Tuberculosis Granulomas Research Articles

Host-directed therapies targeting the tuberculosis granuloma stroma.

Mycobacteria have co-evolved with their hosts resulting in pathogens adept at intracellular survival. Pathogenic mycobacteria actively manipulate infected macrophages to drive granuloma formation while subverting host cell processes to create a permissive niche. Granuloma residency confers phenotypic antimicrobial resistance by physically excluding or neutralising antibiotics. Host-directed therapies (HDTs) combat infection by restoring protective immunity and reducing immunopathology independent of pathogen antimicrobial resistance status. This review covers innovative research that has discovered 'secondary' symptoms of infection in the granuloma stroma are actually primary drivers of infection and that relieving these stromal pathologies with HDTs benefits the host. Advances in our understanding of the relationship between tuberculosis and the host vasculature, haemostatic system and extracellular matrix reorganisation are discussed. Preclinical and clinical use of HDTs against these stromal targets are summarised.

Comparative in-silico proteomic analysis discerns potential granuloma proteins of Yersinia pseudotuberculosis

Yersinia pseudotuberculosis is one of the three pathogenic species of the genus Yersinia. Most studies regarding pathogenesis of Y. pseudotuberculosis are based on the proteins related to Type III secretion system, which is a well-known primary virulence factor in pathogenic Gram-negative bacteria, including Y. pseudotuberculosis. Information related to the factors involved in Y. pseudotuberculosis granuloma formation is scarce. In the present study we have used a computational approach to identify proteins that might be potentially involved in formation of Y. pseudotuberculosis granuloma. A comparative proteome analysis and conserved orthologous protein identification was performed between two different genera of bacteria - Mycobacterium and Yersinia, their only common pathogenic trait being ability to form necrotizing granuloma. Comprehensive analysis of orthologous proteins was performed in proteomes of seven bacterial species. This included M. tuberculosis, M. bovis and M. avium paratuberculosis - the known granuloma forming Mycobacterium species, Y. pestis and Y. frederiksenii - the non-granuloma forming Yersinia species and, Y. enterocolitica - that forms micro-granuloma and, Y. pseudotuberculosis - a prominent granuloma forming Yersinia species. In silico proteome analysis indicated that seven proteins (UniProt id A0A0U1QT64, A0A0U1QTE0, A0A0U1QWK3, A0A0U1R1R0, A0A0U1R1Z2, A0A0U1R2S7, A7FMD4) might play some role in Y. pseudotuberculosis granuloma. Validation of the probable involvement of the seven proposed Y. pseudotuberculosis granuloma proteins was done using transcriptome data analysis and, by mapping on a composite protein-protein interaction map of experimentally proved M. tuberculosis granuloma proteins (RD1 locus proteins, ESAT-6 secretion system proteins and intra-macrophage secreted proteins). Though, additional experiments involving knocking out of each of these seven proteins are required to confirm their role in Y. pseudotuberculosis granuloma our study can serve as a basis for further studies on Y. pseudotuberculosis granuloma.

Appendiceal Mucinous Adenocarcinoma with Concurrent Tuberculous Appendix: An Unusual Overlap of Two Rare Diseases

Background: Primary tumors of the appendix are rare and present with symptoms of acute appendicitis or a palpable right lower quadrant mass. The appendix is also an uncommon site of granulomatous tuberculosis infection for gastrointestinal extra pulmonary disease. This case report highlights an unusual overlap of the two diseases and a brief review of literature.

Proteomic Profiling Reveals the Architecture of Granulomatous Lesions Caused by Tuberculosis and Mycobacterium avium Complex Lung Disease.

Tuberculosis (TB) and Mycobacterium avium complex lung disease (MAC-LD) are both characterized pathologically by granuloma lesions, which are typically composed of a necrotic caseum at the center surrounded by fibrotic cells and lymphocytes. Although the histological characterization of TB and MAC-LD granulomas has been well-documented, their molecular signatures have not been fully evaluated. In this research we applied mass spectrometry-based proteomics combined with laser microdissection to investigate the unique protein markers in human mycobacterial granulomatous lesions. Comparing the protein abundance between caseous and cellular sub-compartments of mycobacterial granulomas, we found distinct differences. Proteins involved in cellular metabolism in transcription and translation were abundant in cellular regions, while in caseous regions proteins related to antimicrobial response accumulated. To investigate the determinants of their heterogeneity, we compared the protein abundance in caseous regions between TB and MAC-LD granulomas. We found that several proteins were significantly abundant in the MAC-LD caseum of which proteomic profiles were different from those of the TB caseum. Immunohistochemistry demonstrated that one of these proteins, Angiogenin, specifically localized to the caseous regions of selected MAC-LD granulomas. We also detected peptides derived from mycobacterial proteins in the granulomas of both diseases. This study provides new insights into the architecture of granulomatous lesions in TB and MAC-LD.

Патоморфологічна характеристика інтестинальних патологій за генералізованого туберкульозу фазанів

The results of a pathomorphological study of intestinal wall of pheasants with tuberculosis were discussed. The object of the study were intestines of pheasants (n=5) which died from generalized tuberculosis. The aim of the study was to describe  and classify pathological changes in the intestinal wall of pheasants with tuberculosis. Materials and research methods. The work was carried out at the department of normal and pathological morphology of KhSZVA. Methods of postmortem autopsy of birds with partial evisceration, macroscopic analysis of the condition of the intestinal wall, pathological examination of its samples, microscopy according to Zichl-Neelsen for the detection of acid-resistant mycobacteria, PCR were used. Result of the research. We revealed tuberculous lesions with varying degrees of intensity and complexity in the intestinal wall of pheasants. Mycobacterium tuberculosis (stick-shaped red colored microorganisms) detected in smears-prints intestine walls altered fragments using Zichl-Neelsen bacterioscopy. Final diagnosis “Tuberculosis of birds” was established based on macroscopic data, histopathological studies of the intestinal wall, Zichl-Neelsen bacterioscopy, PCR results. Tuberculous granulomas of alternative type predominated in the intestinal wall of pheasants. Proliferative granulomas were rarely detected. The complex of post-tuberculous reparative processes and indicators due to them was classified. In the intestinal wall created alterative type of ulceri with perifocal fibrosis as a result of degradation of tuberculosis granulomas. Scarring of ulcerative areas, local edema, abscess-like wall formations, strictures, partial obstruction of intestines were detected. Mixed forms of tuberculous intestinal lesions: nodular-ulcerative, including, with scarring and stenosis; nodular, including drain, with extra- and intramural abscess-like formations were diagnosed in four pheasants. Nodular monoform of intestinal lesions was classified in one pheasant.

Interaction of antitubercular drug candidates with α1-acid glycoprotein produced in pulmonary granulomas

The intracellular pathogen Mycobacterium tuberculosis can survive and replicate within host macrophages. Among various immunomodulatory substances, macrophages also produce α1-acid glycoprotein (AAG) which is secreted into the extracellular matrix of tuberculosis granulomas that represents a specific binding environment. Employing circular dichroism (CD) and UV/VIS absorption spectroscopic methods, we demonstrated and evaluated the AAG binding properties of novel antitubercular drug candidates developed against sensitive and multidrug-resistant strains of M. tuberculosis. As inferred from the CD spectroscopic data, these chemically diverse organic molecules are engulfed within the β-barrel of the protein either in a monomeric or dimeric form. Molecular docking simulations suggested the importance of H-bonds and ligand-aromatic residue π-π stacking interactions in stabilizing the drug molecules at the protein binding site. Based on the estimated Kd values (7–20 μM), AAG could be considered as the significant binding partner of the antitubercular agents studied herein. As such, it may affect the drug distribution and bioavailability not only in serum but also in macrophages and in the extracellular matrix of tuberculosis granulomas.

High content analysis of granuloma histology and neutrophilic inflammation in adult zebrafish infected with Mycobacterium marinum

Infection of zebrafish with natural pathogen Mycobacterium marinum is a useful surrogate for studying the human granulomatous inflammatory response to infection by Mycobacterium tuberculosis. The adaptive immune system of the adult stage zebrafish offers an advance on the commonly used embryo infection model as adult zebrafish form granulomas with striking similarities to human-M. tuberculosis granulomas. Here, we present workflows to perform high content analyses of granulomas in adult zebrafish infected with M. marinum by cryosectioning to take advantage of strong endogenous transgenic fluorescence adapted from common zebrafish embryo infection tools. Specific guides to classifying granuloma necrosis and organisation, quantifying bacterial burden and leukocyte infiltration of granulomas, visualizing foam cell formation, analysing extracellular matrix remodelling and granuloma fibrosis are also provided. We use these methods to characterize neutrophil recruitment to M. marinum granulomas across time and find an inverse relation to granuloma necrosis suggesting granuloma necrosis is not a marker of immunopathology in the natural infection system of the adult zebrafish-M. marinum pairing. The methods can be easily translated to studying the zebrafish adaptive immune response to other chronic and granuloma-forming pathogens.

Neutrophils express pro- and anti-inflammatory cytokines in granulomas from Mycobacterium tuberculosis-infected cynomolgus macaques

Neutrophils are implicated in the pathogenesis of tuberculosis (TB), a disease caused by Mycobacterium tuberculosis infection, but the mechanisms by which they promote disease are not fully understood. Neutrophils can express cytokines that influence TB progression, and so we compared neutrophil and T-cell expression of the Th1 cytokines IFNγ and TNF, the Th2 cytokine IL-4, and regulatory cytokine IL-10 in M. tuberculosis-infected macaques to determine if neutrophil cytokine expression contributes to dysregulated immunity in TB. We found that peripheral blood neutrophils produced cytokines after stimulation by mycobacterial antigens and inactive and viable M. tuberculosis. M. tuberculosis antigen-stimulated neutrophils inhibited antigen-specific T-cell IFNγ production. In lung granulomas, neutrophil cytokine expression resembled T-cell cytokine expression, and although there was histologic evidence for neutrophil interaction with T cells, neutrophil cytokine expression was not correlated with T-cell cytokine expression or bacteria load. There was substantial overlap in the spatial arrangement of cytokine-expressing neutrophils and T cells, but IL-10-expressing neutrophils were also abundant in bacteria-rich areas between caseum and epithelioid macrophages. These results suggest that neutrophils contribute to the cytokine milieu in granulomas and may be important immunoregulatory cells in TB granulomas.

Immunology of Mycobacterium tuberculosis Infections.

Tuberculosis (TB) is a serious global public health challenge that results in significant morbidity and mortality worldwide. TB is caused by infection with the bacilli Mycobacterium tuberculosis (M. tuberculosis), which has evolved a wide variety of strategies in order to thrive within its host. Understanding the complex interactions between M. tuberculosis and host immunity can inform the rational design of better TB vaccines and therapeutics. This chapter covers innate and adaptive immunity against M. tuberculosis infection, including insights on bacterial immune evasion and subversion garnered from animal models of infection and human studies. In addition, this chapter discusses the immunology of the TB granuloma, TB diagnostics, and TB comorbidities. Finally, this chapter provides a broad overview of the current TB vaccine pipeline.

Revisiting hypoxia therapies for tuberculosis.

The spectre of the coming post-antibiotic age demands novel therapies for infectious diseases. Tuberculosis (TB), caused by Mycobacterium tuberculosis, is the single deadliest infection throughout human history. M. tuberculosis has acquired antibiotic resistance at an alarming rate with some strains reported as being totally drug resistant. Host-directed therapies (HDTs) attempt to overcome the evolution of antibiotic resistance by targeting relatively immutable host processes. Here, I hypothesise the induction of hypoxia via anti-angiogenic therapy will be an efficacious HDT against TB. I argue that anti-angiogenic therapy is a modernisation of industrial revolution era sanatoria treatment for TB, and present a view of the TB granuloma as a 'bacterial tumour' that can be treated with anti-angiogenic therapies to reduce bacterial burden and spare host immunopathology. I suggest two complementary modes of action, induction of bacterial dormancy and activation of host hypoxia-induced factor (HIF)-mediated immunity, and define the experimental tools necessary to test this hypothesis.

Metabolic adaptation to glycolysis is a basic defense mechanism of macrophages for Mycobacterium tuberculosis infection.

Macrophages are major components of tuberculosis (TB) granulomas and are responsible for host defenses against the intracellular pathogen, Mycobacterium tuberculosis. We herein showed the strong expression of hypoxia-inducible factor-1α (HIF-1α) in TB granulomas and more rapid death of HIF-1α-conditional knockout mice than wild-type (WT) mice after M. tuberculosis infection. Although interferon-γ (IFN-γ) is a critical host-protective cytokine against intracellular pathogens, HIF-1-deficient macrophages permitted M. tuberculosis growth even after activation with IFN-γ. These results prompted us to investigate the role of HIF-1α in host defenses against infection. We found that the expression of lactate dehydrogenase-A (LDH-A) was controlled by HIF-1α in M. tuberculosis-infected macrophages IFN-γ independently. LDH-A is an enzyme that converts pyruvate to lactate and we found that the intracellular level of pyruvate in HIF-1α-deficient bone marrow-derived macrophages (BMDMs) was significantly higher than in WT BMDMs. Intracellular bacillus replication was enhanced by an increase in intracellular pyruvate concentrations, which were decreased by LDH-A. Mycobacteria in phagosomes took up exogenous pyruvate more efficiently than glucose, and used it as the feasible carbon source for intracellular growth. These results demonstrate that HIF-1α prevents the hijacking of pyruvate in macrophages, making it a fundamental host-protective mechanism against M. tuberculosis.

Clinic - Morphologic and Morphometric Criteria for Differential Diagnosis of Sarcoidosis and Pulmonary Tuberculosis

BACKGROUND:Currently incidence and prevalence of sarcoidosis are increasing. Sarcoidosis is a systemic granulomatous lung disease of unknown aetiology, which is characterised by the involvement of different organ systems, variable disease course affecting young people and possessing an important issue in the modern world. The disease is extremely heterogeneous with an unpredictable clinical course. Interesting clinical cases are described in which, with a sufficient illustration of the stages of the course and diagnosis of sarcoidosis of the lungs and peripheral lymph nodes, the diagnosis was difficult. Late diagnosis and lack of correct therapy make prognosis in patients with lung sarcoidosis unfavourable.AIM:To conduct a morphometric study with the determination of the cellular composition of granulomas for the differential diagnosis of morphogenesis of granulomas in sarcoidosis and pulmonary tuberculosis.MATERIAL AND METHODS:An analysis of transthoracic biopsy of 89 patients with a verified diagnosis of sarcoidosis of the lungs and disseminated form of pulmonary tuberculosis was carried out. The resulting lung tissue material was carried out according to the standard histological method; conducted morphometric analysis.RESULTS:Sarcoid granulomas are characterised by an increase in lymphocytes, indicating the immune character of the lesion, an increase in fibroblasts, fibrocytes, and signs of activation of angiogenesis. While for TB granuloma an increase in the number of granulocytes and epithelioid cells is characteristic. These morphological criteria for the diagnosis of sarcoidosis of the lungs and lymph nodes are necessary for use in the practice of pathologists to verify the clinical diagnosis.CONCLUSION:Developed morphological and morphometric criteria for the differential diagnosis of sarcoidosis and pulmonary tuberculosis must be used in the practice of a pathologist to verify the clinical diagnosis, which will determine the adequate tactics of examination, administration, correction of the disease, and evaluation of the prognosis of the disease, taking into account identified clinical and laboratory data, results of instrumental research methods.

Bronchioalveolar carcinoma in an adult alpaca (Vicugna pacos)

BackgroundThis report describes a case of a bronchiolar adenocarcinoma in a 6-year old alpaca mare. For the first time in an alpaca, neoplasia was classified by histopathology as a lepidic-predominant bronchiolar adenocarcinoma.Case presentationThe mare was referred to the Clinic for Ruminants after a 6-week period of forced breathing and weight loss. The clinical examination included complete blood count, blood chemistry, ultrasound, radiographs and a CT-scan of the thorax. A bilateral pneumothorax and several, structures within the lung parenchyma were diagnosed. Differential diagnosis included neoplasia, tuberculosis and fungal granulomas. The owner requested euthanasia due to the mare’s ongoing deterioration. At postmortem examination, the granulomatous changes in the lungs were histopathologically classified as lepidic dominant bronchiolar adenocarcinoma.ConclusionsNeoplastic diseases are more often seen in South American camelids compared to other farm animal species. The use of a CT scan was helpful in classifying the lung lesions and give a clear prognosis.

Type III interferons are expressed in tuberculosis granulomas and may influence signaling in epithelioid macrophages

Abstract Granulomas are the pathologic hallmark of Mycobacterium tuberculosis (Mtb) infection. Balanced pro- and anti-inflammatory cytokines regulate inflammation in tuberculosis (TB) and determine outcomes at the lesional and organismal level. Understanding what constitutes protective and detrimental inflammation in TB is important for the improvement of current TB therapeutics. The type III interferon family is composed of four isoforms and includes IL-29, IL-28A, IL-28B, and the recently classified IFNλ4. These cytokines may be important regulators of inflammation in TB yet little is known about their relationship with TB or whether they have different properties in granulomas than type I interferons (IFNα/β), a family of cytokines associated with severe TB. To better understand the relationship between IFNλ, IFNα, and TB we characterized IFNλ expression in formalin-fixed paraffin-embedded granulomas from cynomolgus macaques and investigated cytokine expression and STAT phosphorylation by macaque peripheral blood, lung, and lymph node cells. We found that IL-29 and IL-28B are expressed by epithelioid macrophages and neutrophils in granulomas and IFNλ4 had a unique expression in the transcriptionally active region of epithelioid macrophage nuclei suggesting a possible regulatory role for IFNλ4 in these cells. Experiments were also performed to compare IFNα and IFNλ’s effect on antimycobacterial responses in monocyte-derived macrophages, and ability to induce STAT phosphorylation and pro- and anti-inflammatory cytokine expression by T cells, macrophages, monocytes, and neutrophils. Our findings suggest that IFNλ may have unappreciated roles in regulating inflammation at the site of disease in TB.

Spatial and temporal localization of immune transcripts defines hallmarks and diversity in the tuberculosis granuloma

Granulomas are the pathological hallmark of tuberculosis (TB) and the niche where bacilli can grow and disseminate or the immunological microenvironment in which host cells interact to prevent bacterial dissemination. Here we show 34 immune transcripts align to the morphology of lung sections from Mycobacterium tuberculosis-infected mice at cellular resolution. Colocalizing transcript networks at <10 μm in C57BL/6 mouse granulomas increase complexity with time after infection. B-cell clusters develop late after infection. Transcripts from activated macrophages are enriched at subcellular distances from M. tuberculosis. Encapsulated C3HeB/FeJ granulomas show necrotic centers with transcripts associated with immunosuppression (Foxp3, Il10), whereas those in the granuloma rims associate with activated T cells and macrophages. We see highly diverse networks with common interactors in similar lesions. Different immune landscapes of M. tuberculosis granulomas depending on the time after infection, the histopathological features of the lesion, and the proximity to bacteria are here defined.

Oxidized low-density lipoprotein (oxLDL) supports Mycobacterium tuberculosis survival in macrophages by inducing lysosomal dysfunction

Type 2 diabetes mellitus (DM) is a major risk factor for developing tuberculosis (TB). TB-DM comorbidity is expected to pose a serious future health problem due to the alarming rise in global DM incidence. At present, the causal underlying mechanisms linking DM and TB remain unclear. DM is associated with elevated levels of oxidized low-density lipoprotein (oxLDL), a pathologically modified lipoprotein which plays a key role during atherosclerosis development through the formation of lipid-loaded foamy macrophages, an event which also occurs during progression of the TB granuloma. We therefore hypothesized that oxLDL could be a common factor connecting DM to TB. To study this, we measured oxLDL levels in plasma samples of healthy controls, TB, DM and TB-DM patients, and subsequently investigated the effect of oxLDL treatment on human macrophage infection with Mycobacterium tuberculosis (Mtb). Plasma oxLDL levels were significantly elevated in DM patients and associated with high triglyceride levels in TB-DM. Strikingly, incubation with oxLDL strongly increased macrophage Mtb load compared to native or acetylated LDL (acLDL). Mechanistically, oxLDL -but not acLDL- treatment induced macrophage lysosomal cholesterol accumulation and increased protein levels of lysosomal and autophagy markers, while reducing Mtb colocalization with lysosomes. Importantly, combined treatment of acLDL and intracellular cholesterol transport inhibitor (U18666A) mimicked the oxLDL-induced lysosomal phenotype and impaired macrophage Mtb control, illustrating that the localization of lipid accumulation is critical. Collectively, these results demonstrate that oxLDL could be an important DM-associated TB-risk factor by causing lysosomal dysfunction and impaired control of Mtb infection in human macrophages.

Macrophage heterogeneity and plasticity in tuberculosis.

Macrophages are the primary host cells for Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), during its intracellular survival in humans. The pathogen has a remarkable capacity to survive within the hostile environment of macrophages. However, primary infection does not result in active TB disease in most individuals. The majority of individuals remain latently infected, wherein the bacteria are held in check by the host immune response. Nevertheless, such individuals can develop active TB later upon the decline in their immune status. In contrast, in a small fraction of infected individuals, the host immune response fails to control the growth of M. tuberculosis bacilli, and granulomatous TB develops progressively. Elucidating the molecular and phenotypic events that govern the outcome of the infection within macrophages is fundamental to understanding the key features of these cells that could be equally critical in infection control. The molecular details of the M. tuberculosis-macrophage interaction continue to be discerned, and emerging evidence suggests that macrophage population that participate in infection is heterogeneous. While the local environment and developmental origin could influence the phenotypic heterogeneity and functional plasticity of macrophages, M. tuberculosis has also been demonstrated to modulate the polarization of macrophages. In this review, we draw on work investigating specialized macrophage populations and their interactions with M. tuberculosis with respect to pathogenesis and specific immune responses. Understanding the mechanisms that control the repertoire of macrophage phenotypes and behaviors during infection may provide prospects for novel TB control strategies through modulation of immunobiological functions of macrophages.

In Vitro Granuloma Models of Tuberculosis: Potential and Challenges.

Despite intensive research efforts, several fundamental disease processes for tuberculosis (TB) remain poorly understood. A central enigma is that host immunity is necessary to control disease yet promotes transmission by causing lung immunopathology. Our inability to distinguish these processes makes it challenging to design rational novel interventions. Elucidating basic immune mechanisms likely requires both in vivo and in vitro analyses, since Mycobacterium tuberculosis is a highly specialized human pathogen. The classic immune response is the TB granuloma organized in three dimensions within extracellular matrix. Several groups are developing cell culture granuloma models. In January 2018, NIAID convened a workshop, entitled "3-D Human in vitro TB Granuloma Model" to advance the field. Here, we summarize the arguments for developing advanced TB cell culture models and critically review those currently available. We discuss how integrating complementary approaches, specifically organoids and mathematical modeling, can maximize progress, and conclude by discussing future challenges and opportunities.

Clinical, laboratory and radiological characteristics of HIV infection associated with tuberculosis and treatment of such patients

Objective: to analyze and explain the clinical, laboratory and radiological features of HIV infection associated with tuberculosis (HIV/TB) and on this basis to argue the principles of treatment of such patients.The development of active tuberculosis (TB) in HIV-infected patients is accompanied by an increase, while during its treatment, on the contrary, — a decrease in the concentration of viral RNA in the blood. The release of the virus into the blood is due to the activation of lymphocytes caused by mycobacterium tuberculosis (MBT). Therefore, the clinical manifestations of HIV infection and TB in the early stages are similar. TB increases the degree of immunodeficiency in HIV-positive patients, which leads to the associated opportunistic diseases: esophageal candidiasis, cryptococcal meningitis, pneumocystic pneumonia, Kaposhi sarcoma, and etc.With the development of immunodeficiency, the clinical picture of tuberculosis also changes. This is due to the fact that in the context of lowering the immune response, no typical tuberculosis granuloma is formed, the MBT easier spreads to other organs and systems. Therefore, in HIV-positive patientsthere are primary, extra-pulmonary and generalized forms of tuberculosis. According to chest X‑ray, tuberculous changes in HIV-infected patients (as in primary infections) are characterized by more frequent development of adenopathy of hilus, miliary rash, the presence of predominantly interstitial changes and the formation of pleural effusion. At the same time, they are reliably less likely to affect the upper lung parts, not so often formed destruction cavities and atelectasis. Over the past few years, approaches to the providing of antiretroviral treatment (ART) have changed dramatically in patients with HIV/TB. It has been shown that the use of ART in the first 2–8 weeks of treatment for tuberculosis significantly increases the patient's chances of recovery. Currently, ART is administered to all patients with TBregardless of the number of CD4 + T‑lymphocytes.Conclusions. So, the clinical manifestations of HIV infection and TB in the early stages are similar. However, with the development of immunodeficiency, the clinical picture of tuberculosis also changes. In HIV-infected diseases, TB increases the degree of immunodeficiency, which leads to association of other opportunistic diseases. When radiographing the chest cavity, changes in HIV-infected patients are characterized by frequent development of adenopathy of hilus, miliary rash, the presence of predominantly interstitial changes and the formation of pleural effusion. Also in recent years, approaches to prescribing antiretroviral therapy (ART) for patients with HIV/TB have changed. So, the relationship between HIV infection and tuberculosis at the cellular level appears to be very complex and insufficiently studied. Clinical and laboratory, especially immunological, aspects of the development of tuberculosis as a secondary disease in HIV-infected patients require additional studies.

Humanized Mouse Model Mimicking Pathology of Human Tuberculosis for in vivo Evaluation of Drug Regimens.

Human immune system mice are highly valuable for in vivo dissection of human immune responses. Although they were employed for analyzing tuberculosis (TB) disease, there is little data on the spatial organization and cellular composition of human immune cells in TB granuloma pathology in this model. We demonstrate that human immune system mice, generated by transplanted human fetal liver derived hematopoietic stem cells develop a continuum of pulmonary lesions upon Mycobacterium tuberculosis aerosol infection. In particular, caseous necrotic granulomas, which contribute to prolonged TB treatment time, developed, and had cellular phenotypic spatial-organization similar to TB patients. By comparing two recommended drug regimens, we confirmed observations made in clinical settings: Adding Moxifloxacin to a classical chemotherapy regimen had no beneficial effects on bacterial eradication. We consider this model instrumental for deeper understanding of human specific features of TB pathogenesis and of particular value for the pre-clinical drug development pipeline.