Interferon Lambda: A New Sword in Cancer Immunotherapy

The discovery of the interferon-lambda (IFN-λ) family has considerably contributed to our understanding of the role of interferon not only in viral infections but also in cancer. IFN-λproteins belong to the new type III IFN group. Type III IFN is structurally similar to type II IFN (IFN-γ) but functionally identical to type I IFN (IFN-α/β). However, in contrast to type I or type II IFNs, the response to type III IFN is highly cell-type specific. Only epithelial-like cells and to a lesser extent some immune cells respond to IFN-λ. This particular pattern of response is controlled by the differential expression of the IFN-λreceptor, which, in contrast to IFN-α, should result in limited side effects in patients. Recently, we and other groups have shown in several animal models a potent antitumor role of IFN-λthat will open a new challenging era for the current IFN therapy.

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Evidence of corticosteroid action along the nephron

AJP Renal Physiology ◽

10.1152/ajprenal.1984.246.2.f111 ◽

1984 ◽

Vol 246 (2) ◽

pp. F111-F123 ◽

Cited By ~ 3

Author(s):

D. Marver

Keyword(s):

Collecting Duct ◽

Type I ◽

Type Ii ◽

Cortical Collecting Duct ◽

Distal Nephron ◽

Type Iii ◽

Collecting Ducts ◽

Collecting Tubule ◽

Cortical Collecting Tubule

The kidney contains three classes of corticosteroid-binding proteins receptors. They include a mineralocorticoid-specific (Type I), a glucocorticoid-specific (Type II), and a corticosterone-specific (Type III) site. The Type I and Type III sites roughly parallel each other along the nephron, with maximal binding occurring in the late distal convoluted or connecting segment and the cortical and medullary collecting ducts. Type II sites occur throughout the nephron, with maximal concentrations appearing in the proximal tubule and the late distal convoluted-cortical collecting duct region. The function of the Type I sites in the connecting segment is unclear since chronic mineralocorticoid therapy does not influence the potential difference in this segment as it does in the cortical collecting tubule. Furthermore, the specific role of Type II versus Type III sites in the distal nephron is unknown. Finally, the possible influence of sodium on both latent and steroid-induced renal cortical and medullary Na-K-ATPase is discussed.

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SAMHD1 Phosphorylation Coordinates the Anti-HIV-1 Response by Diverse Interferons and Tyrosine Kinase Inhibition

mBio ◽

10.1128/mbio.00819-18 ◽

2018 ◽

Vol 9 (3) ◽

Cited By ~ 15

Author(s):

Matthew A. Szaniawski ◽

Adam M. Spivak ◽

James E. Cox ◽

Jonathan L. Catrow ◽

Timothy Hanley ◽

...

Keyword(s):

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Kinase Inhibitors ◽

Restriction Factor ◽

Type I ◽

Dependent Manner ◽

Type Ii ◽

Type Iii ◽

Type Iii Ifn ◽

Hiv 1

ABSTRACTMacrophages are susceptible to human immunodeficiency virus type 1 (HIV-1) infection despite abundant expression of antiviral proteins. Perhaps the most important antiviral protein is the restriction factor sterile alpha motif domain and histidine/aspartic acid domain-containing protein 1 (SAMHD1). We investigated the role of SAMHD1 and its phospho-dependent regulation in the context of HIV-1 infection in primary human monocyte-derived macrophages and the ability of various interferons (IFNs) and pharmacologic agents to modulate SAMHD1. Here we show that stimulation by type I, type II, and to a lesser degree, type III interferons share activation of SAMHD1 via dephosphorylation at threonine-592 as a consequence of signaling. Cyclin-dependent kinase 1 (CDK1), a known effector kinase for SAMHD1, was downregulated at the protein level by all IFN types tested. Pharmacologic inhibition or small interfering RNA (siRNA)-mediated knockdown of CDK1 phenocopied the effects of IFN on SAMHD1. A panel of FDA-approved tyrosine kinase inhibitors potently induced activation of SAMHD1 and subsequent HIV-1 inhibition. The viral restriction imposed via IFNs or dasatinib could be overcome through depletion of SAMHD1, indicating that their effects are exerted primarily through this pathway. Our results demonstrate that SAMHD1 activation, but not transcriptional upregulation or protein induction, is the predominant mechanism of HIV-1 restriction induced by type I, type II, and type III IFN signaling in macrophages. Furthermore, SAMHD1 activation presents a pharmacologically actionable target through which HIV-1 infection can be subverted.IMPORTANCEOur experimental results demonstrate that SAMHD1 dephosphorylation at threonine-592 represents a central mechanism of HIV-1 restriction that is common to the three known families of IFNs. While IFN types I and II were potent inhibitors of HIV-1, type III IFN showed modest to undetectable activity. Regulation of SAMHD1 by IFNs involved changes in phosphorylation status but not in protein levels. Phosphorylation of SAMHD1 in macrophages occurred at least in part via CDK1. Tyrosine kinase inhibitors similarly induced SAMHD1 dephosphorylation, which protects macrophages from HIV-1 in a SAMHD1-dependent manner. SAMHD1 is a critical restriction factor regulating HIV-1 infection of macrophages.

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Role of Dynamic Contrast Enhanced MRI in Characterization of Breast Lesions

Nepalese Journal of Radiology ◽

10.3126/njr.v4i1.11366 ◽

2014 ◽

Vol 4 (1) ◽

pp. 23-33

Author(s):

P Issar ◽

SK Issar

Keyword(s):

Benign Lesion ◽

Breast Lesions ◽

Type I ◽

Type Ii ◽

Type Iii ◽

Dynamic Contrast Enhanced ◽

Contrast Enhanced ◽

Malignant Lesions

Purpose: To assess the role of Dynamic contrast enhanced magnetic resonance imaging in characterization of breast lesions and to differentiate benign from malignant lesions on the basis of their morphology and enhancement kinetics. Material and Methods: Sixty patients referred to the department of Radiodiagnosis for breast MRI over a period of twenty months were included. Dynamic contrast enhanced (DCE) Magnetic Resonance Imaging (MRI) was performed to differentiate breast lesions on the basis of morphology and enhancement kinetics. The lesions were classified accordingly into type I (progressive enhancement) Type II (plateau) and Type III (washout) kinetics. Morphology and curves of benign and malignant lesions were compared. Result: fifty one benign lesions were detected in 32 patients and 29 malignant lesions were seen in 22 patients, whereas six patients showed normal MRI. It was found that benign lesion were round or oval in shape with well circumscribed margin and showed homogenous contrast enhancement whereas malignant lesions were irregular with spiculated margin and showed heterogenous contrast enhancement. The distribution curve types of benign lesion were Type I (81.25%-26cases), Type II (18.25%-6cases). For malignant lesions Type I (4.54%-1case), Type II (22.72%-5cases) and Type III (72.72%-16cases). Conclusion: The shape of the time- signal intensity curve were an important criteria in differentiating benign from malignant lesions in dynamic breast MR imaging. A type III time curve is a strong indicator of malignancy and is independent of other criteria. DOI: http://dx.doi.org/10.3126/njr.v4i1.11366 Nepalese Journal of Radiology, Vol.4(1) 2014: 23-33

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Interferon-λ Attenuates Rabies Virus Infection by Inducing Interferon-Stimulated Genes and Alleviating Neurological Inflammation

Viruses ◽

10.3390/v12040405 ◽

2020 ◽

Vol 12 (4) ◽

pp. 405

Author(s):

Yingying Li ◽

Ling Zhao ◽

Zhaochen Luo ◽

Yachun Zhang ◽

Lei Lv ◽

...

Keyword(s):

Rabies Virus ◽

Neuronal Damage ◽

Inflammatory Cells ◽

Inhibitory Effect ◽

Type I ◽

Type Iii ◽

Interferon Stimulated Genes ◽

Viral Spread ◽

Type Iii Ifn

Rabies, caused by rabies virus (RABV), is a fatal neurological disease that still causes more than 59,000 human deaths each year. Type III interferon IFN-λs are cytokines with type I IFN-like antiviral activities. Although IFN-λ can restrict the infection for some viruses, especially intestinal viruses, the inhibitory effect against RABV infection remains undefined. In this study, the function of type III IFN against RABV infection was investigated. Initially, we found that IFN-λ2 and IFN-λ3 could inhibit RABV replication in cells. To characterize the role of IFN-λ in RABV infection in a mouse model, recombinant RABVs expressing murine IFN-λ2 or IFN-λ3, termed as rB2c-IFNλ2 or rB2c-IFNλ3, respectively, were constructed and rescued. It was found that expression of IFN-λ could reduce the pathogenicity of RABV and limit viral spread in the brains by different infection routes. Furthermore, expression of IFN-λ could induce the activation of the JAK-STAT pathway, resulting in the production of interferon-stimulated genes (ISGs). It was also found that rRABVs expressing IFN-λ could reduce the production of inflammatory cytokines in primary astrocytes and microgila cells, restrict the opening of the blood-brain barrier (BBB), and prevent excessive infiltration of inflammatory cells into the brain, which could be responsible for the neuronal damage caused by RABV. Consistently, IFN-λ was found to maintain the integrity of tight junction (TJ) protein ZO-1 of BBB to alleviate neuroinflammation in a transwell model. Our study underscores the role of IFN-λ in inhibiting RABV infection, which potentiates IFN-λ as a possible therapeutic agent for the treatment of RABV infection.

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Clinical and Manometric Characteristics of Patients with Achalasia: One Disease with Three Presentations or Three Diseases with One Presentation?

Journal of Gastrointestinal and Liver Diseases ◽

10.15403/jgld-2995 ◽

2020 ◽

Author(s):

Teodora Surdea-Blaga ◽

Liliana David ◽

Andrei Pop ◽

Marcel Tantau ◽

Dan Lucian Dumitrascu

Keyword(s):

Type I ◽

Type Ii ◽

Type Iii ◽

Group Type ◽

Clinical Evolution ◽

Eckardt Score ◽

Resting Pressure ◽

Esophageal Sphincter ◽

Integrated Relaxation Pressure

Background and Aims: The three manometric patterns of achalasia are considered by some authors as different stages in the evolution of the same disorder. The aims of our study were to characterize patients with achalasia, in order to find key differences supporting the idea of progression from one type to the other, and to assess the clinical evolution in time. Methods: From 280 high resolution esophageal manometry recordings we selected unique patients with achalasia. A standardized questionnaire used prior to each manometry recorded their symptoms. Manometric parameters (resting lower esophageal sphincter (LES) pressure, 4s-integrated relaxation pressure (IRP), length of the esophagus, etc.) were recorded. Patients were contacted to establish the clinical evolution. Results: We identified 108 new achalasia cases (mean age 48.2±16.2 years, 52.8% type I, 42.6% type II), 52 (48.1%) women. Dysphagia (98.1%), cough (64.8%), belching (60.2%) and reflux symptoms (53.7%) were frequently reported. Patients with type I achalasia reported more often that dysphagia worsened, compared to type II patients (χ2=7.3, p =0.007). Age, duration of dysphagia, body mass index (p=0.067) and esophageal length were similar in type I and type II achalasia. Resting LES pressure (64.7±22.6 mmHg vs. 54.3±21.6 mmHg, p=0.019) and 4s-IRP (45.3±17.6 mmHg vs. 38.4±15.5 mmHg, p=0.036) were higher in type II compared to type I achalasia. Overweight patients had a lower LES resting pressure and 4s-IRP compared to lean subjects. After a mean follow-up of 36.8±13.4 months, 49 (45.3%) patients responded to our follow-up, and 77.5% had an Eckardt score ≤ 3. Conclusions: Type I achalasia was the most common in our group. Type I patients had lower BMI but similar duration of dysphagia and mean age compared to type II. Type III is seldom and present in older patients. These findings suggest low probability of progression from type III and II to type I achalasia. Patients with type II achalasia had higher resting LES pressure and 4s-IRP than type I achalasia patients.

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Type III Interferon-Mediated Signaling Is Critical for Controlling Live Attenuated Yellow Fever Virus Infection In Vivo

mBio ◽

10.1128/mbio.00819-17 ◽

2017 ◽

Vol 8 (4) ◽

Cited By ~ 31

Author(s):

Florian Douam ◽

Yentli E. Soto Albrecht ◽

Gabriela Hrebikova ◽

Evita Sadimin ◽

Christian Davidson ◽

...

Keyword(s):

Blood Brain Barrier ◽

Yellow Fever ◽

Vaccine Strain ◽

Brain Barrier ◽

Type I ◽

Type Iii ◽

Blood Brain ◽

Type Iii Ifn ◽

Type Iii Interferon

ABSTRACT Yellow fever virus (YFV) is an arthropod-borne flavivirus, infecting ~200,000 people worldwide annually and causing about 30,000 deaths. The live attenuated vaccine strain, YFV-17D, has significantly contributed in controlling the global burden of yellow fever worldwide. However, the viral and host contributions to YFV-17D attenuation remain elusive. Type I interferon (IFN-α/β) signaling and type II interferon (IFN-γ) signaling have been shown to be mutually supportive in controlling YFV-17D infection despite distinct mechanisms of action in viral infection. However, it remains unclear how type III IFN (IFN-λ) integrates into this antiviral system. Here, we report that while wild-type (WT) and IFN-λ receptor knockout (λR−/−) mice were largely resistant to YFV-17D, deficiency in type I IFN signaling resulted in robust infection. Although IFN-α/β receptor knockout (α/βR−/−) mice survived the infection, mice with combined deficiencies in both type I signaling and type III IFN signaling were hypersusceptible to YFV-17D and succumbed to the infection. Mortality was associated with viral neuroinvasion and increased permeability of the blood-brain barrier (BBB). α/βR−/− λR−/− mice also exhibited distinct changes in the frequencies of multiple immune cell lineages, impaired T-cell activation, and severe perturbation of the proinflammatory cytokine balance. Taken together, our data highlight that type III IFN has critical immunomodulatory and neuroprotective functions that prevent viral neuroinvasion during active YFV-17D replication. Type III IFN thus likely represents a safeguard mechanism crucial for controlling YFV-17D infection and contributing to shaping vaccine immunogenicity. IMPORTANCE YFV-17D is a live attenuated flavivirus vaccine strain recognized as one of the most effective vaccines ever developed. However, the host and viral determinants governing YFV-17D attenuation and its potent immunogenicity are still unknown. Here, we analyzed the role of type III interferon (IFN)-mediated signaling, a host immune defense mechanism, in controlling YFV-17D infection and attenuation in different mouse models. We uncovered a critical role of type III IFN-mediated signaling in preserving the integrity of the blood-brain barrier and preventing viral brain invasion. Type III IFN also played a major role in regulating the induction of a potent but balanced immune response that prevented viral evasion of the host immune system. An improved understanding of the complex mechanisms regulating YFV-17D attenuation will provide insights into the key virus-host interactions that regulate host immune responses and infection outcomes as well as open novel avenues for the development of innovative vaccine strategies. IMPORTANCE YFV-17D is a live attenuated flavivirus vaccine strain recognized as one of the most effective vaccines ever developed. However, the host and viral determinants governing YFV-17D attenuation and its potent immunogenicity are still unknown. Here, we analyzed the role of type III interferon (IFN)-mediated signaling, a host immune defense mechanism, in controlling YFV-17D infection and attenuation in different mouse models. We uncovered a critical role of type III IFN-mediated signaling in preserving the integrity of the blood-brain barrier and preventing viral brain invasion. Type III IFN also played a major role in regulating the induction of a potent but balanced immune response that prevented viral evasion of the host immune system. An improved understanding of the complex mechanisms regulating YFV-17D attenuation will provide insights into the key virus-host interactions that regulate host immune responses and infection outcomes as well as open novel avenues for the development of innovative vaccine strategies.

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Differential Regulation of Type I and Type III Interferon Signaling

International Journal of Molecular Sciences ◽

10.3390/ijms20061445 ◽

2019 ◽

Vol 20 (6) ◽

pp. 1445 ◽

Cited By ~ 23

Author(s):

Megan L. Stanifer ◽

Kalliopi Pervolaraki ◽

Steeve Boulant

Keyword(s):

Immune Response ◽

Differential Regulation ◽

Type I ◽

Type Ii ◽

Interferon Signaling ◽

Type Iii ◽

Type I Ifns ◽

Current State ◽

Type Iii Ifn ◽

Type Iii Interferon

Interferons (IFNs) are very powerful cytokines, which play a key role in combatting pathogen infections by controlling inflammation and immune response by directly inducing anti-pathogen molecular countermeasures. There are three classes of IFNs: type I, type II and type III. While type II IFN is specific for immune cells, type I and III IFNs are expressed by both immune and tissue specific cells. Unlike type I IFNs, type III IFNs have a unique tropism where their signaling and functions are mostly restricted to epithelial cells. As such, this class of IFN has recently emerged as a key player in mucosal immunity. Since the discovery of type III IFNs, the last 15 years of research in the IFN field has focused on understanding whether the induction, the signaling and the function of these powerful cytokines are regulated differently compared to type I IFN-mediated immune response. This review will cover the current state of the knowledge of the similarities and differences in the signaling pathways emanating from type I and type III IFN stimulation.

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Lambda Interferon Renders Epithelial Cells of the Respiratory and Gastrointestinal Tracts Resistant to Viral Infections

Journal of Virology ◽

10.1128/jvi.00272-10 ◽

2010 ◽

Vol 84 (11) ◽

pp. 5670-5677 ◽

Cited By ~ 243

Author(s):

Markus Mordstein ◽

Eva Neugebauer ◽

Vanessa Ditt ◽

Birthe Jessen ◽

Toni Rieger ◽

...

Keyword(s):

Epithelial Cells ◽

Respiratory Tract ◽

Viral Infections ◽

Influenza B Virus ◽

Influenza B ◽

Type I ◽

Type I Ifn ◽

Sars Coronavirus ◽

Type Iii ◽

Type Iii Ifn

ABSTRACT Virus-infected cells secrete a broad range of interferons (IFN) which confer resistance to yet uninfected cells by triggering the synthesis of antiviral factors. The relative contributions of the various IFN subtypes to innate immunity against virus infections remain elusive. IFN-α, IFN-β, and other type I IFN molecules signal through a common, universally expressed cell surface receptor, whereas type III IFN (IFN-λ) uses a distinct cell-type-specific receptor complex for signaling. Using mice lacking functional receptors for type I IFN, type III IFN, or both, we found that IFN-λ plays an important role in the defense against several human pathogens that infect the respiratory tract, such as influenza A virus, influenza B virus, respiratory syncytial virus, human metapneumovirus, and severe acute respiratory syndrome (SARS) coronavirus. These viruses were more pathogenic and replicated to higher titers in the lungs of mice lacking both IFN receptors than in mice with single IFN receptor defects. In contrast, Lassa fever virus, which infects via the respiratory tract but primarily replicates in the liver, was not influenced by the IFN-λ receptor defect. Careful analysis revealed that expression of functional IFN-λ receptor complexes in the lung and intestinal tract is restricted to epithelial cells and a few other, undefined cell types. Interestingly, we found that SARS coronavirus was present in feces from infected mice lacking receptors for both type I and type III IFN but not in those from mice lacking single receptors, supporting the view that IFN-λ contributes to the control of viral infections in epithelial cells of both respiratory and gastrointestinal tracts.

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Labelling of non-A, non-B hepatitis infected chimpanzee hepatocytes with nuclease-gold conjugates

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100111367 ◽

1984 ◽

Vol 42 ◽

pp. 250-251

Author(s):

G. D. Gagne ◽

M. F. Miller ◽

D. A. Peterson

Keyword(s):

Endoplasmic Reticulum ◽

Experimental Infection ◽

Uranyl Acetate ◽

Type I ◽

Cellular Injury ◽

Type Ii ◽

Tubular Structures ◽

Type Iii ◽

Type Iv ◽

Infected Chimpanzee

Experimental infection of chimpanzees with non-A, non-B hepatitis (NANB) or with delta agent hepatitis results in the appearance of characteristic cytoplasmic alterations in the hepatocytes. These alterations include spongelike inclusions (Type I), attached convoluted membranes (Type II), tubular structures (Type III), and microtubular aggregates (Type IV) (Fig. 1). Type I, II and III structures are, by association, believed to be derived from endoplasmic reticulum and may be morphogenetically related. Type IV structures are generally observed free in the cytoplasm but sometimes in the vicinity of type III structures. It is not known whether these structures are somehow involved in the replication and/or assembly of the putative NANB virus or whether they are simply nonspecific responses to cellular injury. When treated with uranyl acetate, type I, II and III structures stain intensely as if they might contain nucleic acids. If these structures do correspond to intermediates in the replication of a virus, one might expect them to contain DNA or RNA and the present study was undertaken to explore this possibility.

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Perforator preservation technologies (PPT) based on a new neuro-interventional classification in endovascular treatment of perforator involving aneurysms (piANs)

Chinese Neurosurgical Journal ◽

10.1186/s41016-021-00243-3 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Chen Li ◽

Ao-Fei Liu ◽

Han-Cheng Qiu ◽

Xianli Lv ◽

Ji Zhou ◽

...

Keyword(s):

Endovascular Therapy ◽

Saccular Aneurysm ◽

Type I ◽

Type Ii ◽

Fusiform Aneurysm ◽

Type Iii ◽

Perforating Artery ◽

Protection Technology ◽

Perforating Arteries

Abstract Background Treatment of perforator involving aneurysm (piAN) remains a challenge to open and endovascular neurosurgeons. Our aim is to demonstrate a primary outcome of endovascular therapy for piANs with the use of perforator preservation technologies (PPT) based on a new neuro-interventional classification. Methods The piANs were classified into type I: aneurysm really arises from perforating artery, type II: saccular aneurysm involves perforating arteries arising from its neck (IIa) or dome (IIb), and type III: fusiform aneurysm involves perforating artery. Stent protection technology of PPT was applied in type I and III aneurysms, and coil-basket protection technology in type II aneurysms. An immediate outcome of aneurysmal obliteration after treatment was evaluated (satisfactory obliteration: the saccular aneurysm body is densely embolized (I), leaving a gap in the neck (IIa) or dome (IIb) where the perforating artery arising; fusiform aneurysm is repaired and has a smooth inner wall), and successful perforating artery preservation was defined as keeping the good antegrade flow of those perforators on postoperative angiography. The periprocedural complication was closely monitored, and clinical and angiographic follow-ups were performed. Results Six consecutive piANs (2 ruptured and 4 unruptured; 1 type I, 2 type IIa, 2 type IIb, and 1 type III) in 6 patients (aged from 43 to 66 years; 3 males) underwent endovascular therapy between November 2017 and July 2019. The immediate angiography after treatment showed 6 aneurysms obtained satisfactory obliteration, and all of their perforating arteries were successfully preserved. During clinical follow-up of 13–50 months, no ischemic or hemorrhagic event of the brain occurred in the 6 patients, but has one who developed ischemic event in the territory of involving perforators 4 h after operation and completely resolved within 24 h. Follow-up angiography at 3 to 10M showed patency of the parent artery and perforating arteries of treated aneurysms, with no aneurysmal recurrence. Conclusions Our perforator preservation technologies on the basis of the new neuro-interventional classification seem feasible, safe, and effective in protecting involved perforators while occluding aneurysm.

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