Lymphocytes are detrimental during the early innate immune response against Listeria monocytogenes

Mice deficient in lymphocytes are more resistant than normal mice to Listeria monocytogenes infection during the early innate immune response. This paradox remains unresolved: lymphocytes are required for sterilizing immunity, but their presence during the early stage of the infection is not an asset and may even be detrimental. We found that lymphocyte-deficient mice, which showed limited apoptosis in infected organs, were resistant during the first four days of infection but became susceptible when engrafted with lymphocytes. Engraftment with lymphocytes from type I interferon receptor–deficient (IFN-αβR−/−) mice, which had reduced apoptosis, did not confer increased susceptibility to infection, even when the phagocytes were IFN-αβR+/+. The attenuation of innate immunity was due, in part, to the production of the antiinflammatory cytokine interleukin 10 by phagocytic cells after the apoptotic phase of the infection. Thus, immunodeficient mice were more resistant relative to normal mice because the latter went through a stage of lymphocyte apoptosis that was detrimental to the innate immune response. This is an example of a bacterial pathogen creating a cascade of events that leads to a permissive infective niche early during infection.

Download Full-text

Bacterial Genes Involved in Type I Secretion and Sulfation Are Required to Elicit the Rice Xa21-Mediated Innate Immune Response

Molecular Plant-Microbe Interactions ◽

10.1094/mpmi.2004.17.6.593 ◽

2004 ◽

Vol 17 (6) ◽

pp. 593-601 ◽

Cited By ~ 84

Author(s):

Francisco Goes da Silva ◽

Yuwei Shen ◽

Christopher Dardick ◽

Saul Burdman ◽

Ram C. Yadav ◽

...

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Bacterial Pathogen ◽

Innate Immune ◽

Host Recognition ◽

Leader Peptide ◽

Type I ◽

Protein Sequence Analysis ◽

Secretion Systems ◽

Bacterial Type

Innate immunity to microorganisms relies on the specific sensing of pathogen-associated molecules by host recognition receptors. Whereas studies in animals have largely focused on the recognition of extracellular pathogen-associated molecules by the TLR (toll-like receptor) superfamily, few studies have been carried out in plants, and it is not understood how these molecules are secreted or modified. The rice Xa21 gene encodes a receptor-like kinase that provides immunity against strains of the bacterial pathogen Xanthomonas oryzae pv. oryzae carrying AvrXa21 activity. We identified four X. oryzae pv. oryzae genes that are required for AvrXa21 activity. raxA, raxB, and raxC encode proteins with similarity to a membrane fusion protein, an ATP-binding cassette transporter, and an outer membrane protein, respectively, of bacterial type I secretion systems. The fourth gene, raxST, encodes a sulfotransferase-like protein. Sequence analysis of three naturally occurring X. oryzae pv. oryzae strains no longer recognized by Xa21 revealed alterations in the raxST and raxA genes. The raxC gene complemented an Escherichia coli tolC mutant for secretion of a double glycine-leader peptide confirming the function of raxC in type I secretion. These results indicate that bacterial type I secretion is necessary for Xa21-mediated recognition and immunity and further suggest that type I secretion and modification of pathogen-associated molecules play an important role in triggering the innate immune response in rice.

Download Full-text

Type I interferons and the innate immune response—more than just antiviral cytokines

Molecular Immunology ◽

10.1016/j.molimm.2004.11.008 ◽

2005 ◽

Vol 42 (8) ◽

pp. 869-877 ◽

Cited By ~ 80

Author(s):

Peter L Smith ◽

Giovanna Lombardi ◽

Graham R Foster

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Innate Immune ◽

Type I Interferons ◽

Type I

Download Full-text

High content screening and computational prediction reveal viral genes that suppress innate immune response

10.1101/2021.12.14.472572 ◽

2021 ◽

Author(s):

Tai L Ng ◽

Erika J Olson ◽

Tae Yeon Yoo ◽

H. Sloane Weiss ◽

Yukiye Koide ◽

...

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Nuclear Transport ◽

Computational Prediction ◽

Viral Proteins ◽

Innate Immune ◽

Type I ◽

Viral Genes ◽

Genes Encoding

Suppression of the host innate immune response is a critical aspect of viral replication. Upon infection, viruses may introduce one or more proteins that inhibit key immune pathways, such as the type I interferon pathway. However, the ability to predict and evaluate viral protein bioactivity on targeted pathways remains challenging and is typically done on a single virus/gene basis. Here, we present a medium-throughput high-content cell-based assay to reveal the immunosuppressive effects of viral proteins. To test the predictive power of our approach, we developed a library of 800 genes encoding known, predicted, and uncharacterized human viral genes. We find that previously known immune suppressors from numerous viral families such as Picornaviridae and Flaviviridae recorded positive responses. These include a number of viral proteases for which we further confirmed that innate immune suppression depends on protease activity. A class of predicted inhibitors encoded by Rhabdoviridae viruses was demonstrated to block nuclear transport, and several previously uncharacterized proteins from uncultivated viruses were shown to inhibit nuclear transport of the transcription factors NF-kB and IRF3. We propose that this pathway-based assay, together with early sequencing, gene synthesis, and viral infection studies, could partly serve as the basis for rapid in vitro characterization of novel viral proteins.

Download Full-text

Longitudinal single-cell immune profiling revealed distinct innate immune response in asymptomatic COVID-19 patients

10.1101/2020.09.02.276865 ◽

2020 ◽

Cited By ~ 1

Author(s):

Xiang-Na Zhao ◽

Yue You ◽

Guo-Lin Wang ◽

Hui-Xia Gao ◽

Xiao-Ming Cui ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

T Cell ◽

Single Cell ◽

Innate Immune Response ◽

Clonal Expansion ◽

Innate Immune ◽

Type I ◽

Severe Condition ◽

Asymptomatic Patients

SUMMARYRecent studies have characterized the single-cell immune landscape of host immune response of coronavirus disease 2019 (COVID-19), specifically focus on the severe condition. However, the immune response in mild or even asymptomatic patients remains unclear. Here, we performed longitudinal single-cell transcriptome sequencing and T cell/B cell receptor sequencing on 3 healthy donors and 10 COVID-19 patients with asymptomatic, moderate, and severe conditions. We found asymptomatic patients displayed distinct innate immune responses, including increased CD56briCD16− NK subset, which was nearly missing in severe condition and enrichment of a new Th2-like cell type/state expressing a ciliated cell marker. Unlike that in moderate condition, asymptomatic patients lacked clonal expansion of effector CD8+ T cells but had a robust effector CD4+ T cell clonal expansion, coincide with previously detected SARS-CoV-2-reactive CD4+ T cells in unexposed individuals. Moreover, NK and effector T cells in asymptomatic patients have upregulated cytokine related genes, such as IFNG and XCL2. Our data suggest early innate immune response and type I immunity may contribute to the asymptomatic phenotype in COVID-19 disease, which could in turn deepen our understanding of severe COVID-19 and guide early prediction and therapeutics.

Download Full-text

The C-terminal domain of Salmonid Alphavirus nonstructural protein 2 (nsP2) is essential and sufficient to block RIG-I pathway induction and interferon-mediated antiviral response.

Journal of Virology ◽

10.1128/jvi.01155-21 ◽

2021 ◽

Author(s):

Raphaël Jami ◽

Emilie Mérour ◽

Julie Bernard ◽

Annie Lamoureux ◽

Jean K. Millet ◽

...

Keyword(s):

Immune Response ◽

Immune System ◽

Innate Immune Response ◽

Nuclear Localization ◽

Innate Immune ◽

Type I ◽

Annual Growth Rate ◽

Structural Protein ◽

Terminal Domain ◽

Nuclear Localization Sequences

Salmonid alphavirus (SAV) is an atypical alphavirus, which has a considerable impact on salmon and trout farms. Unlike other alphaviruses such as the chikungunya virus, SAV is transmitted without an arthropod vector, and does not cause cell shut-off during infection. The mechanisms by which SAV escapes the host immune system remain unknown. By studying the role of SAV proteins on the RIG-I signaling cascade, the first line of defense of the immune system during infection, we demonstrated that non-structural protein 2 (nsP2) effectively blocks the induction of type I interferon (IFN). This inhibition, independent of the protease activity carried by nsP2, occurs downstream of IRF3 which is the transcription factor allowing the activation of the IFN promoter and its expression. The inhibitory effect of nsP2 on the RIG-I pathway depends on the localization of nsP2 in the host cell nucleus which is linked to two nuclear localization sequences (NLS) located in its C-terminal part. The C-terminal domain of nsP2 by itself is sufficient and necessary to block IFN induction. Mutation of the NLS of nsP2 is deleterious to the virus. Finally, nsP2 does not interact with IRF3, indicating that its action is possible through a targeted interaction within discrete areas of chromatin, as suggested by its punctate distribution observed in the nucleus. These results therefore demonstrate a major role for nsP2 in the control by SAV of the host cell’s innate immune response. Importance The global consumption of fish continues to rise and the future demand cannot be met by capture fisheries alone due to limited stocks of wild fish. Aquaculture is currently the world’s fastest growing food production sector with an annual growth rate of 6-8 %. Recurrent outbreaks of SAV result in significant economic losses with serious environmental consequences on wild stocks. While the clinical and pathological signs of SAV infection are fairly well known, the molecular mechanisms involved are poorly described. In the present study, we focus on the non-structural protein nsP2 and characterize a specific domain containing nuclear localization sequences that are critical for the inhibition of the host innate immune response mediated by the RIG-I pathway.

Download Full-text

RNA sensors as a mechanism of innate immune evasion among SARS-CoV2, HIV and Nipah viruses

Current Protein and Peptide Science ◽

10.2174/1389203722666210322142725 ◽

2021 ◽

Vol 22 ◽

Author(s):

Dalia Cicily Kattiparambil Dixon ◽

Chameli Ratan ◽

Bhagyalakshmi Nair ◽

Sabitha Mangalath ◽

Rachy Abraham ◽

...

Keyword(s):

Immune Response ◽

Innate Immunity ◽

Innate Immune Response ◽

Vaccine Development ◽

Innate Immune ◽

Interferon Response ◽

Host Immune System ◽

Type I ◽

Adaptive Responses ◽

Rna Sensors

: Innate immunity is the first line of defence elicited by the host immune system to fight against invading pathogens such as viruses and bacteria. From this elementary immune response, the more complex antigen-specific adaptive responses are recruited to provide a long-lasting memory against the pathogens. Innate immunity gets activated when the host cell utilizes a diverse set of receptors known as pattern recognition receptors (PRR) to recognize the viruses that have penetrated the host and respond with cellular processes like complement system, phagocytosis, cytokine release and inflammation and destruction of NK cells. Viral RNA or DNA or viral intermediate products are recognized by receptors like toll-like receptors(TLRs), nucleotide oligomerization domain(NOD)-like receptors (NLRs) and retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) thereby, inducing type I interferon response (IFN) and other proinflammatory cytokines in infected cells or other immune cells. But certain viruses can evade the host innate immune response to replicate efficiently, triggering the spread of the viral infection. The present review describes the similarity in the mechanism chosen by viruses from different families -HIV, SARS-CoV2 and Nipah viruses to evade the innate immune response and how efficiently they establish the infection in the host. The review also addresses the stages of developments of various vaccines against these viral diseases and the challenges encountered by the researchers during vaccine development.

Download Full-text

Effects of Regulatory T Cell Depletion on NK Cell Responses against Listeria monocytogenes in Feline Immunodeficiency Virus Infected Cats

Viruses ◽

10.3390/v11110984 ◽

2019 ◽

Vol 11 (11) ◽

pp. 984

Author(s):

Simões ◽

LaVoy ◽

Dean

Keyword(s):

Immune Response ◽

Listeria Monocytogenes ◽

Dendritic Cell ◽

Innate Immune Response ◽

Feline Immunodeficiency Virus ◽

Innate Immune ◽

Treg Depletion ◽

Cell Responses ◽

Immunodeficiency Virus

Regulatory T cells (Treg) are key players in the maintenance of peripheral tolerance, preventing autoimmune diseases and restraining chronic inflammatory diseases. Evidence suggests Treg cells and NK cells have important roles in feline immunodeficiency virus (FIV) pathogenesis; however, in vivo studies investigating the interplay between these two cell populations are lacking. We previously described innate immune defects in FIV-infected cats characterized by cytokine deficits and impaired natural killer cell (NK) and NK T cell (NKT) functions. In this study, we investigated whether in vivo Treg depletion by treatment with an anti-feline CD25 monoclonal antibody would improve the innate immune response against subcutaneous challenge with Listeria monocytogenes (Lm). Treg depletion resulted in an increased overall number of cells in Lm-draining lymph nodes and increased proliferation of NK and NKT cells in FIV-infected cats. Treg depletion did not normalize expression of perforin or granzyme A by NK and NKT cells, nor did Treg depletion result in improved clearance of Lm. Thus, despite the quantitative improvements in the NK and NKT cell responses to Lm, there was no functional improvement in the early control of Lm. CD1a+ dendritic cell percentages in the lymph nodes of FIV-infected cats were lower than in specific-pathogen-free control cats and failed to upregulate CD80 even when Treg were depleted. Taken together, Treg depletion failed to improve the innate immune response of FIV-infected cats against Lm and this may be due to dendritic cell dysfunction.

Download Full-text

Regulation of the Ebola Virus VP24 Protein by SUMO

Journal of Virology ◽

10.1128/jvi.01687-19 ◽

2019 ◽

Vol 94 (1) ◽

Cited By ~ 6

Author(s):

Santiago Vidal ◽

Ahmed El Motiam ◽

Rocío Seoane ◽

Viktorija Preitakaite ◽

Yanis Hichem Bouzaher ◽

...

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Viral Protein ◽

Matrix Protein ◽

Ebola Virus ◽

Nuclear Translocation ◽

Critical Role ◽

Innate Immune ◽

Type I ◽

Negative Modulator

ABSTRACT Some viruses take advantage of conjugation of ubiquitin or ubiquitin-like proteins to enhance their own replication. One example is Ebola virus, which has evolved strategies to utilize these modification pathways to regulate the viral proteins VP40 and VP35 and to counteract the host defenses. Here, we show a novel mechanism by which Ebola virus exploits the ubiquitin and SUMO pathways. Our data reveal that minor matrix protein VP24 of Ebola virus is a bona fide SUMO target. Analysis of a SUMOylation-defective VP24 mutant revealed a reduced ability to block the type I interferon (IFN) pathway and to inhibit IFN-mediated STAT1 nuclear translocation, exhibiting a weaker interaction with karyopherin 5 and significantly diminished stability. Using glutathione S-transferase (GST) pulldown assay, we found that VP24 also interacts with SUMO in a noncovalent manner through a SIM domain. Mutation of the SIM domain in VP24 resulted in a complete inability of the protein to downmodulate the IFN pathway and in the monoubiquitination of the protein. We identified SUMO deubiquitinating enzyme ubiquitin-specific-processing protease 7 (USP7) as an interactor and a negative modulator of VP24 ubiquitination. Finally, we show that mutation of one ubiquitination site in VP24 potentiates the IFN modulatory activity of the viral protein and its ability to block IFN-mediated STAT1 nuclear translocation, pointing to the ubiquitination of VP24 as a negative modulator of the VP24 activity. Altogether, these results indicate that SUMO interacts with VP24 and promotes its USP7-mediated deubiquitination, playing a key role in the interference with the innate immune response mediated by the viral protein. IMPORTANCE The Ebola virus VP24 protein plays a critical role in escape of the virus from the host innate immune response. Therefore, deciphering the molecular mechanisms modulating VP24 activity may be useful to identify potential targets amenable to therapeutics. Here, we identify the cellular proteins USP7, SUMO, and ubiquitin as novel interactors and regulators of VP24. These interactions may represent novel potential targets to design new antivirals with the ability to modulate Ebola virus replication.

Download Full-text

miR-26a Inhibits Feline Herpesvirus 1 Replication by Targeting SOCS5 and Promoting Type I Interferon Signaling

Viruses ◽

10.3390/v12010002 ◽

2019 ◽

Vol 12 (1) ◽

pp. 2 ◽

Cited By ~ 3

Author(s):

Jikai Zhang ◽

Zhijie Li ◽

Jiapei Huang ◽

Hang Yin ◽

Jin Tian ◽

...

Keyword(s):

Immune Response ◽

Viral Infection ◽

Innate Immune Response ◽

Antiviral Response ◽

Innate Immune ◽

Host Cells ◽

Type I ◽

Type I Ifn ◽

Feline Herpesvirus ◽

Herpesvirus 1

In response to viral infection, host cells activate various antiviral responses to inhibit virus replication. While feline herpesvirus 1 (FHV-1) manipulates the host early innate immune response in many different ways, the host could activate the antiviral response to counteract it through some unknown mechanisms. MicroRNAs (miRNAs) which serve as a class of regulatory factors in the host, participate in the regulation of the host innate immune response against virus infection. In this study, we found that the expression levels of miR-26a were significantly upregulated upon FHV-1 infection. Furthermore, FHV-1 infection induced the expression of miR-26a via a cGAS-dependent pathway, and knockdown of cellular cGAS significantly blocked the expression of miR-26a induced by poly (dA:dT) or FHV-1 infection. Next, we investigated the biological function of miR-26a during viral infection. miR-26a was able to increase the phosphorylation of STAT1 and promote type I IFN signaling, thus inhibiting viral replication. The mechanism study showed that miR-26a directly targeted host SOCS5. Knockdown of SOCS5 increased the phosphorylation of STAT1 and enhanced the type I IFN-mediated antiviral response, and overexpression of suppressor of the cytokine signalling 5 (SOCS5) decreased the phosphorylation of STAT1 and inhibited the type I IFN-mediated antiviral response. Meanwhile, with the knockdown of SOCS5, the upregulated expression of phosphorylated STAT1 and the anti-virus effect induced by miR-26a were significantly inhibited. Taken together, our data demonstrated a new strategy of host miRNAs against FHV-1 infection by enhancing IFN antiviral signaling.

Download Full-text

Stenotrophomonas maltophilia flagellin induces a compartmentalized innate immune response in mouse lung

Journal of Medical Microbiology ◽

10.1099/jmm.0.020107-0 ◽

2010 ◽

Vol 59 (8) ◽

pp. 913-919 ◽

Cited By ~ 12

Author(s):

Ayaid Khadem Zgair ◽

Sanjay Chhibber

Keyword(s):

Immune Response ◽

Innate Immunity ◽

Innate Immune Response ◽

Stenotrophomonas Maltophilia ◽

Interleukin 1 ◽

Interleukin 10 ◽

Innate Immune ◽

Mouse Lung ◽

Necrosis Factor Alpha ◽

Activated Neutrophils

Intranasal (i.n.) instillation of different amounts of purified Stenotrophomonas maltophilia flagellin preparation (1, 5 and 15 μg) in BALB/c mice stimulated a transient innate immune response in the lungs. This was characterized by infiltration of different kinds of leukocytes (neutrophils, monocytes and lymphocytes), production of various inflammatory mediators (tumour necrosis factor alpha, interleukin 1 beta, interleukin 10, nitric oxide, myeloperoxidase and malondialdehyde) and activated alveolar macrophages (AMs). The proinflammatory cytokine production resulted in accumulation of activated neutrophils and macrophages and their products following immunostimulation with flagellin. The activation of AMs by flagellin was non-specific as AMs obtained from flagellin-treated animals, even after 4 h of exposure, were found to engulf and kill S. maltophilia and Staphylococcus aureus efficiently compared to macrophages obtained from control animals. i.n. instillation of 5 μg flagellin resulted in the generation of an effective innate immunity compared to other flagellin doses. Our data provide strong evidence that S. maltophilia flagellin stimulates innate immunity in mouse lung.

Download Full-text