Mitofusin 2-Deficiency Suppresses Mycobacterium tuberculosis Survival in Macrophages

Apoptosis is an important host defense mechanism against mycobacterial infection. However, the molecular mechanisms regulating apoptosis during mycobacterial infection are not well known. Recent reports suggest that bacterial infection regulates mitochondrial fusion and fission in various ways. Here, we investigated the role of mitochondria in Mycobacterium tuberculosis (Mtb)-infected macrophages. Mtb H37Rv (Rv) infection induced mitofusin 2 (MFN2) degradation, leading to mitochondrial fission. Interestingly, Mtb H37Ra (Ra) infection induced significantly greater mitochondrial fragmentation than Rv infection. Mtb-mediated Parkin, an E3 ubiquitin ligase, contributed to the degradation of MFN2. To evaluate the role of endoplasmic reticulum stress in the production of Parkin during Mtb infection, we analyzed Parkin production in 4-phenylbutyric acid (4-PBA)-pretreated macrophages. Pretreatment with 4-PBA reduced Parkin production in Mtb-infected macrophages. In contrast, the level of MFN2 production recovered to a level similar to that of the unstimulated control. In addition, Ra-infected macrophages had reduced mitochondrial membrane potential (MMP) compared to those infected with Rv. Interestingly, intracellular survival of mycobacteria was decreased in siMFN2-transfected macrophages; in contrast, overexpression of MFN2 in macrophages increased Mtb growth compared with the control.

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Dram1 confers resistance to Salmonella infection

10.1101/2021.03.21.436194 ◽

2021 ◽

Author(s):

Samrah Masud ◽

Rui Zhang ◽

Tomasz K. Prajsnar ◽

Annemarie H. Meijer

Keyword(s):

Defense Mechanism ◽

Early Response ◽

Protective Role ◽

Infection Model ◽

Transgenic Zebrafish ◽

Functional Link ◽

Morpholino Knockdown ◽

Host Defense Mechanism ◽

Important Host

Dram1 is a stress and infection inducible autophagy modulator that functions downstream of transcription factors p53 and NFκB. Using a zebrafish embryo infection model, we have previously shown that Dram1 provides protection against the intracellular pathogen Mycobacterium marinum by promoting the p62-dependent xenophagy of bacteria that have escaped into the cytosol. However, the possible interplay between Dram1 and other anti-bacterial autophagic mechanisms remains unknown. Recently, LC3-associated phagocytosis (LAP) has emerged as an important host defense mechanism that requires components of the autophagy machinery and targets bacteria directly in phagosomes. Our previous work established LAP as the main autophagic mechanism by which macrophages restrict growth of Salmonella Typhimurium in a systemically infected zebrafish host. We therefore employed this infection model to investigate the possible role of Dram1 in LAP. Morpholino knockdown or CRISPR/Cas9-mediated mutation of Dram1 led to reduced host survival and increased bacterial burden during S. Typhimurium infections. In contrast, overexpression of dram1 by mRNA injection curtailed Salmonella replication and reduced mortality of the infected host. During the early response to infection, GFP-Lc3 levels in transgenic zebrafish larvae correlated with the dram1 expression level, showing over two-fold reduction of GFP-Lc3-Salmonella association in dram1 knockdown or mutant embryos and an approximately 30% increase by dram1 overexpression. Since LAP is known to require the activity of the phagosomal NADPH oxidase, we used a Salmonella biosensor strain to detect bacterial exposure to reactive oxygen species (ROS) and found that the ROS response was largely abolished in the absence of dram1. Together, these results demonstrate the host protective role of Dram1 during S. Typhimurium infection and suggest a functional link between Dram1 and the induction of LAP.

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The IL-33-ILC2 pathway protects from amebic colitis

Mucosal Immunology ◽

10.1038/s41385-021-00442-2 ◽

2021 ◽

Author(s):

Md Jashim Uddin ◽

Jhansi L. Leslie ◽

Stacey L. Burgess ◽

Noah Oakland ◽

Brandon Thompson ◽

...

Keyword(s):

Tissue Damage ◽

Cell Injury ◽

Defense Mechanism ◽

Protozoan Parasite ◽

Lymphoid Cells ◽

Amebic Colitis ◽

Host Defense Mechanism ◽

Important Host ◽

Murine Colon

AbstractEntamoeba histolytica is a pathogenic protozoan parasite that causes intestinal colitis, diarrhea, and in some cases, liver abscess. Through transcriptomics analysis, we observed that E. histolytica infection was associated with increased expression of IL-33 mRNA in both the human and murine colon. IL-33, the IL-1 family cytokine, is released after cell injury to alert the immune system of tissue damage. Treatment with recombinant IL-33 protected mice from amebic infection and intestinal tissue damage; moreover, blocking IL-33 signaling made mice more susceptible to amebiasis. IL-33 limited the recruitment of inflammatory immune cells and decreased the pro-inflammatory cytokine IL-6 in the cecum. Type 2 immune responses were upregulated by IL-33 treatment during amebic infection. Interestingly, administration of IL-33 protected RAG2–/– mice but not RAG2−/−γc−/− mice, demonstrating that IL-33-mediated protection required the presence of innate lymphoid cells (ILCs). IL-33 induced recruitment of ILC2 but not ILC1 and ILC3 in RAG2−/− mice. At baseline and after amebic infection, there was a significantly higher IL13+ILC2s in C57BL/J mice, which are naturally resistant to amebiasis, than CBA/J mice. Adoptive transfer of ILC2s to RAG2−/−γc−/− mice restored IL-33-mediated protection. These data reveal that the IL-33-ILC2 pathway is an important host defense mechanism against amebic colitis.

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Lactobacillus inhibitor production against Escherichia coli and coaggregation ability with uropathogens

Canadian Journal of Microbiology ◽

10.1139/m88-063 ◽

1988 ◽

Vol 34 (3) ◽

pp. 344-351 ◽

Cited By ~ 159

Author(s):

Gregor Reid ◽

Jacqueline A. McGroarty ◽

Rosanne Angotti ◽

Roger L. Cook

Keyword(s):

Escherichia Coli ◽

Defense Mechanism ◽

Inhibitory Effect ◽

Second Phase ◽

Vitro Assay ◽

E Coli ◽

Host Defense Mechanism ◽

Important Host ◽

Two Phases

Previous investigations have shown that certain strains of lactobacilli can competitively exclude uropathogens from attaching to uroepithelial cells and from causing urinary tract infection in animals. The finding of an inhibitory effect produced by Lactobacillus casei ssp. rhamnosus GR-1 against the growth of uropathogens was investigated further using two Escherichia coli indicator strains Hu 734 and ATCC 25922. There were two phases to the inhibitor studies. The first one using an agar sandwich technique showed that the inhibitor activity was heat stable and inhibitory to the E. coli. The second phase showed that MRS broth provided optimum lactobacilli growth and inhibitor production. In addition, the inhibition was present under conditions buffering for acid and pH. The data indicated that the inhibitory effect was not due to bacteriophages or hydrogen peroxide. Strain GR-1 was found to coaggregate with E. coli ATCC 25922 in urine, a phenomenon that has not previously been reported for urogenital bacteria. An in vitro assay system was developed to study the coaggregation of various lactobacilli and uropathogens. The results demonstrated that highest coaggregation scores occurred after 4 h incubation at 37 °C with lactobacilli and two type-1 fimbriated E. coli strains. Of the nine lactobacilli strains tested, each was found to coaggregate with 2 or more of the 13 uropathogens. The dominance of inhibitor-producing lactobacilli on the urogenital epithelium and the ability of these organisms to interact closely with uropathogens would constitute an important host defense mechanism against infection.

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MARCO+ lymphatic endothelial cells sequester arboviruses to limit viremia and viral dissemination

10.1101/2021.06.10.447957 ◽

2021 ◽

Author(s):

Kathryn S Carpentier ◽

Ryan M Sheridan ◽

Cormac J Lucas ◽

Bennett J Davenport ◽

Frances S Li ◽

...

Keyword(s):

Endothelial Cells ◽

Defense Mechanism ◽

Scavenger Receptor ◽

Transmission Efficiency ◽

Lymphatic Endothelial Cells ◽

Viral Dissemination ◽

Viral Spread ◽

Host Defense Mechanism ◽

Important Host ◽

Draining Lymph Node

While viremia in the vertebrate host is a major determinant of arboviral reservoir competency, transmission efficiency, and disease severity, immune mechanisms that control arboviral viremia are poorly defined. Here, we identify critical roles for the scavenger receptor MARCO in controlling viremia during arthritogenic alphavirus infections in mice. Following subcutaneous inoculation, alphavirus particles drain via the lymph and are rapidly captured by MARCO+ lymphatic endothelial cells (LECs) in the draining lymph node (dLN), limiting viral spread to the bloodstream. Upon reaching the bloodstream, alphavirus particles are cleared from the circulation by MARCO-expressing Kupffer cells in the liver, limiting viremia and further viral dissemination. MARCO-mediated accumulation of alphavirus particles in the dLN and liver is an important host defense mechanism as viremia and viral tissue burdens are elevated in MARCO-/- mice and disease is more severe. These findings uncover a previously unrecognized arbovirus scavenging role for LECs and improve our mechanistic understanding of viremia control during arboviral infections.

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Alterations in serum opsonic activity and complement levels in pneumococcal disease

Infection and Immunity ◽

10.1128/iai.29.3.1062-1066.1980 ◽

1980 ◽

Vol 29 (3) ◽

pp. 1062-1066

Author(s):

G S Giebink ◽

T H Dee ◽

Y Kim ◽

P G Quie

Keyword(s):

Host Defense ◽

Complement Activation ◽

Pneumococcal Disease ◽

Capsular Polysaccharide ◽

Defense Mechanism ◽

Polysaccharide Antigen ◽

Opsonic Activity ◽

Factor B ◽

Host Defense Mechanism ◽

Important Host

Pneumococcal opsonic activity and concentrations of pneumococcal capsular polysaccharide antigen, C3, C4 factor B, C3 and factor B breakdown products were measured in the serum obtained acutely from 12 patients with serious pneumococcal disease. One patient showed markedly reduced pneumococcal opsonic activity, borderline-low C3, and the presence of C3 and factor B breakdown products and died. Although eight additional patients showed depressed levels of C3 or C4 or the presence of C3 or factor B breakdown products, none had reduced pneumococcal opsonic activity. All of the three remaining patients had normal opsonic activity and C3 and C4 levels. Covalescent serum was obtained from eight patients; six had normal C3 and C4 levels, and two had persistent C4 depression. These data show that complement is activated during pneumococcal disease and suggest that extensive complement activation may impair pneumococcal opsonic activity in certain patients and thereby compromise an important host defense mechanism.

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GPR183 regulates interferons and bacterial growth during Mycobacterium tuberculosis infection: interaction with type 2 diabetes and TB disease severity

10.1101/2020.07.15.203398 ◽

2020 ◽

Cited By ~ 1

Author(s):

Stacey Bartlett ◽

Adrian Tandhyka Gemiarto ◽

Minh Dao Ngo ◽

Haressh Sajiir ◽

Semira Hailu ◽

...

Keyword(s):

Type 2 Diabetes ◽

Mycobacterium Tuberculosis ◽

Disease Severity ◽

Mycobacterial Infection ◽

Mycobacterium Tuberculosis Infection ◽

Important Regulator ◽

Chest X Ray ◽

Mycobacterial Growth

AbstractOxidized cholesterols have emerged as important signaling molecules of immune function, but little is known about the role of these oxysterols during mycobacterial infections. We found that expression of the oxysterol-receptor GPR183 was reduced in blood from patients with tuberculosis (TB) and type 2 diabetes (T2D) compared to TB patients without T2D and was associated with TB disease severity on chest x-ray. GPR183 activation by 7α,25-hydroxycholesterol (7α,25-OHC) reduced growth of Mycobacterium tuberculosis (Mtb) and Mycobacterium bovis BCG in primary human monocytes, an effect abrogated by the GPR183 antagonist GSK682753. Growth inhibition was associated with reduced IFN-β and IL-10 expression and enhanced autophagy. Mice lacking GPR183 had significantly increased lung Mtb burden and dysregulated IFNs during early infection. Together, our data demonstrate that GPR183 is an important regulator of intracellular mycobacterial growth and interferons during mycobacterial infection.Graphical Abstract

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Connecting the dots: Translating the vaginal microbiome into a drug

The Journal of Infectious Diseases ◽

10.1093/infdis/jiaa676 ◽

2020 ◽

Author(s):

Laurel A Lagenaur ◽

Anke Hemmerling ◽

Charles Chiu ◽

Steve Miller ◽

Peter P Lee ◽

...

Keyword(s):

Defense Mechanism ◽

Treatment Options ◽

Interesting Case ◽

Vaginal Microbiota ◽

Lactobacillus Species ◽

Obstetric Outcomes ◽

Urogenital Infections ◽

Host Defense Mechanism ◽

Important Host ◽

New Treatment

Abstract A Lactobacillus-dominated vaginal microbiota (VMB) has been associated with health and considered an important host defense mechanism against urogenital infections. Conversely, depletion of lactobacilli and increased microbial diversity, or dysbiosis, increases the risk of adverse gynecologic and obstetric outcomes. A common clinical condition that exemplifies dysbiosis is bacterial vaginosis (BV). BV is currently treated with antibiotics, but frequently recurs, due in part to persistent dysbiosis and failure of endogenous lactobacilli to repopulate the vagina. New treatment options are therefore needed to address recurrent urogenital infections, including BV. The VMB represents an interesting case study for the development of microbiome-based therapeutics. Compared to the gut, the vaginal microbiota is relatively simple and optimally dominated by one or several species of one genus, i.e. Lactobacillus. Further, hydrogen peroxide (H2O2)-producing species, such as L. crispatus, show the strongest associations with vaginal health and are depleted in dysbiosis. Thus, replenishing the dysbiotic VMB with protective vaginal Lactobacillus species could be a promising approach to prevent recurrent infections and improve women’s health. In this article we discuss confirmation of this approach with the microbiome-based biologic drug, LACTIN-V (Lactobacillus crispatus CTV-05), focusing on prevention of BV recurrence.

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Phagocytosis and the microtubule cytoskeleton

Biochemistry and Cell Biology ◽

10.1139/o02-142 ◽

2002 ◽

Vol 80 (5) ◽

pp. 509-515 ◽

Cited By ~ 35

Author(s):

Rene E Harrison ◽

Sergio Grinstein

Keyword(s):

Host Defense ◽

Defense Mechanism ◽

Fc Receptor ◽

Signaling Proteins ◽

Microtubule Cytoskeleton ◽

Complex Sequence ◽

Sequence Of Events ◽

Host Defense Mechanism

Phagocytosis is a critical host defense mechanism used by macrophages and neutrophils to clear invading pathogens. The complex sequence of events resulting in internalization and degradation of the pathogens is a coordinated process involving lipids, signaling proteins, and the cytoskeleton. Here, we examine the role of the microtubule cytoskeleton in supporting both the engulfment of pathogens and their elimination within phagolysosomes.Key words: macrophage, microtubule, phagocytosis, maturation, Fc receptor.

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