scholarly journals In vivo single cell transcriptomics reveals Klebsiella pneumoniae rewiring of lung macrophages to promote infection

2021 ◽  
Author(s):  
Amy Dumigan ◽  
Oisin Cappa ◽  
Brenda Morris ◽  
Joana sa-Pessoa Graca Santos ◽  
Ricardo Calderon-Gonzalez ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Single Cell ◽  
Macrophage Polarization ◽  
Resistant Bacteria ◽  
Human Macrophage ◽  
Type I ◽  
Dependent Manner ◽  
Type I Ifn ◽  
Lung Macrophages

The strategies deployed by antibiotic resistant bacteria to counteract host defences are poorly understood. Here, we elucidate a novel host-pathogen interaction that results in the control of lung macrophage polarisation by the human pathogen Klebsiella pneumoniae. We identify interstitial macrophages (IMs) as the main population of lung macrophages associated with Klebsiella. Single cell transcriptomics and trajectory analysis of cells uncover that type I IFN and IL10 signalling, and macrophage polarization are characteristic of infected IMs, whereas Toll-like receptor (TLR) and Nod-like receptor signalling are features of infected alveolar macrophages. Klebsiella-induced macrophage polarization is a singular M2-type we termed M(Kp). To rewire macrophages towards M(Kp), K. pneumoniae hijacks a hitherto unknown TLR-type I IFN-IL10-STAT6 innate axis. Absence of STAT6 limits the intracellular survival of Klebsiella whereas the inhibition of STAT6 facilitates the clearance of the pathogen in vivo. Glycolysis characterises M(Kp) metabolism, and inhibition of glycolysis results in clearance of intracellular Klebsiella. We demonstrate the capsule polysaccharide is the Klebsiella factor governing M(Kp). Klebsiella also skews human macrophage polarization towards M(Kp) in a type I IFN-IL10-STAT6-dependent manner. Altogether, our work demonstrates that Klebsiella induction of M(Kp) represents a hitherto unknown strategy to overcome host restriction during pneumonia.

scholarly journals Induction of type I interferons and interferon-inducible Mx genes during respiratory syncytial virus infection and reinfection in cotton rats

2008 ◽  
Vol 89 (1) ◽  
pp. 261-270 ◽  
Author(s):  
Lioubov M. Pletneva ◽  
Otto Haller ◽  
David D. Porter ◽  
Gregory A. Prince ◽  
Jorge C. G. Blanco
Keyword(s):  
Gene Expression ◽  
Respiratory Syncytial Virus ◽  
Virus Replication ◽  
Surrogate Marker ◽  
Type I Interferons ◽  
Type I ◽  
Dependent Manner ◽  
Type I Ifn ◽  
Syncytial Virus

Respiratory syncytial virus (RSV) is the primary cause of bronchiolitis in young children. In general, RSV is considered to be a poor inducer of type I (alpha/beta) interferons (IFNs). Measurement of active type I IFN production during infection in vivo is demanding, as multiple IFN subtypes with overlapping activities are produced. In contrast, Mx gene expression, which is tightly regulated by type I IFN expression, is easily determined. This study therefore measured Mx expression as a reliable surrogate marker of type I IFN activity during RSV infection in vivo in a cotton rat model. It was shown that expression of Mx genes was dramatically augmented in the lungs of infected animals in a dose- and virus strain-dependent manner. The expression of Mx genes in the lungs was paralleled by their induction in the nose and spleen, although in spleen no simultaneous virus gene expression was detected. Reinfection of RSV-immune animals leads to abortive virus replication in the lungs. Thus, type I IFN and Mx gene expression was triggered in reinfected animals, even though virus could not be isolated from their lungs. Furthermore, it was demonstrated that immunity to RSV wanes with time. Virus replication and Mx gene expression became more prominent with increasing intervals between primary infection and reinfection. These results highlight the role of type I IFN in modulation of the immune response to RSV.

scholarly journals Cardif-Mediated Signaling Controls the Initial Innate Response to Dengue Virus In Vivo

2009 ◽  
Vol 83 (16) ◽  
pp. 8276-8281 ◽  
Author(s):  
Stuart T. Perry ◽  
Tyler R. Prestwood ◽  
Steven M. Lada ◽  
Chris A. Benedict ◽  
Sujan Shresta
Keyword(s):  
Dengue Virus ◽  
Denv Infection ◽  
Lymphoid Tissues ◽  
Type I ◽  
Dependent Manner ◽  
Type I Ifn ◽  
Wild Type ◽  
Innate Defense ◽  
Viral Loads

ABSTRACT The role of Cardif-dependent signaling in controlling dengue virus (DENV) infection and regulating type I interferon (IFN) production in vivo was examined in Cardif-deficient mice. DENV RNA levels were significantly elevated in both the serum and lymphoid tissues of Cardif−/− mice at early times compared to those in wild-type animals. Type I IFN production was delayed in these locales of Cardif−/− mice until 18 h postinfection, indicating that Cardif regulates the initial type I IFN response in lymphoid tissues. In contrast, DENV viral loads in nonlymphoid tissues were similar between Cardif−/− and wild-type mice. These results reveal that RNA helicase-mediated sensing acts as a first line of innate defense against DENV infection in vivo and functions in a tissue-dependent manner.

scholarly journals Klebsiella pneumoniae hijacks the Toll-IL-1R protein SARM1 in a type I IFN-dependent manner to antagonize host immunity.

2021 ◽  
Author(s):  
Claudia Feriotti ◽  
Joana sa-Pessoa Graca Santos ◽  
Ricardo Calderon-Gonzalez ◽  
Lili Gu ◽  
Brenda Morris ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Map Kinases ◽  
Control Cell ◽  
Effector Proteins ◽  
Fine Tuning ◽  
Type I ◽  
Dependent Manner ◽  
Type I Ifn ◽  
Type I Ifns ◽  
Open Question

Many bacterial pathogens antagonize host defence responses by translocating effector proteins into cells. It remains an open question how those pathogens not encoding effectors counteract anti-bacterial immunity. Here, we show that Klebsiella pneumoniae hijacks the evolutionary conserved innate immune protein SARM1 to control cell intrinsic immunity. Klebsiella exploits SARM1 to regulate negatively MyD88 and TRIF-governed inflammation, and the activation of the MAP kinases ERK and JNK. SARM1 is required for Klebsiella induction of IL10 by fine-tuning the p38-type I IFN axis. SARM1 inhibits the activation of Klebsiella-induced absent in melanoma 2 inflammasome to limit IL1β production, suppressing further inflammation. Klebsiella exploits type I IFNs to induce SARM1 in a capsule and LPS O-polysaccharide-dependent manner via TLR4-TRAM-TRIF-IRF3-IFNAR1 pathway. Absence of SARM1 reduces the intracellular survival of K. pneumonaie in macrophages whereas sarm1 deficient mice control the infection. Altogether, our results illustrate a hitherto unknown anti-immunology strategy deployed by a human pathogen.

Effects of Berberine on Expression of LOX-1 and SR-BI in Human Macrophage-Derived Foam Cells Induced by ox-LDL

2010 ◽  
Vol 38 (06) ◽  
pp. 1161-1169 ◽  
Author(s):  
Siming Guan ◽  
Bin Wang ◽  
Wei Li ◽  
Jinghuan Guan ◽  
Xin Fang
Keyword(s):  
Scavenger Receptor ◽  
Ldl Receptor ◽  
Foam Cells ◽  
Time Dependent ◽  
Human Macrophage ◽  
Type I ◽  
Dependent Manner ◽  
Atp Binding Cassette Transporter ◽  
Abca1 Expression ◽  
Class B

This study investigates the effects of beriberine on the expression of lectin-like ox-LDL receptor-1 (LOX-1), scavenger receptor A (SR-A), SR class B type I (SR-BI) and ATP-binding cassette transporter A1 (ABCA1) in human macrophage-derived foam cells induced by ox-LDL. Different concentrations of Berberine were co-cultured with THP-1 derived foam cells. The mRNA and protein expressions of LOX-1, SR-A, SR-BI and ABCA1 were determined by RT-PCR and Western blot analysis, respectively. Ox-LDL significantly increased the expression of LOX-1 and inhibited the expression of SR-BI in a dose- and time-dependent manner. Berberine significantly inhibited the effects of ox-LDL in a dose- and time-dependent manner. Moreover, ox-LDL significantly promoted ABCA1 expression. However, berberine had no effect on SR-A or ABCA1 expression. Berberine can inhibit the expression of LOX-1 and promote the expression of SR-BI in macrophage-derived foam cells. Therefore, berberine could be used to treat atherosclerotic diseases.

A novel mouse model based on intersectional genetics enables unambiguous in vivo discrimination between plasmacytoid and other dendritic cells and their comparative characterization

2022 ◽  
Author(s):  
Michael Valente ◽  
Nils Collinet ◽  
Thien-Phong Vu Manh ◽  
Karima Naciri ◽  
Gilles Bessou ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Steady State ◽  
Mouse Model ◽  
Single Cell ◽  
Ex Vivo ◽  
High Specificity ◽  
Type I ◽  
Specific Expression ◽  
Physiological Functions

Plasmacytoid dendritic cells (pDC) were identified about 20 years ago, based on their unique ability to rapidly produce copious amounts of all subsets of type I and type III interferon (IFN-I/III) upon virus sensing, while being refractory to infection. Yet, the identity and physiological functions of pDC are still a matter of debate, in a large part due to their lack of specific expression of any single cell surface marker or gene that would allow to track them in tissues and to target them in vivo with high specificity and penetrance. Indeed, recent studies showed that previous methods that were used to identify or deplete pDC also targeted other cell types, including pDC-like cells and transitional DC (tDC) that were proposed to be responsible for all the antigen presentation ability previously attributed to steady state pDC. Hence, improving our understanding of the nature and in vivo choreography of pDC physiological functions requires the development of novel tools to unambiguously identify and track these cells, including in comparison to pDC-like cells and tDC. Here, we report successful generation of a pDC-reporter mouse model, by using an intersectional genetic strategy based on the unique co-expression of Siglech and Pacsin1 in pDC. This pDC-Tomato mouse strain allows specific ex vivo and in situ detection of pDC. Breeding them with Zbtb46GFP mice allowed side-by-side purification and transcriptional profiling by single cell RNA sequencing of bona fide pDC, pDC-like cells and tDC, in comparison to type 1 and 2 conventional DC (cDC1 and cDC2), both at steady state and during a viral infection, revealing diverging activation patterns of pDC-like cells and tDC. Finally, by breeding pDC-Tomato mice with Ifnb1EYFP mice, we determined the choreography of pDC recruitment to the micro-anatomical sites of viral replication in the spleen, with initially similar but later divergent behaviors of the pDC that engaged or not into IFN-I production. Our novel pDC-Tomato mouse model, and newly identified gene modules specific to combinations of DC types and activations states, will constitute valuable resources for a deeper understanding of the functional division of labor between DC types and its molecular regulation at homeostasis and during viral infections.

scholarly journals MicroRNA-132-3p suppresses type I IFN response through targeting IRF1 to facilitate H1N1 influenza A virus infection

2019 ◽  
Vol 39 (12) ◽  
Author(s):  
Fangyi Zhang ◽  
Xuefeng Lin ◽  
Xiaodong Yang ◽  
Guangjian Lu ◽  
Qunmei Zhang ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Peripheral Blood ◽  
Influenza A ◽  
Expression Profiles ◽  
Protein A ◽  
H1n1 Influenza ◽  
Type I ◽  
Dependent Manner ◽  
Type I Ifn

Abstract Increasing evidence has indicated that microRNAs (miRNAs) have essential roles in innate immune responses to various viral infections; however, the role of miRNAs in H1N1 influenza A virus (IAV) infection is still unclear. The present study aimed to elucidate the role and mechanism of miRNAs in IAV replication in vitro. Using a microarray assay, we analyzed the expression profiles of miRNAs in peripheral blood from IAV patients. It was found that miR-132-3p was significantly up-regulated in peripheral blood samples from IAV patients. It was also observed that IAV infection up-regulated the expression of miR-132-3p in a dose- and time-dependent manner. Subsequently, we investigated miR-132-3p function and found that up-regulation of miR-132-3p promoted IAV replication, whereas knockdown of miR-132-3p repressed replication. Meanwhile, overexpression of miR-132-3p could inhibit IAV triggered INF-α and INF-β production and IFN-stimulated gene (ISG) expression, including myxovirus protein A (MxA), 2′,5′-oligoadenylate synthetases (OAS), and double-stranded RNA-dependent protein kinase (PKR), while inhibition of miR-132-3p enhanced IAV triggered these effects. Of note, interferon regulatory factor 1 (IRF1), a well-known regulator of the type I IFN response, was identified as a direct target of miR-132-3p during HIN1 IAV infection. Furthermore, knockdown of IRF1 by si-IRF1 reversed the promoting effects of miR-132-3p inhibition on type I IFN response. Taken together, up-regulation of miR-132-3p promotes IAV replication by suppressing type I IFN response through its target gene IRF1, suggesting that miR-132-3p could represent a novel potential therapeutic target of IAV treatment.

scholarly journals Innate triggering and antiviral effector functions of activin A

2021 ◽  
Author(s):  
Kinda Al-Hourani ◽  
Narayan Ramamurthy ◽  
Emanuele Marchi ◽  
Ruth M Eichinger ◽  
Lian N Lee ◽  
...  
Keyword(s):  
Viral Infection ◽  
Influenza A ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Activin A ◽  
Type I ◽  
Type I Ifn ◽  
Effector Functions

First-line defence against viral infection is contingent upon rapid detection of conserved viral structural and genomic motifs by germline-encoded pattern recognition receptors, followed by activation of the type I IFN system and establishment of an intracellular antiviral state. Novel antiviral functions of bone morphogenetic protein and related activin cytokines, acting in conjunction with, and independently of, type I IFN, have recently been described. Activin A mediates multiple innate and adaptive immune functions, including antiviral effects. However, how such effects are mediated and how activin might be triggered by viral infection have not been defined. Here we addressed this in vivo and in vitro, in humans and mice. Transcriptomic analyses delineated strikingly congruent patterns of gene regulation in hepatocytes stimulated with recombinant activin A and IFNα in vitro. Activin A mRNA, encoded by INHBA, is induced upon activation of RIG-I, MDA5 and TLR7/8 viral nucleic acid sensors in vitro, across multiple cell lines and in human peripheral blood mononuclear cells. In vivo, infection of mice with influenza A also upregulated Inhba mRNA in the lung; this local upregulation of Inhba is retained in MAVS knockout mice, indicating a role for non-RIG-I-like receptors in its induction. Activin induction and signalling were also detectable in patients with chronic viral hepatitis. Together, these data suggest Activin A is triggered in parallel with type I IFN responses and can trigger related antiviral effector functions. This model has implications for the development of targeted antiviral therapies, in addition to revealing novel facets of activin biology.

scholarly journals Revisiting the role of IRF3 in inflammation and immunity by conditional and specifically targeted gene ablation in mice

2018 ◽  
Vol 115 (20) ◽  
pp. 5253-5258 ◽  
Author(s):  
Hideyuki Yanai ◽  
Shiho Chiba ◽  
Sho Hangai ◽  
Kohei Kometani ◽  
Asuka Inoue ◽  
...  
Keyword(s):  
Immune Cell ◽  
Cell Types ◽  
Type I ◽  
Type I Ifn ◽  
Cell Type ◽  
Gene Ablation ◽  
Cell Type Specific

IFN regulatory factor 3 (IRF3) is a transcription regulator of cellular responses in many cell types that is known to be essential for innate immunity. To confirm IRF3’s broad role in immunity and to more fully discern its role in various cellular subsets, we engineered Irf3-floxed mice to allow for the cell type-specific ablation of Irf3. Analysis of these mice confirmed the general requirement of IRF3 for the evocation of type I IFN responses in vitro and in vivo. Furthermore, immune cell ontogeny and frequencies of immune cell types were unaffected when Irf3 was selectively inactivated in either T cells or B cells in the mice. Interestingly, in a model of lipopolysaccharide-induced septic shock, selective Irf3 deficiency in myeloid cells led to reduced levels of type I IFN in the sera and increased survival of these mice, indicating the myeloid-specific, pathogenic role of the Toll-like receptor 4–IRF3 type I IFN axis in this model of sepsis. Thus, Irf3-floxed mice can serve as useful tool for further exploring the cell type-specific functions of this transcription factor.

scholarly journals Autophagy Contributes to Host Immunity and Protection against Zika Virus Infection via Type I IFN Signaling

2020 ◽  
Vol 2020 ◽  
pp. 1-15 ◽  
Author(s):  
Yuyi Huang ◽  
Yujie Wang ◽  
Shuhui Meng ◽  
Zhuohang Chen ◽  
Haifan Kong ◽  
...  
Keyword(s):  
Virus Infection ◽  
Cell Line ◽  
Zika Virus ◽  
Fetal Brain ◽  
Host Immunity ◽  
Type I ◽  
Type I Ifn ◽  
Zikv Infection

Recent studies have indicated that the Zika virus (ZIKV) has a significant impact on the fetal brain, and autophagy is contributing to host immune response and defense against virus infection. Here, we demonstrate that ZIKV infection triggered increased LC3 punctuation in mouse monocyte-macrophage cell line (RAW264.7), mouse microglial cell line (BV2), and hindbrain tissues, proving the occurrence of autophagy both in vitro and in vivo. Interestingly, manual intervention of autophagy, like deficiency inhibited by 3-MA, can reduce viral clearance in RAW264.7 cells upon ZIKV infection. Besides, specific siRNA strategy confirmed that autophagy can be activated through Atg7-Atg5 and type I IFN signaling pathway upon ZIKV infection, while knocking down of Atg7 and Atg5 effectively decreased the ZIKV clearance in phagocytes. Furthermore, we analyzed that type I IFN signaling could contribute to autophagic clearance of invaded ZIKV in phagocytes. Taken together, our findings demonstrate that ZIKV-induced autophagy is favorable to activate host immunity, particularly through type I IFN signaling, which participates in host protection and defense against ZIKV infection.

scholarly journals Rhesus Macaque Rhadinovirus Encodes a Viral Interferon Regulatory Factor To Disrupt Promyelocytic Leukemia Nuclear Bodies and Antagonize Type I Interferon Signaling

2019 ◽  
Vol 93 (6) ◽  
Author(s):  
Laura K. Springgay ◽  
Kristin Fitzpatrick ◽  
Byung Park ◽  
Ryan D. Estep ◽  
Scott W. Wong
Keyword(s):  
Immune Response ◽  
Rhesus Macaque ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
Type I ◽  
Type I Ifn ◽  
Regulatory Factors ◽  
Successful Infection ◽  
Promyelocytic Leukemia Nuclear Bodies

ABSTRACTInterferon (IFN) production and the subsequent induction of IFN-stimulated genes (ISGs) are highly effective innate strategies utilized by cells to protect against invading pathogens, including viruses. Critical components involved in this innate process are promyelocytic leukemia nuclear bodies (PML-NBs), which are subnuclear structures required for the development of a robust IFN response. As such, PML-NBs serve as an important hurdle for viruses to overcome to successfully establish an infection. Both Kaposi’s sarcoma-associated herpesvirus (KSHV) and the closely related rhesus macaque rhadinovirus (RRV) are unique for encoding viral homologs of IFN regulatory factors (termed vIRFs) that can manipulate the host immune response by multiple mechanisms. All four KSHV vIRFs inhibit the induction of IFN, while vIRF1 and vIRF2 can inhibit ISG induction downstream of the IFN receptor. Less is known about the RRV vIRFs. RRV vIRF R6 can inhibit the induction of IFN by IRF3; however, it is not known whether any RRV vIRFs inhibit ISG induction following IFN receptor signaling. In our present study, we demonstrate that the RRV vIRF R12 aids viral replication in the presence of the type I IFN response. This is achieved in part through the disruption of PML-NBs and the inhibition of robust ISG transcription.IMPORTANCEKSHV and RRV encode a unique set of homologs of cellular IFN regulatory factors, termed vIRFs, which are hypothesized to help these viruses evade the innate immune response and establish infections in their respective hosts. Our work elucidates the role of one RRV vIRF, R12, and demonstrates that RRV can dampen the type I IFN response downstream of IFN signaling, which would be important for establishing a successful infectionin vivo.

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