Bacteriophage therapy for the treatment of Mycobacterium tuberculosis infections in humanized mice.

The continuing emergence of new strains of antibiotic-resistant bacteria has renewed interest in phage therapy; however, there has been limited progress in applying phage therapy to multi-drug resistant Mycobacterium tuberculosis (Mtb) infections. In this study, we show that bacteriophage strains D29 and DS6A can efficiently lyse Mtb H37Rv in 7H10 agar plates. However, only phage DS6A efficiently kills H37Rv in liquid culture and in Mtb-infected human primary macrophages.

Development of quality control parameters for two Bhutanese medicinal plants ( Bunge and (DC.) Benth. ex C.B.Clarke) using traditional and modern pharmacognostical platforms.

Bhutan's scholarly traditional medical system is called Bhutanese medicine (BSM). It was integrated with the modern healthcare system in 1967. Over 200 medicinal plants are used to produce more than 100 poly-ingredient medicinal formulations.

Regenerative Signatures in Bronchioalveolar Lavage of Acute Respiratory Distress Syndrome.

Background: In patients with severe acute respiratory distress syndrome (ARDS) associated with sepsis, lung recovery is considerably delayed, and mortality is much high. More insight into the process of lung regeneration in ARDS patients is needed. Exosomes are important cargos for intercellular communication by serving as autocrine and/or paracrine.

Bacteriophage therapy for the treatment of Mycobacterium tuberculosis infections in humanized mice.

The continuing emergence of new strains of antibiotic-resistant bacteria has renewed interest in phage therapy; however, there has been limited progress in applying phage therapy to multi-drug resistant Mycobacterium tuberculosis (Mtb) infections. In this study, we tested three bacteriophage strains for their Mtb-killing activities and found that two of them efficiently lysed Mtb H37Rv in 7H10 agar plates. However, only phage DS6A efficiently killed H37Rv in liquid culture and in Mtb-infected human primary macrophages.

Metabolites enhance innate resistance to human Mycobacterium tuberculosis infection.

To determine the mechanisms that mediate resistance to Mycobacterium tuberculosis (M. tuberculosis) infection in household contacts (HHCs) of patients with tuberculosis (TB), we followed 452 latent TB infection-negative (LTBI-) HHCs for 2 years. Those who remained LTBI- throughout the study were identified as nonconverters.

Decreased Interleukin-1 Family Cytokine Production in Patients with Nontuberculous Mycobacterial Lung Disease.

Nontuberculous mycobacteria (NTM) cause pulmonary disease in individuals without obvious immunodeficiency. This study was initiated to gain insight into the immunological factors that predispose persons to NTM pulmonary disease (NTMPD). Blood was obtained from 15 pairs of NTMPD patients and their healthy household contacts.

Histone deacetylase-2 controls IL-1β production through the regulation of NLRP3 expression and activation in tuberculosis infection.

Histone deacetylases (HDACs) are critical immune regulators. However, their roles in interleukin-1β (IL-1β) production remain unclear. By screening 11 zinc-dependent HDACs with chemical inhibitors, we found that HDAC1 inhibitor, 4-(dimethylamino)-N-[6-(hydroxyamino)-6-oxohexyl]-benzamide (DHOB), enhanced IL-1β production by macrophage and dendritic cells upon TLR4 stimulation or infection through IL-1β maturation via elevated NLRP3 expression, increased cleaved caspase-1, and enhanced ASC oligomerization.

Early IL-17A production helps establish Mycobacterium intracellulare infection in mice.

Nontuberculous mycobacteria (NTM) infection is common in patients with structural lung damage. To address how NTM infection is established and causes lung damage, we established an NTM mouse model by intranasal inoculation of clinical isolates of M. intracellulare.

Mycobacterium tuberculosis stimulates IL-1β production by macrophages in an ESAT-6 dependent manner with the involvement of serum amyloid A3.

Despite its critical roles in immune responses against tuberculosis infection and immune pathology, the molecular details of interleukin (IL)-1β production in tuberculosis infection remain elusive. To explore IL-1β production in tuberculosis infection, we infected mouse bone marrow-derived macrophages (BMDM) with Mycobacterium tuberculosis (Mtb) H37Rv, its early secreted antigenic target protein of 6 kDa (ESAT-6) gene deletion (H37Rv:Δ3875) or complemented strain (H37Rv:Δ3875C) and evaluated IL-1β production. H37Rv induced significantly increased IL-1β production by BMDMs compared to non-infected BMDMs.

Correction: IL-22 produced by type 3 innate lymphoid cells (ILC3s) reduces the mortality of type 2 diabetes mellitus (T2DM) mice infected with Mycobacterium tuberculosis.

[This corrects the article DOI: 10.1371/journal.ppat.

Ornithine-A urea cycle metabolite enhances autophagy and controls Mycobacterium tuberculosis infection.

Macrophages are professional phagocytes known to play a vital role in controlling Mycobacterium tuberculosis (Mtb) infection and disease progression. Here we compare Mtb growth in mouse alveolar (AMs), peritoneal (PMs), and liver (Kupffer cells; KCs) macrophages and in bone marrow-derived monocytes (BDMs). KCs restrict Mtb growth more efficiently than all other macrophages and monocytes despite equivalent infections through enhanced autophagy.

The potential impacts of early secreted antigenic target of 6 kDa of Mycobacterium tuberculosis on KSHV-infected cells.

Kaposi's sarcoma-associated herpesvirus (KSHV) causes several human cancers, including Kaposi's sarcoma (KS) and primary effusion lymphoma, which are mostly seen in immunocompromised patients, such as human immunodefeciency virus (HIV)+ individuals. Tuberculosis (TB), caused by the bacterial pathogen Mycobacterium tuberculosis (Mtb), remains one of the deadliest infectious diseases in the world. The risk of developing TB is dramatically higher in people living with HIV than among those without HIV infection.

BCG vaccination reduces the mortality of Mycobacterium tuberculosis-infected type 2 diabetes mellitus mice.

Diabetes is a significant risk factor for the development of active tuberculosis. In this study, we used a mouse model of type 2 diabetes mellitus (T2DM) to determine the effect of prior Bacillus Calmette-Guérin (BCG) vaccination on immune responses to Mycobacterium tuberculosis (Mtb) infection. We found that, at 6-7 months after Mtb infection, 90% of the Mtb-infected T2DM mice died, whereas only 50% of BCG-vaccinated T2DM-Mtb-infected mice died.

IL-22 produced by type 3 innate lymphoid cells (ILC3s) reduces the mortality of type 2 diabetes mellitus (T2DM) mice infected with Mycobacterium tuberculosis.

Previously, we found that pathological immune responses enhance the mortality rate of Mycobacterium tuberculosis (Mtb)-infected mice with type 2 diabetes mellitus (T2DM). In the current study, we evaluated the role of the cytokine IL-22 (known to play a protective role in bacterial infections) and type 3 innate lymphoid cells (ILC3s) in regulating inflammation and mortality in Mtb-infected T2DM mice. IL-22 levels were significantly lower in Mtb-infected T2DM mice than in nondiabetic Mtb-infected mice.

Proliferative regulation of alveolar epithelial type 2 progenitor cells by human gene.

Lung epithelial sodium channel (ENaC) encoded by genes is essential for maintaining transepithelial salt and fluid homeostasis in the airway and the lung. Compared to α, β, and γ subunits, the role of respiratory δ-ENaC has not been studied due to the lack of animal models. : We characterized full-length human δ-ENaC expressed in both oocytes and humanized transgenic mice.

Influenza Virus Infection Induces ZBP1 Expression and Necroptosis in Mouse Lungs.

Programmed cell death and especially necroptosis, a programmed and regulated form of necrosis, have been recently implicated in the progression and outcomes of influenza in mouse models. Moreover, Z-DNA/RNA binding protein 1 (ZBP1) has been identified as a key signaling molecule for necroptosis induced by Influenza A virus (IAV). Direct evidence of IAV-induced necroptosis has not been shown in infected lungs .

Microbiome Diversity in Sputum of Nontuberculous Mycobacteria Infected Women with a History of Breast Cancer.

Background/aims: The nontuberculous mycobacterial lung disease (NTM), caused by Mycobacterium avium complex (MAC) is an increasing health problem in the USA and worldwide. The NTM disease is prevalent in Caucasian women with a current diagnosis or history of breast cancer (BCa), posing a significant challenge towards treatment. We hypothesize that NTM affected women with considerable therapeutic resistance may harbor pathogenic microbes other than nontuberculous mycobacterium, aiding in disease progression and therapeutic resistance.

Alcohol enhances type 1 interferon-α production and mortality in young mice infected with Mycobacterium tuberculosis.

In the current study, we used a mouse model and human blood samples to determine the effects of chronic alcohol consumption on immune responses during Mycobacterium tuberculosis (Mtb) infection. Alcohol increased the mortality of young mice but not old mice with Mtb infection. CD11b+Ly6G+ cells are the major source of IFN-α in the lungs of Mtb-infected alcohol-fed young mice, and IFN-α enhances macrophage necroptosis in the lungs.

Elevated Cyclic AMP Inhibits Mycobacterium tuberculosis-Stimulated T-cell IFN-γ Secretion Through Type I Protein Kinase A.

Cyclic adenosine monophosphate (cAMP) is critical in immune regulation, and its role in tuberculosis infection remains unclear. We determined the levels of cAMP in peripheral blood mononuclear cells (PBMC) from tuberculosis patients and the mechanisms for cAMP suppression of IFN-γ production. PBMC from tuberculosis patients contained significantly elevated cAMP than latent tuberculosis infected subjects (LTBI), with an inverse correlation with IFN-γ production.

Early Secreted Antigenic Target of 6-kDa of Mycobacterium tuberculosis Stimulates IL-6 Production by Macrophages through Activation of STAT3.

As early secreted antigenic target of 6 kDa (ESAT-6) of Mycobacterium tuberculosis (Mtb) is an essential virulence factor and macrophages are critical for tuberculosis infection and immunity, we studied ESAT-6 stimulated IL-6 production by macrophages. ESAT-6 stimulated significantly higher IL-6 secretion by murine bone marrow derived macrophages (BMDM) compared to culture filtrate protein 10 kDa (CFP10) and antigen 85A. Polymyxin B, an LPS blocker, did not affect ESAT-6 stimulated macrophage IL-6 production.

Proteases and oxidant stress control organic dust induction of inflammatory gene expression in lung epithelial cells.

Background: Persistant inflammatory responses to infectious agents and other components in organic dust underlie lung injury and development of respiratory diseases. Organic dust components responsible for eliciting inflammation and the mechanisms by which they cause lung inflammation are not fully understood. We studied the mechanisms by which protease activities in poultry dust extracts and intracellular oxidant stress induce inflammatory gene expression in A549 and Beas2B lung epithelial cells.

The early secreted antigenic target of 6 kD of Mycobacterium tuberculosis inhibits the proliferation and differentiation of human peripheral blood CD34 cells.

Abnormalities in hematopoiesis are common in tuberculosis patients and highly prevalent in AIDS patients with tuberculosis coinfection. To explore the potential role of the early secreted antigenic target of 6-kD (ESAT-6) of Mycobacterium tuberculosis (Mtb) in abnormal hematopoiesis in tuberculosis, we studied the effect of ESAT-6 on proliferation and differentiation of in vitro-expanded CD34 cells isolated from the peripheral blood of the healthy donors. ESAT-6 but not control protein antigen 85A (Ag85A) of Mtb inhibited the proliferation of CD34 cell derived peripheral blood stem/progenitor cells (PBSPC) in a dose dependent manner when determined by MTT-assay.