parts of Asia and Africa. This case report by

  PublisherOA PDFDOI

• Trehalose dimycolate inhibits phagosome maturation and promotes intracellular <i>M. tuberculosis</i> growth via noncanonical SNARE interaction

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-12-16 · 2 citations

  preprintOpen access

  Abstract Mycobacterial cell envelopes are rich in unusual lipids and glycans that play key roles during infection and vaccination. The most abundant envelope glycolipid is trehalose dimycolate (TDM). TDM compromises the host response to mycobacterial species via multiple mechanisms, including inhibition of phagosome maturation. The molecular mechanism by which TDM inhibits phagosome maturation has been elusive. We find that a clickable, photoaffinity TDM probe recapitulates key phenotypes of native TDM in macrophage host cells and binds several host SNARE proteins, including VTI1B, STX8, and VAMP2. VTI1B and STX8 normally promote endosome fusion by forming a complex with VAMP8. However, in the presence of Mycobacterium tuberculosis , VTI1B and STX8 complex with VAMP2, which in turn decreases VAMP8 binding. VAMP2 acts together with mycolate structure to inhibit phagosome maturation and promotes intracellular M. tuberculosis replication. Thus one mechanism by which TDM constrains the innate immune response to M. tuberculosis is via non-canonical SNARE complexation. Significance Statement Glycolipids from the Mycobacterium tuberculosis cell envelope, particularly trehalose dimycolate (TDM), play major roles in subverting the immune response to this intracellular pathogen. How subversion occurs is often unclear because glycans and lipids are technically challenging to study in cells. We discovered that a TDM-mimicking chemical probe interacts with three host SNARE proteins, including two that regulate endosome fusion and one that does not. The presence of TDM or M. tuberculosis triggers abnormal binding of these SNAREs, which in turn inhibits the fusion of M. tuberculosis -containing phagosomes with lysosomes and promotes M. tuberculosis replication. Our work provides an unusual example of a bacterial pathogen restricting the immune response via glycolipid-SNARE interactions.

  PublisherOA PDFDOI

• Absence of c-Maf and IL-10 enables Type I IFN enhancement of innate responses to low-dose LPS in alveolar macrophages

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-05-26 · 1 citations

  preprintOpen accessSenior authorCorresponding

  SUMMARY Alveolar macrophages (AMs) are lower-airway resident myeloid cells and are among the first to respond to inhaled pathogens. Here, we interrogate AM innate sensing to Pathogen Associated Molecular Patterns (PAMPs) and determine AMs have decreased responses to low- dose LPS compared to other macrophages, as measured by TNF, IL-6, Ifnb , and Ifit3 . We find the reduced response to low-dose LPS correlates with minimal TLR4 and CD14 surface expression, despite sufficient internal expression of TLR4. Additionally, we find that AMs do not produce IL-10 in response to a variety of PAMPs due to low expression of transcription factor c- Maf and that lack of IL-10 production contributes to an enhancement of pro-inflammatory responses by Type I IFN. Our findings demonstrate that AMs have cell-intrinsic dampened responses to LPS, which is enhanced by type I IFN exposure. These data implicate conditions where AMs may have reduced or enhanced sentinel responses to bacterial infections. HIGHLIGHTS Alveolar macrophages (AMs) do not produce TNF or IL-6 in response to low-dose LPS due to minimal surface expression of TLR4 and CD14 Lack of AM IL-10 production is dependent on low c-Maf expression Exogenous c-Maf expression increases AM IL-10 production IFNβ enhances AM TNF and IL-6 responses to low-dose LPS and this is dependent on a lack of IL-10

  PublisherOA PDFDOI

• Exposure to Mycobacterium remodels alveolar macrophages and the early innate response to Mycobacterium tuberculosis infection

  PLoS Pathogens · 2024-01-18 · 52 citations

  articleOpen accessSenior authorCorresponding

  Alveolar macrophages (AMs) play a critical role during Mycobacterium tuberculosis (Mtb) infection as the first cells in the lung to encounter bacteria. We previously showed that AMs initially respond to Mtb in vivo by mounting a cell-protective, rather than pro-inflammatory response. However, the plasticity of the initial AM response was unknown. Here, we characterize how previous exposure to Mycobacterium, either through subcutaneous vaccination with Mycobacterium bovis (scBCG) or through a contained Mtb infection (coMtb) that mimics aspects of concomitant immunity, impacts the initial response by AMs. We find that both scBCG and coMtb accelerate early innate cell activation and recruitment and generate a stronger pro-inflammatory response to Mtb in vivo by AMs. Within the lung environment, AMs from scBCG vaccinated mice mount a robust interferon-associated response, while AMs from coMtb mice produce a broader inflammatory response that is not dominated by Interferon Stimulated Genes. Using scRNAseq, we identify changes to the frequency and phenotype of airway-resident macrophages following Mycobacterium exposure, with enrichment for both interferon-associated and pro-inflammatory populations of AMs. In contrast, minimal changes were found for airway-resident T cells and dendritic cells after exposures. Ex vivo stimulation of AMs with Pam3Cys, LPS and Mtb reveal that scBCG and coMtb exposures generate stronger interferon-associated responses to LPS and Mtb that are cell-intrinsic changes. However, AM profiles that were unique to each exposure modality following Mtb infection in vivo are dependent on the lung environment and do not emerge following ex vivo stimulation. Overall, our studies reveal significant and durable remodeling of AMs following exposure to Mycobacterium, with evidence for both AM-intrinsic changes and contributions from the altered lung microenvironments. Comparisons between the scBCG and coMtb models highlight the plasticity of AMs in the airway and opportunities to target their function through vaccination or host-directed therapies.

  PublisherOA PDFDOI

• Exposure to <i>mycobacterium</i> remodels alveolar macrophages and the early innate response to <i>Mycobacterium tuberculosis</i> infection

  bioRxiv (Cold Spring Harbor Laboratory) · 2022-09-19 · 3 citations

  preprintOpen accessSenior authorCorresponding

  Abstract Alveolar macrophages (AMs) play a critical role during Mycobacterium tuberculosis (Mtb) infection as the first cells in the lung to encounter bacteria. We previously showed that AMs initially respond to Mtb in vivo by mounting a cell-protective, rather than pro-inflammatory response. However, the plasticity of the initial AM response was unknown. Here, we characterize how previous exposure to mycobacterium , either through subcutaneous vaccination with Mycobacterium bovis (scBCG) or through a contained Mtb infection (coMtb) that mimics aspects of concomitant immunity, impacts the initial response by AMs. We find that both scBCG and coMtb accelerate early innate cell activation and recruitment and generate a stronger pro-inflammatory response to Mtb in vivo by AMs. Within the lung environment, AMs from scBCG vaccinated mice mount a robust interferon-associated response, while AMs from coMtb mice produce a broader inflammatory response that is not dominated by Interferon Stimulated Genes. Using scRNAseq, we identify changes to the frequency and phenotype of airway-resident macrophages following mycobacterium exposure, with enrichment for both interferon-associated and pro-inflammatory populations of AMs. In contrast, minimal changes were found for airway-resident T cells and dendritic cells after exposures. Ex vivo stimulation of AMs with Pam3Cys, LPS and Mtb reveal that scBCG and coMtb exposures generate stronger interferon-associated responses to LPS and Mtb that are cell-intrinsic changes. However, AM profiles that were unique to each exposure modality following Mtb infection in vivo are dependent on the lung environment and do not emerge following ex vivo stimulation. Overall, our studies reveal significant and durable remodeling of AMs following exposure to mycobacterium, with evidence for both AM-intrinsic changes and contributions from the altered lung microenvironments. Comparisons between the scBCG and coMtb models highlight the plasticity of AMs in the airway and opportunities to target their function through vaccination or host-directed therapies. Author Summary Tuberculosis, a disease caused by the bacteria Mycobacterium tuberculosis (Mtb), claims around 1.6 million lives each year, making it one of the leading causes of death worldwide by an infectious agent. Based on principles of conventional immunological memory, prior exposure to either Mtb or M. bovis BCG leads to antigen-specific long-lasting changes to the adaptive immune response that can be effective at protecting against subsequent challenge. However, how these exposures may also impact the innate immune response is less understood. Alveolar macrophages are tissue-resident myeloid cells that play an important role during Mtb infection as innate immune sentinels in the lung and the first host cells to respond to infection. Here, we examined how prior mycobacterium exposure, either through BCG vaccination or a model of contained Mtb infection impacts the early innate response by alveolar macrophages. We find that prior exposure remodels the alveolar macrophage response to Mtb through both cell-intrinsic changes and signals that depend on the altered lung environment. These findings suggest that the early innate immune response could be targeted through vaccination or host-directed therapy and could complement existing strategies to enhance the host response to Mtb.

  PublisherOA PDFDOI

Frequent coauthors

• Xinchun Chen

  Shenzhen University

  28 shared

• Samuel M. Behar

  University of Massachusetts Chan Medical School

  26 shared

• Bruce D. Walker

  St Vincent's Hospital Sydney

  24 shared

• Toshiyuki Miura

  Tsukuba University of Technology

  23 shared

• Alan Aderem

  22 shared

• Cláudio Nunes-Alves

  University of Oxford

  20 shared

• Girija Goyal

  20 shared

• Florencia Pereyra

  Fundación IRAUy

  20 shared

Labs

• Rothchild LabPI

Education

• Ph.D., Immunology

  Harvard University

  2014

• B.S.

  Brown University

  2005