Pathogenic Effects of IFIT2 and Interferon-β during Fatal SystemicCandida albicansInfection

ABSTRACTA balanced immune response to infection is essential to prevent the pathology and tissue damage that can occur from an unregulated or hyperactive host defense. Interferons (IFNs) are critical mediators of the innate defense to infection, and in this study we evaluated the contribution of a specific gene coding for IFIT2 induced by type I IFNs in a murine model of disseminatedCandida albicans. Invasive candidiasis is a frequent challenge during immunosuppression or surgical medical interventions, andC. albicansis a common culprit that leads to high rates of mortality. When IFIT2 knockout mice were infected systemically withC. albicans, they were found to have improved survival and reduced fungal burden compared to wild-type mice. One of the mechanisms by which IFIT2 increases the pathological effects of invasiveC. albicansappears to be suppression of NADPH oxidase activation. Loss of IFIT2 increases production of reactive oxygen species by leukocytes, and we demonstrate that IFIT2 is a binding partner of a critical regulatory subunit of NADPH oxidase, p67phox. Since the administration of IFN has been used therapeutically to combat viral infections, cancer, and multiple sclerosis, we evaluated administration of IFN-β to mice prior toC. albicansinfection. IFN-β treatment promoted pathology and death fromC. albicansinfection. We provide evidence that IFIT2 increases the pathological effects of invasiveC. albicansand that administration of IFN-β has deleterious effects during infection.IMPORTANCEThe attributable mortality associated with systemicC. albicansinfections in health care settings is significant, with estimates greater than 40%. This life-threatening disease is common in patients with weakened immune systems, either due to disease or as a result of therapies. Type I interferons (IFN) are cytokines of the innate defense response that are used as immune modulators in the treatment of specific cancers, viral infections, and multiple sclerosis. In this study, we show using a murine model that the loss of a specific IFN-stimulated gene coding for IFIT2 improves survival following systemicC. albicansinfection. This result infers a harmful effect of IFN duringC. albicansinfection and is supported by our finding that administration of IFN-β prior to invasive infection promotes fatal pathology. The findings contribute to our understanding of the innate immune response toC. albicans, and they suggest that IFN therapies present a risk factor for disseminated candidiasis.

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NADPH Oxidase and Guanylate Binding Protein 5 Restrict Survival of Avirulent Type III Strains of Toxoplasma gondii in Naive Macrophages

mBio ◽

10.1128/mbio.01393-18 ◽

2018 ◽

Vol 9 (4) ◽

Cited By ~ 10

Author(s):

Sumit K. Matta ◽

Kelley Patten ◽

Quiling Wang ◽

Bae-Hoon Kim ◽

John D. MacMicking ◽

...

Keyword(s):

Toxoplasma Gondii ◽

Nadph Oxidase ◽

Binding Protein ◽

Parasitic Infections ◽

Type I ◽

Content Type ◽

Innate Defense ◽

Type Iii ◽

Ifn Γ ◽

Guanylate Binding Protein

ABSTRACT Phagocytic cells are the first line of innate defense against intracellular pathogens, and yet Toxoplasma gondii is renowned for its ability to survive in macrophages, although this paradigm is based on virulent type I parasites. Surprisingly, we find that avirulent type III parasites are preferentially cleared in naive macrophages, independent of gamma interferon (IFN-γ) activation. The ability of naive macrophages to clear type III parasites was dependent on enhanced activity of NADPH oxidase (Nox)-generated reactive oxygen species (ROS) and induction of guanylate binding protein 5 (Gbp5). Macrophages infected with type III parasites (CTG strain) showed a time-dependent increase in intracellular ROS generation that was higher than that induced by type I parasites (GT1 strain). The absence of Nox1 or Nox2, gp91 subunit isoforms of the Nox complex, reversed ROS-mediated clearance of CTG parasites. Consistent with this finding, both Nox1−/− and Nox2−/− mice showed higher susceptibility to CTG infection than wild-type mice. Additionally, Gbp5 expression was induced upon infection and the enhanced clearance of CTG strain parasites was reversed in Gbp5−/− macrophages. Expression of a type I ROP18 allele in CTG prevented clearance in naive macrophages, suggesting that it plays a role counteracting Gbp5. Although ROS and Gbp5 have been linked to activation of the NLRP3 inflammasome, clearance of CTG parasites did not rely on induction of pyroptosis. Collectively, these findings reveal that not all strains of T. gondii are adept at avoiding clearance in macrophages and define new roles for ROS and Gbps in controlling this important intracellular pathogen. IMPORTANCE Toxoplasma infections in humans and other mammals are largely controlled by IFN-γ produced by the activated adaptive immune system. However, we still do not completely understand the role of cell-intrinsic functions in controlling Toxoplasma or other apicomplexan infections. The present work identifies intrinsic activities in naive macrophages in counteracting T. gondii infection. Using an avirulent strain of T. gondii, we highlight the importance of Nox complexes in conferring protection against parasite infection both in vitro and in vivo. We also identify Gbp5 as a novel macrophage factor involved in limiting intracellular infection by avirulent strains of T. gondii. The rarity of human infections caused by type III strains suggests that these mechanisms may also be important in controlling human toxoplasmosis. These findings further extend our understanding of host responses and defense mechanisms that act to control parasitic infections at the cellular level.

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High-Density Blood Transcriptomics Reveals Precision Immune Signatures of SARS-CoV-2 Infection in Hospitalized Individuals

Frontiers in Immunology ◽

10.3389/fimmu.2021.694243 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jeremy W. Prokop ◽

Nicholas L. Hartog ◽

Dave Chesla ◽

William Faber ◽

Chanise P. Love ◽

...

Keyword(s):

Gene Expression ◽

Immune Response ◽

Viral Infections ◽

Secretory Granules ◽

Mitotic Cell ◽

Hospitalized Patients ◽

High Density ◽

Type I ◽

Secondary Infections ◽

Blood Transcriptomics

The immune response to COVID-19 infection is variable. How COVID-19 influences clinical outcomes in hospitalized patients needs to be understood through readily obtainable biological materials, such as blood. We hypothesized that a high-density analysis of host (and pathogen) blood RNA in hospitalized patients with SARS-CoV-2 would provide mechanistic insights into the heterogeneity of response amongst COVID-19 patients when combined with advanced multidimensional bioinformatics for RNA. We enrolled 36 hospitalized COVID-19 patients (11 died) and 15 controls, collecting 74 blood PAXgene RNA tubes at multiple timepoints, one early and in 23 patients after treatment with various therapies. Total RNAseq was performed at high-density, with >160 million paired-end, 150 base pair reads per sample, representing the most sequenced bases per sample for any publicly deposited blood PAXgene tube study. There are 770 genes significantly altered in the blood of COVID-19 patients associated with antiviral defense, mitotic cell cycle, type I interferon signaling, and severe viral infections. Immune genes activated include those associated with neutrophil mechanisms, secretory granules, and neutrophil extracellular traps (NETs), along with decreased gene expression in lymphocytes and clonal expansion of the acquired immune response. Therapies such as convalescent serum and dexamethasone reduced many of the blood expression signatures of COVID-19. Severely ill or deceased patients are marked by various secondary infections, unique gene patterns, dysregulated innate response, and peripheral organ damage not otherwise found in the cohort. High-density transcriptomic data offers shared gene expression signatures, providing unique insights into the immune system and individualized signatures of patients that could be used to understand the patient’s clinical condition. Whole blood transcriptomics provides patient-level insights for immune activation, immune repertoire, and secondary infections that can further guide precision treatment.

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Interferon-Stimulated Gene (ISG)-Expression Screening Reveals the Specific Antibunyaviral Activity of ISG20

Journal of Virology ◽

10.1128/jvi.02140-17 ◽

2018 ◽

Vol 92 (13) ◽

Cited By ~ 11

Author(s):

Junjie Feng ◽

Arthur Wickenhagen ◽

Matthew L. Turnbull ◽

Veronica V. Rezelj ◽

Felix Kreher ◽

...

Keyword(s):

Viral Infections ◽

Rhesus Macaques ◽

Type I ◽

Emerging Viruses ◽

Content Type ◽

Expression Screening ◽

Interferon Stimulated Genes ◽

Life Threatening

ABSTRACT Bunyaviruses pose a significant threat to human health, prosperity, and food security. In response to viral infections, interferons (IFNs) upregulate the expression of hundreds of interferon-stimulated genes (ISGs), whose cumulative action can potently inhibit the replication of bunyaviruses. We used a flow cytometry-based method to screen the ability of ∼500 unique ISGs from humans and rhesus macaques to inhibit the replication of Bunyamwera orthobunyavirus (BUNV), the prototype of both the Peribunyaviridae family and the Bunyavirales order. Candidates possessing antibunyaviral activity were further examined using a panel of divergent bunyaviruses. Interestingly, one candidate, ISG20, exhibited potent antibunyaviral activity against most viruses examined from the Peribunyaviridae , Hantaviridae , and Nairoviridae families, whereas phleboviruses ( Phenuiviridae ) largely escaped inhibition. Similar to the case against other viruses known to be targeted by ISG20, the antibunyaviral activity of ISG20 is dependent upon its functional RNase activity. Through use of an infectious virus-like particle (VLP) assay (based on the BUNV minigenome system), we confirmed that gene expression from all 3 viral segments is strongly inhibited by ISG20. Using in vitro evolution, we generated a substantially ISG20-resistant BUNV and mapped the determinants of ISG20 sensitivity/resistance. Taking all the data together, we report that ISG20 is a broad and potent antibunyaviral factor but that some bunyaviruses are remarkably ISG20 resistant. Thus, ISG20 sensitivity/resistance may influence the pathogenesis of bunyaviruses, many of which are emerging viruses of clinical or veterinary significance. IMPORTANCE There are hundreds of bunyaviruses, many of which cause life-threatening acute diseases in humans and livestock. The interferon (IFN) system is a key component of innate immunity, and type I IFNs limit bunyaviral propagation both in vitro and in vivo . Type I IFN signaling results in the upregulation of hundreds of IFN-stimulated genes (ISGs), whose concerted action generates an “antiviral state.” Although IFNs are critical in limiting bunyaviral replication and pathogenesis, much is still unknown about which ISGs inhibit bunyaviruses. Using ISG-expression screening, we examined the ability of ∼500 unique ISGs to inhibit Bunyamwera orthobunyavirus (BUNV), the prototypical bunyavirus. Using this approach, we identified ISG20, an interferon-stimulated exonuclease, as a potent inhibitor of BUNV. Interestingly, ISG20 possesses highly selective antibunyaviral activity, with multiple bunyaviruses being potently inhibited while some largely escape inhibition. We speculate that the ability of some bunyaviruses to escape ISG20 may influence their pathogenesis.

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How fragile we are. Influence of STimulator of INterferon Genes, STING, variants on pathogen recognition and immune response efficiency

10.1101/2021.07.12.452045 ◽

2021 ◽

Author(s):

Jeremy Morere ◽

Cecilia Hognon ◽

Tom Miclot ◽

Tao Jiang ◽

Elise Dumont ◽

...

Keyword(s):

Immune Response ◽

Molecular Mechanisms ◽

Viral Infections ◽

Inflammatory Diseases ◽

Dynamical Behavior ◽

Structural Features ◽

Type I Interferons ◽

Machine Learning Techniques ◽

Type I ◽

Interaction Patterns

The STimulator of INterferon Genes (STING) protein is a cornerstone of the human immune response. Its activation by cGAMP upon the presence of cytosolic DNA stimulates the production of type I interferons and inflammatory cytokines which are crucial for protecting cells from infections. STING signaling pathway can also influence both tumor-suppressive and tumor-promoting mechanisms, rendering it an appealing target for drug design. In the human population, several STING variants exist and exhibit dramatic differences in their activity, impacting the efficiency of the host defense against infections. Understanding the differential molecular mechanisms exhibited by these variants is of utmost importance notably towards personalized medicine treatments against diseases such as viral infections (COVID-19, Dengue...), cancers, or auto-inflammatory diseases. Owing to micro-seconds scale molecular modeling simulations and post-processing by contacts analysis and Machine Learning techniques, we reveal the dynamical behavior of four STING variants (wild type, G230A, R293Q, and G230A-R293Q) and we rationalize the variability of efficiency observed experimentally. Our results show that the decrease of STING activity is linked to a stiffening of key-structural features of the binding cavity, together with changes of the interaction patterns within the protein.

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Exacerbated Apoptosis of Cells Infected with Infectious Bursal Disease Virus upon Exposure to Interferon Alpha

Journal of Virology ◽

10.1128/jvi.00364-18 ◽

2018 ◽

Vol 92 (11) ◽

Cited By ~ 4

Author(s):

Liliana L. Cubas-Gaona ◽

Elisabet Diaz-Beneitez ◽

Marina Ciscar ◽

José F. Rodríguez ◽

Dolores Rodríguez

Keyword(s):

Immune Response ◽

Infectious Bursal Disease Virus ◽

Infectious Bursal Disease ◽

Type I ◽

B Cell Depletion ◽

Content Type ◽

Tnf Α ◽

Bursal Disease ◽

Infected Cells ◽

Main Factors

ABSTRACTInfectious bursal disease virus (IBDV) belongs to theBirnaviridaefamily and is the etiological agent of a highly contagious and immunosuppressive disease (IBD) that affects domestic chickens (Gallus gallus). IBD or Gumboro disease leads to high rates of morbidity and mortality of infected animals and is responsible for major economic losses to the poultry industry worldwide. IBD is characterized by a massive loss of IgM-bearing B lymphocytes and the destruction of the bursa of Fabricius. The molecular bases of IBDV pathogenicity are still poorly understood; nonetheless, an exacerbated cytokine immune response and B cell depletion due to apoptosis are considered main factors that contribute to the severity of the disease. Here we have studied the role of type I interferon (IFN) in IBDV infection. While IFN pretreatment confers protection against subsequent IBDV infection, the addition of IFN to infected cell cultures early after infection drives massive apoptotic cell death. Downregulation of double-stranded RNA (dsRNA)-dependent protein kinase (PKR), tumor necrosis factor alpha (TNF-α), or nuclear factor κB (NF-κB) expression drastically reduces the extent of apoptosis, indicating that they are critical proteins in the apoptotic response induced by IBDV upon treatment with IFN-α. Our results indicate that IBDV genomic dsRNA is a major viral factor that contributes to the triggering of apoptosis. These findings provide novel insights into the potential mechanisms of IBDV-induced immunosuppression and pathogenesis in chickens.IMPORTANCEIBDV infection represents an important threat to the poultry industry worldwide. IBDV-infected chickens develop severe immunosuppression, which renders them highly susceptible to secondary infections and unresponsive to vaccination against other pathogens. The early dysregulation of the innate immune response led by IBDV infection and the exacerbated apoptosis of B cells have been proposed as the main factors that contribute to virus-induced immunopathogenesis. Our work contributes for the first time to elucidating a potential mechanism driving the apoptotic death of IBDV-infected cells upon exposure to type I IFN. We provide solid evidence about the critical importance of PKR, TNF-α, and NF-κB in this phenomenon. The described mechanism could facilitate the early clearance of infected cells, thereby aiding in the amelioration of IBDV-induced pathogenesis, but it could also contribute to B cell depletion and immunosuppression. The balance between these two opposing effects might be dramatically affected by the genetic backgrounds of both the host and the infecting virus strain.

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Pulmonary Iron Limitation Induced by Exogenous Type I IFN Protects Mice fromCryptococcus gattiiIndependently of T Cells

mBio ◽

10.1128/mbio.00799-19 ◽

2019 ◽

Vol 10 (3) ◽

Cited By ~ 4

Author(s):

Michael J. Davis ◽

Shannon Moyer ◽

Elizabeth S. Hoke ◽

Edward Sionov ◽

Katrin D. Mayer-Barber ◽

...

Keyword(s):

Immune Response ◽

T Cell ◽

Cryptococcus Neoformans ◽

Cryptococcus Gattii ◽

Iron Limitation ◽

Type I ◽

Type I Ifn ◽

Aids Patients ◽

Content Type ◽

Immune Pathways

ABSTRACTCryptococcus neoformanscauses deadly mycosis primarily in AIDS patients, whereasCryptococcus gattiiinfects mostly non-HIV patients, even in regions with high burdens of HIV/AIDS and an established environmental presence ofC. gattii. As HIV induces type I IFN (t1IFN), we hypothesized that t1IFN would differentially affect the outcome ofC. neoformansandC. gattiiinfections. Exogenous t1IFN induction using stabilized poly(I·C) (pICLC) improved murine outcomes in either cryptococcal infection. InC. neoformans-infected mice, pICLC activity was associated withC. neoformanscontainment and classical Th1 immunity. In contrast, pICLC activity againstC. gattiidid not require any immune factors previously associated withC. neoformansimmunity: T, B, and NK cells, IFN-γ, and macrophages were all dispensable. Interestingly,C. gattiipICLC activity depended on β-2-microglobulin, which impacts iron levels among other functions. Iron supplementation reversed pICLC activity, suggestingC. gattiipICLC activity requires iron limitation. Also, pICLC induced a set of iron control proteins, some of which were directly inhibitory to cryptococcusin vitro, suggesting t1IFN regulates iron availability in the pulmonary air space fluids. Thus, exogenous induction of t1IFN significantly improves the outcome of murine infection byC. gattiiandC. neoformansbut by distinct mechanisms; theC. gattiieffect was mediated by iron limitation, while the effect onC. neoformansinfection was through induction of classical T-cell-dependent immunity. Together this difference in types of T-cell-dependent t1IFN immunity for differentCryptococcusspecies suggests a possible mechanism by which HIV infection may select againstC. gattiibut notC. neoformans.IMPORTANCECryptococcus neoformansandCryptococcus gattiicause fatal infection in immunodeficient and immunocompetent individuals. While these fungi are sibling species,C. gattiiinfects very few AIDS patients, whileC. neoformansinfection is an AIDS-defining illness, suggesting that the host response to HIV selectsC. neoformansoverC. gattii. We used a viral mimic molecule (pICLC) to stimulate the immune response, and pICLC treatment improved mouse outcomes from both species. pICLC-induced action againstC. neoformanswas due to activation of well-defined immune pathways known to deterC. neoformans, whereas these immune pathways were dispensable for pICLC treatment ofC. gattii. Since these immune pathways are eventually destroyed by HIV/AIDS, our data help explain why the antiviral immune response in AIDS patients is unable to controlC. neoformansinfection but is protective againstC. gattii. Furthermore, pICLC induced tighter control of iron in the lungs of mice, which inhibitedC. gattii, thus suggesting an entirely new mode of nutritional immunity activated by viral signals.

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Modulation of an Allergic Immune Response via the Mucosal Route in a Murine Model of Inhalative Type–I Allergy

International Archives of Allergy and Immunology ◽

10.1159/000024048 ◽

1999 ◽

Vol 118 (2-4) ◽

pp. 129-132 ◽

Cited By ~ 4

Author(s):

U. Wiedermann ◽

B. Jahn-Schmid ◽

A. Repa ◽

D. Kraft ◽

C. Ebner

Keyword(s):

Immune Response ◽

Murine Model ◽

Type I ◽

Type I Allergy ◽

Mucosal Route ◽

Allergic Immune Response

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Vpu-Deficient HIV Strains Stimulate Innate Immune Signaling Responses in Target Cells

Journal of Virology ◽

10.1128/jvi.00424-12 ◽

2012 ◽

Vol 86 (16) ◽

pp. 8499-8506 ◽

Cited By ~ 20

Author(s):

Brian P. Doehle ◽

Kristina Chang ◽

Lamar Fleming ◽

John McNevin ◽

Florian Hladik ◽

...

Keyword(s):

Immune Response ◽

Innate Immunity ◽

Host Cell ◽

Innate Immune Response ◽

Innate Immune ◽

Target Cells ◽

Major Public Health Problem ◽

Type I ◽

Innate Defense ◽

Hiv 1

Acute virus infection induces a cell-intrinsic innate immune response comprising our first line of immunity to limit virus replication and spread, but viruses have developed strategies to overcome these defenses. HIV-1 is a major public health problem; however, the virus-host interactions that regulate innate immune defenses against HIV-1 are not fully defined. We have recently identified the viral protein Vpu to be a key determinant responsible for HIV-1 targeting and degradation of interferon regulatory factor 3 (IRF3), a central transcription factor driving host cell innate immunity. IRF3 plays a major role in pathogen recognition receptor (PRR) signaling of innate immunity to drive the expression of type I interferon (IFN) and interferon-stimulated genes (ISGs), including a variety of HIV restriction factors, that serve to limit viral replication directly and/or program adaptive immunity. Here we interrogate the cellular responses to target cell infection with Vpu-deficient HIV-1 strains. Remarkably, in the absence of Vpu, HIV-1 triggers a potent intracellular innate immune response that suppresses infection. Thus, HIV-1 can be recognized by PRRs within the host cell to trigger an innate immune response, and this response is unmasked only in the absence of Vpu. Vpu modulation of IRF3 therefore prevents virus induction of specific innate defense programs that could otherwise limit infection. These observations show that HIV-1 can indeed be recognized as a pathogen in infected cells and provide a novel and effective platform for defining the native innate immune programs of target cells of HIV-1 infection.

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Deletion of Irf3 and Irf7 Genes in Mice Results in Altered Interferon Pathway Activation and Granulocyte-Dominated Inflammatory Responses to Influenza A Infection

Journal of Innate Immunity ◽

10.1159/000450705 ◽

2016 ◽

Vol 9 (2) ◽

pp. 145-161 ◽

Cited By ~ 20

Author(s):

Bastian Hatesuer ◽

Hang Thi Thu Hoang ◽

Peggy Riese ◽

Stephanie Trittel ◽

Ingo Gerhauser ◽

...

Keyword(s):

Immune Response ◽

Knockout Mice ◽

Influenza A ◽

Viral Infections ◽

Inflammatory Responses ◽

Adaptive Immune Response ◽

Strong Increase ◽

Type I ◽

Influenza A Viruses ◽

Double Knockout

The interferon (IFN) pathway plays an essential role in the innate immune response following viral infections and subsequent shaping of adaptive immunity. Infections with influenza A viruses (IAV) activate the IFN pathway after the recognition of pathogen-specific molecular patterns by respective pattern recognition receptors. The IFN regulatory factors IRF3 and IRF7 are key players in the regulation of type I and III IFN genes. In this study, we analyzed the role of IRF3 and IRF7 for the host response to IAV infections in Irf3-/-, Irf7-/-, and Irf3-/-Irf7-/- knockout mice. While the absence of IRF3 had only a moderate impact on IFN expression, deletion of IRF7 completely abolished IFNα production after infection. In contrast, lack of both IRF3 and IRF7 resulted in the absence of both IFNα and IFNβ after IAV infection. In addition, IAV infection of double knockout mice resulted in a strong increase of mortality associated with a massive influx of granulocytes in the lung and reduced activation of the adaptive immune response.

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TRIMming Type I Interferon-Mediated Innate Immune Response in Antiviral and Antitumor Defense

Viruses ◽

10.3390/v13020279 ◽

2021 ◽

Vol 13 (2) ◽

pp. 279

Author(s):

Ling Wang ◽

Shunbin Ning

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Stress Responses ◽

Viral Infections ◽

Immune Escape ◽

E3 Ligase ◽

Innate Immune ◽

Type I ◽

Antiviral Immune Response ◽

Wide Range

The tripartite motif (TRIM) family comprises at least 80 members in humans, with most having ubiquitin or SUMO E3 ligase activity conferred by their N-terminal RING domain. TRIMs regulate a wide range of processes in ubiquitination- or sumoylation-dependent manners in most cases, and fewer as adaptors. Their roles in the regulation of viral infections, autophagy, cell cycle progression, DNA damage and other stress responses, and carcinogenesis are being increasingly appreciated, and their E3 ligase activities are attractive targets for developing specific immunotherapeutic strategies for immune diseases and cancers. Given their importance in antiviral immune response, viruses have evolved sophisticated immune escape strategies to subvert TRIM-mediated mechanisms. In this review, we focus on their regulation of IFN-I-mediated innate immune response, which plays key roles in antiviral and antitumor defense.

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