Tuberculosis Granulomas Research Articles

Comparative analysis of five etiological detecting techniques for the positive rates in the diagnosis of tuberculous granuloma

PurposeTo examine the relationship between the positive rate and types of necrosis in pathological examinations of tuberculosis granulomas with necrosis, to improve the detection rate of positive cases. MethodsSpecimens from 381 patients were collected in Wuhan Pulmonary Hospital from Jan 2022 to Feb 2023. The samples were examined using various methods such as AFB smear microscopy, mycobacterial culture, PCR, SAT-TB, and X-pert MTB/RIF rapid molecular detection. ResultThere were 3 types of necrosis. Including 270 cases of caseous necrosis, 30 cases of coagulation necrosis, and 76 cases of an abscess. Five cases were non-necrotizing granulomas.In the pathological specimen testing for tuberculosis, five detection techniques were used and their positive rates detected in descending order were X-pert, TBDNA, SAT-TB, tuberculosis culture, AFB. Comparison between different examinations in the group: X-pert had the highest positive rate in each group, and it was significantly higher than TBDNA (P < 0.01) in caseous necrosis specimens. Compared with the same examination between the groups, the detection rates of X-pert and TBDNA in abscess and caseous necrosis specimens were significantly higher than in coagulation necrosis specimens (P < 0.01). ConclusionThe positive rates of the five etiological detection techniques in tuberculous granuloma with different types of necrosis were quite different. The specimens of caseous necrosis or abscess could be selected for detection, and X-pert had the highest positive rate.

TB granuloma: CD30 co-stimulation for CD4+ T cell co-operation.

Tuberculosis granuloma T cells express an array of mediators including the CD30 co-stimulatory receptor and its ligand, CD153. CD4 T effector cells require signals through CD30, potentially provided co-operatively by other T cells, to completely differentiate and protect against disease (Foreman et al., 2023. J. Exp. Med.https://doi.org/10.1084/jem.20222090).

A Case Report of Primary Eyelid Tuberculosis

Purpose: To report a rare case of primary eyelid tuberculosis treated using systemic anti-tuberculosis medications.Case summary: A 30-year-old male presented to our hospital with an upper eyelid mass in the left eye for 1 month. An atypical cystic mass, pale yellow in color with a smooth surface, was observed on the medial side of the left upper eyelid. There were no associated ophthalmic or systemic symptoms. Excisional biopsy of the mass was performed under local anesthesia and histopathological examination revealed chronic granulomatous inflammation with central Langhans-type giant cells. Acid-fast bacilli smear was negative, but polymerase chain reaction for &lt;i&gt;Mycobacterium tuberculosis&lt;/i&gt; was positive. There were no significant findings in blood tests and chest radiographs. The patient was diagnosed with primary eyelid tuberculosis and treated with systemic anti-tuberculosis medications for 6 months. There were no complications or recurrences during 1 year of follow-up.Conclusions: Although eyelid tuberculosis is rare, early diagnosis through biopsy is important when a granulomatous tuberculosis lesion is suspected. Delayed diagnosis can lead to serious cosmetic and functional complications. Appropriate systemic anti-tuberculosis medications are required to treat these cases.

Validation of proteins associated with pathological damage in human tuberculosis granulomas: study protocol.

The presence of the Tuberculosis (TB) disease-causing pathogen, Mycobacterium Tuberculosis (Mtb), induces the development of a pathological feature termed granuloma, which the host uses to contain the bacteria. However, the granuloma may dissociate resulting in detrimental caseation of the lung. The disease contributes to a growing global burden of lung function challenges, warranting for more understanding of the TB-induced immunopathology. The current study aims to explore in detail host factors that drive pathological features of TB contributing to extensive lung tissue destruction. Lung tissue sections obtained from patients undergoing surgical resection will be processed and analyzed using histopathological assays including Immunohistochemistry, Immunofluorescence, Hematoxylin and Eosin staining and Laser Capture Microdissection. The findings will provide key host factors that associate with exacerbated lung immunopathology during TB.

Investigating the comorbidity of COPD and tuberculosis, a computational study

Recent research has shown that people who suffer from chronic obstructive pulmonary disease (COPD) have a greater propensity to contract and develop tuberculosis (TB) than the general population. Not only is the hazard ratio for contracting active tuberculosis triple that of the general population for those with COPD, but that the probability of death from any cause during the first year was double that of the tuberculosis population as a whole. This observation suggests that patients with COPD are less likely to progress to latent tuberculosis infection (LTBI) and are more likely to develop active tuberculosis than the general population. While similar susceptibility rates to TB are known to occur in populations with other ailments of the lung, particularly HIV, emphysema or asthma, patients with COPD (both emphysema and chronic bronchitis) are statistically more at risk for the disease. To examine the comorbidity effects of COPD on tuberculosis disease and granuloma formation, the process by which Mycobacterium tuberculosis (Mtb) is either contained or disseminates, we used a multi-scale model that integrates pathophysiological and immunopathological aspects of COPD and TB. Depicting chronic obstructive pulmonary disease smoker and non-smoker populations, we integrate agent-based models (ABM) of cellular immune response, physiological models of pulmonary capacity for COPD smoker/non-smoker, systems biology models of macrophage immune response to Mtb, and metabolic models to capture intracellular and extracellular Mtb metabolism and proliferation. We use our model to investigate key drivers of disease outcomes of clearance, granuloma-based containment, and disseminated disease in individuals with COPD and TB for smoking and non-smoking populations.

A Multimodal Desorption Electrospray Ionisation Workflow Enabling Visualisation of Lipids and Biologically Relevant Elements in a Single Tissue Section.

The colocation of elemental species with host biomolecules such as lipids and metabolites may shed new light on the dysregulation of metabolic pathways and how these affect disease pathogeneses. Alkali metals have been the subject of extensive research, are implicated in various neurodegenerative and infectious diseases and are known to disrupt lipid metabolism. Desorption electrospray ionisation (DESI) is a widely used approach for molecular imaging, but previous work has shown that DESI delocalises ions such as potassium (K) and chlorine (Cl), precluding the subsequent elemental analysis of the same section of tissue. The solvent typically used for the DESI electrospray is a combination of methanol and water. Here we show that a novel solvent system, (50:50 (%v/v) MeOH:EtOH) does not delocalise elemental species and thus enables elemental mapping to be performed on the same tissue section post-DESI. Benchmarking the MeOH:EtOH electrospray solvent against the widely used MeOH:H2O electrospray solvent revealed that the MeOH:EtOH solvent yielded increased signal-to-noise ratios for selected lipids. The developed multimodal imaging workflow was applied to a lung tissue section containing a tuberculosis granuloma, showcasing its applicability to elementally rich samples displaying defined structural information.

The use of multiplex imaging techniques to characterize tuberculous granuloma heterogeneity.

Caseous granulomas are pathological hallmarks of tuberculosis (TB), and increasing evidence suggests that TB granuloma composition is highly temporally and spatially heterogenous in both animal models and humans. Traditional pathological techniques are limited in their ability to reveal the heterogeneity present in TB granulomas. Multiplex tissue imaging tools combined with powerful, high resolution spatial analysis have enabled the detection of various cell phenotypes, aiding in the visualization of the granuloma complex and revealing the interactions between immune cells and nonimmune cells. This updated understanding of tuberculous granuloma heterogeneity offers vital insights for researchers aiming to uncover the immunoregulatory mechanisms underlying granuloma formation during TB pathogenesis. More detailed granuloma classification systems will also be of use for precision medicine, and for identifying biological targets for host-directed therapeutics in TB patients. This article is categorized under: Infectious Diseases > Genetics/Genomics/Epigenetics Infectious Diseases > Biomedical Engineering Infectious Diseases > Molecular and Cellular Physiology.

Inhibition of indoleamine dioxygenase leads to better control of tuberculosis adjunctive to chemotherapy.

The expression of indoleamine 2,3-dioxygenase (IDO), a robust immunosuppressant, is significantly induced in macaque tuberculosis (TB) granulomas, where it is expressed on IFN-responsive macrophages and myeloid-derived suppressor cells. IDO expression is also highly induced in human TB granulomas, and products of its activity are detected in patients with TB. In vivo blockade of IDO activity resulted in the reorganization of the granuloma with substantially greater T cells being recruited to the core of the lesions. This correlated with better immune control of TB and reduced lung M. tuberculosis burdens. To study if the IDO blockade strategy can be translated to a bona fide host-directed therapy in the clinical setting of TB, we studied the effect of IDO inhibitor 1-methyl-d-tryptophan adjunctive to suboptimal anti-TB chemotherapy. While two-thirds of controls and one-third of chemotherapy-treated animals progressed to active TB, inhibition of IDO adjunctive to the same therapy protected macaques from TB, as measured by clinical, radiological, and microbiological attributes. Although chemotherapy improved proliferative T cell responses, adjunctive inhibition of IDO further enhanced the recruitment of effector T cells to the lung. These results strongly suggest the possibility that IDO inhibition can be attempted adjunctive to anti-TB chemotherapy in clinical trials.

Subcellular localization and therapeutic efficacy of polymeric micellar nanoparticles encapsulating bedaquiline for tuberculosis treatment in zebrafish.

The combination drug regimens that have long been used to treat tuberculosis (TB), caused by Mycobacterium tuberculosis, are fraught with problems such as frequent administration, long duration of treatment, and harsh adverse effects, leading to the emergence of multidrug resistance. Moreover, there is no effective preventive vaccine against TB infection. In this context, nanoparticles (NPs) have emerged as a potential alternative method for drug delivery. Encapsulating antibiotics in biodegradable NPs has been shown to provide effective therapy and reduced toxicity against M. tuberculosis in different mammalian models, when compared to conventional free drug administration. Here, we evaluate the localization, therapeutic efficacy and toxic effects of polymeric micellar NPs encapsulating a promising but highly hydrophobic and toxic antitubercular drug bedaquiline (BQ) in zebrafish embryos infected with Mycobacterium marinum. Our study shows that the NP formulation of BQ improves survival and reduces bacterial burden in the infected embryos after treatment when compared to its free form. The intravenously injected BQ NPs have short circulation times due to their rapid and efficient uptake into the endothelial cells, as observed by correlative light and electron microscopy (CLEM).

Studying the tumor microenvironment under pressure

Meenal Datta is an assistant professor in the Department of Aerospace and Mechanical Engineering at the University of Notre Dame. Prof Datta received her PhD in Chemical and Biological Engineering from Tufts University in 2018, after which she completed a postdoctoral fellowship at Harvard Medical School and Massachusetts General Hospital. Her research focuses on deciphering the atypical tumor microenvironment that drives disease progression and treatment resistance in incurable cancers. By understanding and overcoming the biological, chemical, electrical, and mechanical abnormalities found in solid tumors, new therapeutic approaches can be discovered. Prof. Datta specializes in multidisciplinary and mechanism-based preclinical research that has the potential to be rapidly translated to improve treatment approaches in the clinic. She has spent her time as a researcher deciphering and reprogramming abnormal tissue microenvironments that present in a variety of diseases ranging from virulent tuberculosis to benign schwannoma to deadly glioblastoma that, surprisingly, share unifying features: abnormal blood vessels, abundant extracellular matrix, immunosuppression, and mechanopathologies. During her PhD, Dr Datta normalized the aberrant blood vasculature found in pulmonary tuberculosis granulomas to improve drug delivery. In her postdoctoral training, Dr Datta re-engineered the immunosuppressive brain tumor microenvironment to improve glioblastoma response to immunotherapy. As the director of the Tumor Immune Microenvironment &amp; Mechanics Lab at Notre Dame (the TIME lab). Prof Datta’s research group is applying engineering fundamentals and problem-solving approaches to explore mechano-immunological phenomena in the tumor microenvironment and discover novel biophysical targets of interest.

Reinventing the human tuberculosis (TB) granuloma: Learning from the cancer field.

Tuberculosis (TB) remains one of the deadliest infectious diseases in the world and every 20 seconds a person dies from TB. An important attribute of human TB is induction of a granulomatous inflammation that creates a dynamic range of local microenvironments in infected organs, where the immune responses may be considerably different compared to the systemic circulation. New and improved technologies for in situ quantification and multimodal imaging of mRNA transcripts and protein expression at the single-cell level have enabled significantly improved insights into the local TB granuloma microenvironment. Here, we review the most recent data on regulation of immunity in the TB granuloma with an enhanced focus on selected in situ studies that enable spatial mapping of immune cell phenotypes and functions. We take advantage of the conceptual framework of the cancer-immunity cycle to speculate how local T cell responses may be enhanced in the granuloma microenvironment at the site of Mycobacterium tuberculosis infection. This includes an exploratory definition of "hot", immune-inflamed, and "cold", immune-excluded TB granulomas that does not refer to the level of bacterial replication or metabolic activity, but to the relative infiltration of T cells into the infected lesions. Finally, we reflect on the current knowledge and controversy related to reactivation of active TB in cancer patients treated with immune checkpoint inhibitors such as PD-1/PD-L1 and CTLA-4. An understanding of the underlying mechanisms involved in the induction and maintenance or disruption of immunoregulation in the TB granuloma microenvironment may provide new avenues for host-directed therapies that can support standard antibiotic treatment of persistent TB disease.

Miliary Bovine Tuberculosis in Buffaloes in Al-Muthanna Governorate, Iraq

Background: Bubalus bubalis (river buffaloes) are widely distributed in the southern marshes of Iraq. This study intends to record a case of miliary tuberculosis in buffalo for the first time in Al Muthanna abattoir, Iraq, with its clinical, gross, and histopathological findings and microbiological investigations.&#x0D; Case Description: Ten years old buffalo showed chronic cough, infertility, emaciation, debilitation, lower milk production, loss of weight, and loss of appetite for 2 months; during meat inspection, thousands of various size typical tubercles, yellowish, granulomatous, and caseous lesions were distributed over all the body.&#x0D; Results: Microscopically, features of tuberculosis granuloma lesions were observed and revealed oval or round caseous necrosis with irregular central areas. Moreover, mineralization was enclosed by a thin to a broad layer of diverse inflammatory cells and solid collagenous connective tissue sheath. Moreover, a direct smear from the lesion stained by the Ziehl-Neelsen stain showed a slightly curved, red, and straight rod that was seen alone or in clusters, indicating the bacilli of tuberculosis. Additionally, the growing bacteria on the Löwenstein-Jensen media slant revealed flat, smooth, moist, white, not pigmented colonies suggestive of M. Bovis that revealed typical results with traditional biochemical tests, including negative reaction to nitrate reduction, niacin test, and deamination of pyrazinamide.&#x0D; Conclusion: For the author’s knowledge, this is the first case report of miliary bovine tuberculosis in buffalo in Iraq. The diagnosis was made according to clinical signs, gross pathology, and histopathological features supported by Ziehl-Neelsen stain and bacterial isolation. The author recommends future epidemiological molecular studies to improve the diagnosis tools of bovine tuberculosis in Iraq and investigate the causative agent M. Bovis to establish the roles for disease control that becomes much more challenging.

Systems biology approaches to investigate the role of granulomas in TB-HIV coinfection.

The risk of active tuberculosis disease is 15-21 times higher in those coinfected with human immunodeficiency virus-1 (HIV) compared to tuberculosis alone, and tuberculosis is the leading cause of death in HIV+ individuals. Mechanisms driving synergy between Mycobacterium tuberculosis (Mtb) and HIV during coinfection include: disruption of cytokine balances, impairment of innate and adaptive immune cell functionality, and Mtb-induced increase in HIV viral loads. Tuberculosis granulomas are the interface of host-pathogen interactions. Thus, granuloma-based research elucidating the role and relative impact of coinfection mechanisms within Mtb granulomas could inform cohesive treatments that target both pathogens simultaneously. We review known interactions between Mtb and HIV, and discuss how the structure, function and development of the granuloma microenvironment create a positive feedback loop favoring pathogen expansion and interaction. We also identify key outstanding questions and highlight how coupling computational modeling with in vitro and in vivo efforts could accelerate Mtb-HIV coinfection discoveries.

Radiomics combined with clinical features in distinguishing non-calcifying tuberculosis granuloma and lung adenocarcinoma in small pulmonary nodules.

AimTo evaluate the performance of radiomics models with the combination of clinical features in distinguishing non-calcified tuberculosis granuloma (TBG) and lung adenocarcinoma (LAC) in small pulmonary nodules.MethodologyWe conducted a retrospective analysis of 280 patients with pulmonary nodules confirmed by surgical biopsy from January 2017 to December 2020. Samples were divided into LAC group (n = 143) and TBG group (n = 137). We assigned them to a training dataset (n = 196) and a testing dataset (n = 84). Clinical features including gender, age, smoking, CT appearance (size, location, spiculated sign, lobulated shape, vessel convergence, and pleural indentation) were extracted and included in the radiomics models. 3D slicer and FAE software were used to delineate the Region of Interest (ROI) and extract clinical features. The performance of the model was evaluated by the Area Under the Receiver Operating Characteristic (ROC) Curve (AUC).ResultsBased on the model selection, clinical features gender, and age in the LAC group and TBG group showed a significant difference in both datasets (P < 0.05). CT appearance lobulated shape was also significantly different in the LAC group and TBG group (Training dataset, P = 0.034; Testing dataset, P = 0.030). AUC were 0.8344 (95% CI [0.7712–0.8872]) and 0.751 (95% CI [0.6382–0.8531]) in training and testing dataset, respectively.ConclusionWith the capacity to detect differences between TBG and LAC based on their clinical features, radiomics models with a combined of clinical features may function as the potential non-invasive tool for distinguishing TBG and LAC in small pulmonary nodules.

Spatial multiomic profiling reveals the novel polarization of foamy macrophages within necrotic granulomatous lesions developed in lungs of C3HeB/FeJ mice infected with Mycobacterium tuberculosis.

Infection with Mycobacterium tuberculosis leads to the development of tuberculosis (TB) with the formation of granulomatous lesions. Foamy macrophages (FM) are a hallmark of TB granulomas, because they provide the primary platform of M. tuberculosis proliferation and the main source of caseous necrosis. In this study, we applied spatial multiomic profiling to identify the signatures of FM within the necrotic granulomas developed in a mouse model resembling human TB histopathology. C3HeB/FeJ mice were infected with M. tuberculosis to induce the formation of necrotic granulomas in the lungs. Using laser microdissection, necrotic granulomas were fractionated into three distinct regions, including the central caseous necrosis, the rim containing FM, and the peripheral layer of macrophages and lymphocytes, and subjected to proteomic and transcriptomic analyses. Comparison of proteomic and transcriptomic analyses of three distinct granulomatous regions revealed that four proteins/genes are commonly enriched in the rim region. Immunohistochemistry confirmed the localization of identified signatures to the rim of necrotic granulomas. We also investigated the localization of the representative markers for M1 macrophages in granulomas because the signatures of the rim included M2 macrophage markers. The localization of both macrophage markers suggests that FM in necrotic granulomas possessed the features of M1 or M2 macrophages. Gene set enrichment analysis of transcriptomic profiling revealed the upregulation of genes related to M2 macrophage activation and mTORC1 signaling in the rim. These results will provide new insights into the process of FM biogenesis, leading to further understanding of the pathophysiology of TB granulomas.

Anti-Tuberculosis Activity of Three Carbapenems, Clofazimine and Nitazoxanide Using a Novel Ex Vivo Phenotypic Drug Susceptibility Model of Human Tuberculosis.

We evaluated a novel physiological 3-D bioelectrospray model of the tuberculosis (TB) granuloma to test the activity of a known anti-TB drug, clofazimine; three carbapenems with potential activity, including one currently used in therapy; and nitazoxanide, an anti-parasitic compound with possible TB activity (all chosen as conventional drug susceptibility was problematical). PBMCs collected from healthy donors were isolated and infected with M. tuberculosis H37Rv lux (i.e., luciferase). Microspheres were generated with the infected cells; the anti-microbial compounds were added and bacterial luminescence was monitored for at least 21 days. Clavulanate was added to each carbapenem to inhibit beta-lactamases. M. tuberculosis (MTB) killing efficacy was dose dependent. Clofazimine was the most effective drug inhibiting MTB growth at 2 mg/L with good killing activity at both concentrations tested. It was the only drug that killed bacteria at the lowest concentration tested. Carbapenems showed modest initial activity that was lost at around day 10 of incubation and clavulanate did not increase killing activity. Of the carbapenems tested, tebipenem was the most efficient in killing MTB, albeit at a high concentration. Nitazoxanide was effective only at concentrations not achievable with current dosing (although this might partly have been an artefact related to extensive protein binding).

Tuberculous granuloma and cervical lymphadenopathy in an immunocompetent patient: a case report

Tuberculosis (TB) is one of the top 10 infectious diseases causing mortality worldwide. In 2019, approximately 10 million people were diagnosed with TB, with 5.6 million men, 3.2 million women, and 1.2 million children. One of the hallmarks of the course of TB is tuberculous granuloma. In this study, we reported a case of TB granuloma and further workup to exclude other etiologies. A 52-year-old man presented with a complaint of a lump on his left neck. There was a history of prolonged productive cough, weight loss, and shortness of breath. Chest radiograph and FNAB of the lump suggested pulmonary TB while the rapid molecular test was negative. The patient was also suspected of malignancy; but the trans-thoracal biopsy did not reveal any malignant cells. The patient was eventually diagnosed with granuloma due to primary TB with cervical lymphadenopathy. Tuberculous granuloma is one of the most common pulmonary granulomas and a hallmark of the course of TB. It is characterized by the immune system forming an environment to control the spread of the infection. In cases of tuberculous granuloma with negative rapid molecular test, further investigations should be conducted to find evidence of TB infection. Activated TB granuloma can spread to the surrounding tissues or organs. A negative rapid molecular test result does not necessarily exclude TB in endemic regions; thus, further investigations such as CT scans or histopathological examination are required to find features of TB infection.

Type III IFNs (IFNλs) expressed in tuberculosis (TB) granulomas enhance anti-mycobacterial activity of macrophages

Abstract Granulomas are the pathologic hallmark of Mycobacterium tuberculosis (Mtb) infection. How a granuloma functions at limiting Mtb growth depends on the qualitative balance of pro- and anti-inflammatory cytokines in these lesions. Understanding which cytokines constitute protective and detrimental inflammation in TB is important for the improvement of current TB therapeutics. The type III interferon (IFN) family is composed of four isoforms and includes IL-29, IL-28A, IL-28B, and IFNλ4. These cytokines may be important regulators of inflammation in TB, yet little is known about their relation with TB or whether they have different properties in granulomas than type I IFN (IFNα/β), which is associated with severe TB. We identified that IFNλ is expressed at a significantly higher level in TB granulomas than non-disease lung, and negatively correlates with the CFU/granuloma. IHC characterization of IFNλ expression in granulomas revealed neutrophils and macrophages expressing IFNλ1 and IFNλ4, with neutrophils having a higher percentage of IFNλ expression. IFNλ1 and IFNλ4 differed in their intracellular localization, IFNλ4 having a significantly higher nuclear localization in macrophages than IFNλ1. IFNλ1 treatment of monocyte-derived macrophages induced the expression of different proinflammatory genes at the transcript level and costimulatory molecules like CD86 at the protein level. Further, pretreatment of macrophages with IFNλ1 inhibited the transcriptional activity in a reporter Mtb strain and follow-up experiments suggested this was accompanied by increased acidification of macrophage lysosomes. Our findings suggest that IFNλs may have unappreciated roles in regulating inflammation at the site of disease in TB. Supported by Grant from NIH entitled Pitt HIV-TB Research and Training Program in India (grant number: D43 TW010039)

CD4 Tcells are rapidly depleted from tuberculosis granulomas following acute SIV co-infection.

HIV/Mycobacterium tuberculosis (Mtb) co-infected individuals have an increased risk of tuberculosis prior to loss of peripheral CD4 Tcells, raising the possibility that HIV co-infection leads to CD4 Tcell depletion in lung tissue before it is evident in blood. Here, we use rhesus macaques to study the early effects of simian immunodeficiency virus (SIV) co-infection on pulmonary granulomas. Two weeks after SIV inoculation of Mtb-infected macaques, Mtb-specific CD4 Tcells are dramatically depleted from granulomas, before CD4 Tcell loss in blood, airways, and lymph nodes, or increases in bacterial loads or radiographic evidence of disease. Spatially, CD4 Tcells are preferentially depleted from the granuloma core and cuff relative to B cell-rich regions. Moreover, live imaging of granuloma explants show that intralesional CD4 Tcell motility is reduced after SIV co-infection. Thus, granuloma CD4 Tcells may be decimated before many co-infected individuals experience the first symptoms of acute HIV infection.

The tuberculosis resistance protein TOLLIP prevents disease progression by regulating the integrated stress response in alveolar macrophages.

Abstract Genetic variation associated with decreased TOLLIP expression in macrophages is a tuberculosis (TB) risk factor. However, the fundamental mechanisms underlying TOLLIP’s role in TB pathogenesis and macrophage function are unknown. To understand why TOLLIP strongly influences Mtb-macrophage interactions, we infected B6 mice lacking Tollip (Tollip−/−) with Mtb and evaluated lung-resident macrophage function and clinical response. Tollip−/− mice developed worsened Mtb disease with profuse lipid-laden foamy macrophages in their lungs. This phenotype was intrinsic to AM, as Tollip−/− AM, but not other lung-resident macrophage subtypes, from mixed bone marrow chimeras selectively harbored excessive Mtb bacilli and intracellular lipid. Global gene expression analysis of Mtb-infected, Tollip−/− AM demonstrated alteration in dozens of genes consistent with the integrated stress response (ISR), which adapts cells to variable environmental conditions and is associated with TB progression. Administration of mycolic acid, an Mtb cell wall lipid, to Tollip−/− macrophages induced lipid accumulation, ISR, and increased intracellular Mtb burden. Pharmacologic ISR inhibition restored host defense in Tollip−/− mice and improved Mtb outcomes overall. In humans, TOLLIP mRNA expression was increased in caseous TB granulomas, providing translational relevance for our observations. Taken together, TOLLIP deficiency in AMs induces foam cell formation and ISR after Mtb infection, which permits increased replication and drives immunopathology. These findings illustrate a major mechanism by which TOLLIP-deficient individuals are susceptible to TB disease and suggest novel targets for TB host-directed therapy.