scholarly journals Targeting CARD9 with Small-Molecule Therapeutics Inhibits Innate Immune Signaling and Inflammatory Response to Pneumocystis carinii β-Glucans

2020 ◽  
Vol 64 (11) ◽  
Author(s):  
Theodore J. Kottom ◽  
Eva M. Carmona ◽  
Andrew H. Limper
Keyword(s):  
Cell Wall ◽  
Small Molecule ◽  
Pneumocystis Carinii ◽  
Innate Immune ◽  
Necrosis Factor Alpha ◽  
Immune Signaling ◽  
Content Type ◽  
Innate Immune Signaling ◽  
Molecule Inhibitor ◽  
Small Molecule Therapeutics

ABSTRACT Pneumocystis jirovecii, the opportunistic fungus that causes Pneumocystis pneumonia (PCP) in humans, is a significant contributor to morbidity and mortality in immunocompromised patients. Given the profound deleterious inflammatory effects of the major β-glucan cell wall carbohydrate constituents of Pneumocystis through Dectin-1 engagement and downstream caspase recruitment domain-containing protein 9 (CARD9) immune activation, we sought to determine whether the pharmacodynamic activity of the known CARD9 inhibitor BRD5529 might have a therapeutic effect on macrophage innate immune signaling and subsequent downstream anti-inflammatory activity. The small-molecule inhibitor BRD5529 was able to significantly reduce both phospho-p38 and phospho-pERK1 signaling and tumor necrosis factor alpha (TNF-α) release during stimulation of macrophages with Pneumocystis cell wall β-glucans.

scholarly journals Hepacivirus NS3/4A Proteases Interfere with MAVS Signaling in both Their Cognate Animal Hosts and Humans: Implications for Zoonotic Transmission

2016 ◽  
Vol 90 (23) ◽  
pp. 10670-10681 ◽  
Author(s):  
Anggakusuma ◽  
Richard J. P. Brown ◽  
Dominic H. Banda ◽  
Daniel Todt ◽  
Gabrielle Vieyres ◽  
...  
Keyword(s):  
Mammalian Species ◽  
Companion Animals ◽  
Adaptor Protein ◽  
Innate Immune ◽  
Zoonotic Transmission ◽  
Common Mechanism ◽  
Zoonotic Potential ◽  
Immune Signaling ◽  
Content Type ◽  
Innate Immune Signaling

ABSTRACTMultiple novel members of the genusHepacivirushave recently been discovered in diverse mammalian species. However, to date, their replication mechanisms and zoonotic potential have not been explored in detail. The NS3/4A serine protease of hepatitis C virus (HCV) is critical for cleavage of the viral polyprotein. It also cleaves the cellular innate immune adaptor MAVS, thus decreasing interferon (IFN) production and contributing to HCV persistence in the human host. To investigate the conservation of fundamental aspects of the hepaciviral life cycle, we explored if MAVS cleavage and suppression of innate immune signaling represent a common mechanism employed across different clades of the genusHepacivirusto enhance viral replication. To estimate the zoonotic potential of these nonhuman hepaciviruses, we assessed if their NS3/4A proteases were capable of cleaving human MAVS. NS3/4A proteases of viruses infecting colobus monkeys, rodents, horses, and cows cleaved the MAVS proteins of their cognate hosts and interfered with the ability of MAVS to induce the IFN-β promoter. All NS3/4A proteases from nonhuman viruses readily cleaved human MAVS. Thus, NS3/4A-dependent cleavage of MAVS is a conserved replication strategy across multiple clades within the genusHepacivirus. Human MAVS is susceptible to cleavage by these nonhuman viral proteases, indicating that it does not pose a barrier for zoonotic transmission of these viruses to humans.IMPORTANCEVirus infection is recognized by cellular sensor proteins triggering innate immune signaling and antiviral defenses. While viruses have evolved strategies to thwart these antiviral programs in their cognate host species, these evasion mechanisms are often ineffective in a novel host, thus limiting viral transmission across species. HCV, the best-characterized member of the genusHepaciviruswithin the familyFlaviviridae, uses its NS3/4A protease to disrupt innate immune signaling by cleaving the cellular adaptor protein MAVS. Recently, a large number of HCV-related viruses have been discovered in various animal species, including wild, livestock, and companion animals. We show that the NS3/4A proteases of these hepaciviruses from different animals and representing various clades of the genus cleave their cognate host MAVS proteins in addition to human MAVS. Therefore, cleavage of MAVS is a common strategy of hepaciviruses, and human MAVS is likely unable to limit replication of these nonhuman viruses upon zoonotic exposure.

scholarly journals Critical Role for MyD88-Mediated Neutrophil Recruitment during Clostridium difficile Colitis

2012 ◽  
Vol 80 (9) ◽  
pp. 2989-2996 ◽  
Author(s):  
Irene Jarchum ◽  
Mingyu Liu ◽  
Chao Shi ◽  
Michele Equinda ◽  
Eric G. Pamer
Keyword(s):  
Clostridium Difficile ◽  
Inflammatory Responses ◽  
Adaptor Protein ◽  
Neutrophil Recruitment ◽  
Innate Immune ◽  
Antibiotic Administration ◽  
Immune Signaling ◽  
Content Type ◽  
Innate Immune Signaling ◽  
Deficient Mice

ABSTRACTClostridium difficilecan infect the large intestine and cause colitis when the normal intestinal microbiota is altered by antibiotic administration. Little is known about the innate immune signaling pathways that marshal inflammatory responses toC. difficileinfection and whether protective and pathogenic inflammatory responses can be dissociated. Toll-like receptors predominantly signal via the MyD88 adaptor protein and are important mediators of innate immune signaling in the intestinal mucosa. Here, we demonstrate that MyD88-mediated signals trigger neutrophil and CCR2-dependent Ly6Chimonocyte recruitment to the colonic lamina propria (cLP) during infection, which prevent dissemination of bystander bacteria to deeper tissues. Mortality is markedly increased in MyD88-deficient mice followingC. difficileinfection, as are parameters of mucosal tissue damage and inflammation. Antibody-mediated depletion of neutrophils markedly increases mortality, while attenuated recruitment of Ly6Chimonocytes in CCR2-deficient mice does not alter the course ofC. difficileinfection. Expression of CXCL1, a neutrophil-recruiting chemokine, is impaired in the cLP of MyD88−/−mice. Our studies suggest that MyD88-mediated signals promote neutrophil recruitment by inducing expression of CXCL1, thereby providing critical early defense againstC. difficile-mediated colitis.

scholarly journals KDM6B overexpression activates innate immune signaling and impairs hematopoiesis in mice

2018 ◽  
Vol 2 (19) ◽  
pp. 2491-2504 ◽  
Author(s):  
Yue Wei ◽  
Hong Zheng ◽  
Naran Bao ◽  
Shan Jiang ◽  
Carlos E. Bueso-Ramos ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Therapeutic Potential ◽  
Innate Immune ◽  
Immune Stimulation ◽  
Immune Signaling ◽  
Hematopoietic Stem ◽  
Innate Immune Signaling ◽  
Molecule Inhibitor ◽  
Stem And Progenitor Cells ◽  
Myelomonocytic Leukemia

Abstract KDM6B is an epigenetic regulator that mediates transcriptional activation during differentiation, including in bone marrow (BM) hematopoietic stem and progenitor cells (HSPCs). Overexpression of KDM6B has been reported in BM HSPCs of patients with myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). Whether the overexpression of KDM6B contributes to the pathogenesis of these diseases remains to be elucidated. To study this, we generated a Vav-KDM6B mouse model, which overexpresses KDM6B in the hematopoietic compartment. KDM6B overexpression alone led to mild hematopoietic phenotype, and chronic innate immune stimulation of Vav-KDM6B mice with the Toll-like receptor (TLR) ligand lipopolysaccharide (LPS) resulted in significant hematopoietic defects. These defects recapitulated features of MDS and CMML, including leukopenia, dysplasia, and compromised repopulating function of BM HSPCs. Transcriptome studies indicated that KDM6B overexpression alone could lead to activation of disease-relevant genes such as S100a9 in BM HSPCs, and when combined with innate immune stimulation, KDM6B overexpression resulted in more profound overexpression of innate immune and disease-relevant genes, indicating that KDM6B was involved in the activation of innate immune signaling in BM HSPCs. Finally, pharmacologic inhibition of KDM6B with the small molecule inhibitor GSK-J4 ameliorated the ineffective hematopoiesis observed in Vav-KDM6B mice. This effect was also observed when GSK-J4 was applied to the primary BM HSPCs of patients with MDS by improving their repopulating function. These results indicate that overexpression of KDM6B mediates activation of innate immune signals and has a role in MDS and CMML pathogenesis, and that KDM6B targeting has therapeutic potential in these myeloid disorders.

scholarly journals Evidence for Proinflammatory β-1,6 Glucans in the Pneumocystis carinii Cell Wall

2015 ◽  
Vol 83 (7) ◽  
pp. 2816-2826 ◽  
Author(s):  
Theodore J. Kottom ◽  
Deanne M. Hebrink ◽  
Paige E. Jenson ◽  
Gunnar Gudmundsson ◽  
Andrew H. Limper
Keyword(s):  
Cell Wall ◽  
Inflammatory Responses ◽  
Pneumocystis Carinii ◽  
Necrosis Factor Alpha ◽  
Cellular Activation ◽  
Respiratory Impairment ◽  
Glucan Synthase ◽  
Content Type ◽  
Membrane Microdomain ◽  
Cell Plasma

Inflammation is a major cause of respiratory impairment duringPneumocystispneumonia. Studies support a significant role for cell wall β-glucans in stimulating inflammatory responses. Fungal β-glucans are comprised ofd-glucose homopolymers containing β-1,3-linked glucose backbones with β-1,6-linked glucose side chains. Prior studies inPneumocystis cariniihave characterized β-1,3 glucan components of the organism. However, recent investigations in other organisms support important roles for β-1,6 glucans, predominantly in mediating host cellular activation. Accordingly, we sought to characterize β-1,6 glucans in the cell wall ofPneumocystisand to establish their activity in lung cell inflammation. Immune staining revealed specific β-1,6 localization inP. cariniicyst walls. Homology-based cloning facilitated characterization of a functionalP. cariniikre6(Pckre6) β-1,6 glucan synthase inPneumocystisthat, when expressed inkre6-deficientSaccharomyces cerevisiae, restored cell wall stability. Recently synthesized β-1,6 glucan synthase inhibitors decreased the ability of isolatedP. cariniipreparations to generate β-1,6 carbohydrate. In addition, isolated β-1,6 glucan fractions fromPneumocystiselicited vigorous tumor necrosis factor alpha (TNF-α) responses from macrophages. These inflammatory responses were significantly dampened by inhibition of host cell plasma membrane microdomain function. Together, these studies indicate that β-1,6 glucans are present in theP. cariniicell wall and contribute to lung cell inflammatory activation during infection.

scholarly journals Hexa-Acylated Lipid A Is Required for Host Inflammatory Response to Neisseria gonorrhoeae in Experimental Gonorrhea

2013 ◽  
Vol 82 (1) ◽  
pp. 184-192 ◽  
Author(s):  
Xiyou Zhou ◽  
Xi Gao ◽  
Peter M. Broglie ◽  
Chahnaz Kebaier ◽  
James E. Anderson ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Lipid A ◽  
Innate Immune ◽  
Immune Recognition ◽  
Toll Like Receptor ◽  
Inflammatory Signaling ◽  
Toll Like Receptor 4 ◽  
Immune Signaling ◽  
Content Type ◽  
Innate Immune Signaling

ABSTRACTNeisseria gonorrhoeaecauses gonorrhea, a sexually transmitted infection characterized by inflammation of the cervix or urethra. However, a significant subset of patients withN. gonorrhoeaeremain asymptomatic, without evidence of localized inflammation. Inflammatory responses toN. gonorrhoeaeare generated by host innate immune recognition ofN. gonorrhoeaeby several innate immune signaling pathways, including lipooligosaccharide (LOS) and other pathogen-derived molecules through activation of innate immune signaling systems, including toll-like receptor 4 (TLR4) and the interleukin-1β (IL-1β) processing complex known as the inflammasome. The lipooligosaccharide ofN. gonorrhoeaehas a hexa-acylated lipid A.N. gonorrhoeaestrains that carry an inactivatedmsbB(also known aslpxL1) gene produce a penta-acylated lipid A and exhibit reduced biofilm formation, survival in epithelial cells, and induction of epithelial cell inflammatory signaling. We now show thatmsbB-deficientN. gonorrhoeaeinduces less inflammatory signaling in human monocytic cell lines and murine macrophages than the parent organism. The penta-acylated LOS exhibits reduced toll-like receptor 4 signaling but does not affectN. gonorrhoeae-mediated activation of the inflammasome. We demonstrate thatN. gonorrhoeaemsbBis dispensable for initiating and maintaining infection in a murine model of gonorrhea. Interestingly, infection withmsbB-deficientN. gonorrhoeaeis associated with less localized inflammation. Combined, these data suggest that TLR4-mediated recognition ofN. gonorrhoeaeLOS plays an important role in the pathogenesis of symptomatic gonorrhea infection and that alterations in lipid A biosynthesis may play a role in determining symptomatic and asymptomatic infections.

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