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1.
J Interferon Cytokine Res ; 42(8): 421-429, 2022 08.
Article in English | MEDLINE | ID: mdl-35914102

ABSTRACT

Tuberculosis (TB) caused by the pathogenic bacterium Mycobacterium tuberculosis (Mtb) is one of the most lethal infectious diseases in the world. Presently, Bacillus Calmette-Guerin, the vaccine approved for use against TB, does not offer complete protection against the disease, which necessitates the development of new therapeutics to treat this infection. Overexpression of transforming growth factor beta (TGF-ß) is associated with pulmonary profibrotic changes. The inactive TGF-ß secreted is activated through its cleavage and release by αv integrins. Integrin-mediated regulation of TGF-ß is considered as a master switch in the profibrotic process and a potential therapeutic target. Thus, in this study, we sought to determine if treatment with a broad range antagonist of integrins, CWHM-12, has the potency to inhibit pulmonary fibrosis and enhance Mtb control in a highly susceptible mouse model of Mtb infection, namely the C3Heb/FeJ (FeJ). CWHM-12 treatment at the early stages of Mtb infection was efficacious in reducing disease severity and inflammation associated with decreased iNOS, MIP-2, and IL-10 production without degradation of collagen. This suggests a potential for CWHM-12 targeting of TGF-ß to be explored as an adjunct therapeutic for early Mtb infection.


Subject(s)
Mycobacterium tuberculosis , Tuberculosis , Animals , Integrins , Mice , Transforming Growth Factor beta/metabolism , Transforming Growth Factors , Tuberculosis/drug therapy , Tuberculosis/prevention & control
3.
Vaccines (Basel) ; 9(3)2021 Mar 02.
Article in English | MEDLINE | ID: mdl-33801372

ABSTRACT

Streptococcus pneumoniae (Spn) is a bacterial pathogen known to colonize the upper respiratory tract and cause serious opportunistic diseases such as pneumonia, bacteremia, sepsis and meningitis. As a consequence, millions of attributable deaths occur annually, especially among infants, the elderly and immunocompromised individuals. Although current vaccines, composed of purified pneumococcal polysaccharide in free form or conjugated to a protein carrier, are widely used and have been demonstrated to be effective in target groups, Spn has continued to colonize and cause life-threatening disease in susceptible populations. This lack of broad protection highlights the necessity of improving upon the current "gold standard" pneumococcal vaccines to increase protection both by decreasing colonization and reducing the incidence of sterile-site infections. Over the past century, most of the pneumococcal proteins that play an essential role in colonization and pathogenesis have been identified and characterized. Some of these proteins have the potential to serve as antigens in a multi-valent protein vaccine that confers capsule independent protection. This review seeks to summarize the benefits and limitations of the currently employed vaccine strategies, describes how leading candidate proteins contribute to pneumococcal disease development, and discusses the potential of these proteins as protective antigens-including as a hybrid construct.

5.
Cell Rep ; 32(8): 108062, 2020 08 25.
Article in English | MEDLINE | ID: mdl-32846120

ABSTRACT

Pneumonias caused by influenza A virus (IAV) co- and secondary bacterial infections are characterized by their severity and high mortality rate. Previously, we have shown that bacterial pore-forming toxin (PFT)-mediated necroptosis is a key driver of acute lung injury during bacterial pneumonia. Here, we evaluate the impact of IAV on PFT-induced acute lung injury during co- and secondary Streptococcus pneumoniae (Spn) infection. We observe that IAV synergistically sensitizes lung epithelial cells for PFT-mediated necroptosis in vitro and in murine models of Spn co-infection and secondary infection. Pharmacoelogical induction of oxidative stress without virus sensitizes cells for PFT-mediated necroptosis. Antioxidant treatment or inhibition of necroptosis reduces disease severity during secondary bacterial infection. Our results advance our understanding on the molecular basis of co- and secondary bacterial infection to influenza and identify necroptosis inhibition and antioxidant therapy as potential intervention strategies.


Subject(s)
Influenza, Human/complications , Lung/microbiology , Necroptosis/genetics , Oxidative Stress/genetics , Animals , Humans , Mice
6.
J Clin Invest ; 130(6): 3098-3112, 2020 06 01.
Article in English | MEDLINE | ID: mdl-32134742

ABSTRACT

Neutrophil accumulation is associated with lung pathology during active tuberculosis (ATB). However, the molecular mechanism or mechanisms by which neutrophils accumulate in the lung and contribute to TB immunopathology are not fully delineated. Using the well-established mouse model of TB, our new data provide evidence that the alarmin S100A8/A9 mediates neutrophil accumulation during progression to chronic TB. Depletion of neutrophils or S100A8/A9 deficiency resulted in improved Mycobacterium tuberculosis (Mtb) control during chronic but not acute TB. Mechanistically, we demonstrate that, following Mtb infection, S100A8/A9 expression is required for upregulation of the integrin molecule CD11b specifically on neutrophils, mediating their accumulation during chronic TB disease. These findings are further substantiated by increased expression of S100A8 and S100A9 mRNA in whole blood in human TB progressors when compared with nonprogressors and rapidly decreased S100A8/A9 protein levels in the serum upon TB treatment. Furthermore, we demonstrate that S100A8/A9 serum levels along with chemokines are useful in distinguishing between ATB and asymptomatic Mtb-infected latent individuals. Thus, our results support targeting S100A8/A9 pathways as host-directed therapy for TB.


Subject(s)
CD11b Antigen/immunology , Calgranulin A/immunology , Calgranulin B/immunology , Mycobacterium tuberculosis/immunology , Neutrophil Infiltration/immunology , Neutrophils/immunology , Tuberculosis/immunology , Animals , CD11b Antigen/genetics , Calgranulin A/genetics , Calgranulin B/genetics , Mice , Mice, Knockout , Neutrophils/pathology , Tuberculosis/genetics , Tuberculosis/pathology , Tuberculosis/therapy
7.
Nature ; 517(7536): 612-5, 2015 Jan 29.
Article in English | MEDLINE | ID: mdl-25470057

ABSTRACT

Pathogenic mycobacteria induce the formation of complex cellular aggregates called granulomas that are the hallmark of tuberculosis. Here we examine the development and consequences of vascularization of the tuberculous granuloma in the zebrafish-Mycobacterium marinum infection model, which is characterized by organized granulomas with necrotic cores that bear striking resemblance to those of human tuberculosis. Using intravital microscopy in the transparent larval zebrafish, we show that granuloma formation is intimately associated with angiogenesis. The initiation of angiogenesis in turn coincides with the generation of local hypoxia and transcriptional induction of the canonical pro-angiogenic molecule Vegfaa. Pharmacological inhibition of the Vegf pathway suppresses granuloma-associated angiogenesis, reduces infection burden and limits dissemination. Moreover, anti-angiogenic therapies synergize with the first-line anti-tubercular antibiotic rifampicin, as well as with the antibiotic metronidazole, which targets hypoxic bacterial populations. Our data indicate that mycobacteria induce granuloma-associated angiogenesis, which promotes mycobacterial growth and increases spread of infection to new tissue sites. We propose the use of anti-angiogenic agents, now being used in cancer regimens, as a host-targeting tuberculosis therapy, particularly in extensively drug-resistant disease for which current antibiotic regimens are largely ineffective.


Subject(s)
Angiogenesis Inhibitors/pharmacology , Mycobacterium Infections, Nontuberculous/microbiology , Mycobacterium marinum/drug effects , Mycobacterium marinum/growth & development , Neovascularization, Pathologic/microbiology , Signal Transduction/drug effects , Zebrafish/microbiology , Angiogenesis Inhibitors/therapeutic use , Animals , Antibiotics, Antitubercular/pharmacology , Bacterial Load/drug effects , Disease Models, Animal , Drug Synergism , Granuloma/drug therapy , Granuloma/metabolism , Granuloma/microbiology , Granuloma/pathology , Hypoxia/metabolism , Hypoxia/microbiology , Hypoxia/pathology , Larva/drug effects , Larva/microbiology , Macrophages/metabolism , Macrophages/microbiology , Macrophages/pathology , Mycobacterium Infections, Nontuberculous/drug therapy , Mycobacterium Infections, Nontuberculous/metabolism , Mycobacterium Infections, Nontuberculous/pathology , Mycobacterium marinum/pathogenicity , Neovascularization, Pathologic/drug therapy , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Receptors, Vascular Endothelial Growth Factor/metabolism , Tuberculosis/drug therapy , Tuberculosis/microbiology , Tuberculosis/pathology , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Vascular Endothelial Growth Factor A/metabolism , Zebrafish/growth & development
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