Junín Virus Infection of Human Hematopoietic Progenitors Impairs In Vitro Proplatelet Formation and Platelet Release via a Bystander Effect Involving Type I IFN Signaling

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.

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Type I interferon underlies severe disease associated with Junín virus infection in mice

eLife ◽

10.7554/elife.55352 ◽

2020 ◽

Vol 9 ◽

Author(s):

Brady T Hickerson ◽

Eric J Sefing ◽

Kevin W Bailey ◽

Arnaud J Van Wettere ◽

Manuel L Penichet ◽

...

Keyword(s):

Severe Disease ◽

Hemorrhagic Fever ◽

Interferon Α ◽

Hemorrhagic Disease ◽

Type I ◽

Type I Ifn ◽

Junin Virus ◽

Human Transferrin Receptor ◽

Transferrin Receptor 1 ◽

Junín Virus

Junín virus (JUNV) is one of five New World mammarenaviruses (NWMs) that causes fatal hemorrhagic disease in humans and is the etiological agent of Argentine hemorrhagic fever (AHF). The pathogenesis underlying AHF is poorly understood; however, a prolonged, elevated interferon-α (IFN-α) response is associated with a negative disease outcome. A feature of all NWMs that cause viral hemorrhagic fever is the use of human transferrin receptor 1 (hTfR1) for cellular entry. Here, we show that mice expressing hTfR1 develop a lethal disease course marked by an increase in serum IFN-α concentration when challenged with JUNV. Further, we provide evidence that the type I IFN response is central to the development of severe JUNV disease in hTfR1 mice. Our findings identify hTfR1-mediated entry and the type I IFN response as key factors in the pathogenesis of JUNV infection in mice.

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Junín Virus Infection Activates the Type I Interferon Pathway in a RIG-I-Dependent Manner

PLoS Neglected Tropical Diseases ◽

10.1371/journal.pntd.0001659 ◽

2012 ◽

Vol 6 (5) ◽

pp. e1659 ◽

Cited By ~ 45

Author(s):

Cheng Huang ◽

Olga A. Kolokoltsova ◽

Nadezdha E. Yun ◽

Alexey V. Seregin ◽

Allison L. Poussard ◽

...

Keyword(s):

Virus Infection ◽

Type I Interferon ◽

Type I ◽

Dependent Manner ◽

Junin Virus ◽

Interferon Pathway ◽

Junín Virus

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Author response: Type I interferon underlies severe disease associated with Junín virus infection in mice

10.7554/elife.55352.sa2 ◽

2020 ◽

Author(s):

Brady T Hickerson ◽

Eric J Sefing ◽

Kevin W Bailey ◽

Arnaud J Van Wettere ◽

Manuel L Penichet ◽

...

Keyword(s):

Virus Infection ◽

Type I Interferon ◽

Severe Disease ◽

Author Response ◽

Type I ◽

Response Type ◽

Junin Virus ◽

Junín Virus

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Decision letter: Type I interferon underlies severe disease associated with Junín virus infection in mice

10.7554/elife.55352.sa1 ◽

2020 ◽

Author(s):

Juan Carlos de la Torre

Keyword(s):

Virus Infection ◽

Type I Interferon ◽

Severe Disease ◽

Type I ◽

Junin Virus ◽

Junín Virus

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Megakaryocytes of patients with MYH9-related thrombocytopenia present an altered proplatelet formation

Thrombosis and Haemostasis ◽

10.1160/th09-01-0068 ◽

2009 ◽

Vol 102 (07) ◽

pp. 90-96 ◽

Cited By ~ 39

Author(s):

Alessandro Malara ◽

Stefania Badalucco ◽

Valeria Bozzi ◽

Mauro Torti ◽

Carlo L. Balduini ◽

...

Keyword(s):

Bone Marrow ◽

Type I Collagen ◽

Autosomal Dominant ◽

Lower Number ◽

Type I ◽

Related Disease ◽

Platelet Release ◽

Proplatelet Formation ◽

Myosin Iia

Summary MYH9-related disease (MYH9-RD) is an autosomal-dominant thrombocytopenia caused by mutations of MYH9, the gene for the heavy chain of myosin-IIA. Pathogenesis of thrombocytopenia of MYH9-RD is unknown. Recent studies in mice demonstrated that myosin-IIA is an inhibitor of proplatelet formation (PPF), and suggested that it could be involved in the suppression of PPF exerted by megakaryocyte adhesion to type I collagen, which regulates the timing of platelet release within bone marrow. However, the consequences on PPF of the heterozygous mutations causative of the MYH9-RD have never been investigated. We studied the in-vitro PPF by megakaryocytes obtained from four patients carrying the p.D1424N or the p.R1933X mutations. We demonstrated that MYH9-RD megakaryocytes completely lose the physiologic suppression of proplatelet extension exerted by interaction with type I collagen, thus supporting the hypothesis that a premature platelet release within bone marrow contributes to pathogenesis of MYH9-related thrombocytopenia. Moreover, proplatelets extended by MYH9-RD megakaryocytes presented a significant defect in branching in secondary processes (p=0.001) and formed a significantly lower number of proplatelet tips (p=0.005). Since platelets are assembled at the level of proplatelet tips, this defect could further contribute to pathogenesis of thrombocytopenia of MYH9-RD patients.

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In VivoConditions Enable IFNAR-Independent Type I Interferon Production by Peritoneal CD11b+Cells upon Thogoto Virus Infection

Journal of Virology ◽

10.1128/jvi.00744-16 ◽

2016 ◽

Vol 90 (20) ◽

pp. 9330-9337 ◽

Cited By ~ 5

Author(s):

Georg Kochs ◽

Martina Anzaghe ◽

Stefanie Kronhart ◽

Valentina Wagner ◽

Patricia Gogesch ◽

...

Keyword(s):

Virus Infection ◽

Positive Feedback ◽

Molecular Mechanisms ◽

Viral Infections ◽

Type I Interferons ◽

Type I ◽

Type I Ifn ◽

Cell Type ◽

Type I Ifns

ABSTRACTType I interferons (IFNs) crucially contribute to host survival upon viral infections. Robust expression of type I IFNs (IFN-α/β) and induction of an antiviral state critically depend on amplification of the IFN signal via the type I IFN receptor (IFNAR). A small amount of type I IFN produced early upon virus infection binds the IFNAR and activates a self-enhancing positive feedback loop, resulting in induction of large, protective amounts of IFN-α. Unexpectedly, we found robust, systemic IFN-α expression upon infection of IFNAR knockout mice with the orthomyxovirus Thogoto virus (THOV). The IFNAR-independent IFN-α production requiredin vivoconditions and was not achieved duringin vitroinfection. Using replication-incompetent THOV-derived virus-like particles, we demonstrate that IFNAR-independent type I IFN induction depends on viral polymerase activity but is largely independent of viral replication. To discover the cell type responsible for this effect, we used type I IFN reporter mice and identified CD11b+F4/80+myeloid cells within the peritoneal cavity of infected animals as the main source of IFNAR-independent type I IFN, corresponding to the particular tropism of THOV for this cell type.IMPORTANCEType I IFNs are crucial for the survival of a host upon most viral infections, and, moreover, they shape subsequent adaptive immune responses. Production of protective amounts of type I IFN critically depends on the positive feedback amplification via the IFNAR. Unexpectedly, we observed robust IFNAR-independent type I IFN expression upon THOV infection and unraveled molecular mechanisms and determined the tissue and cell type involved. Our data indicate that the host can effectively use alternative pathways to induce type I IFN responses if the classical feedback amplification is not available. Understanding how type I IFN can be produced in large amounts independently of IFNAR-dependent enhancement will identify mechanisms which might contribute to novel therapeutic strategies to fight viral pathogens.

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Effect of Ribavirin on Junin Virus Infection in Guinea Pigs

Zoonoses and Public Health ◽

10.1111/j.1863-2378.2011.01447.x ◽

2012 ◽

Vol 59 (4) ◽

pp. 278-285 ◽

Cited By ~ 13

Author(s):

M. Salazar ◽

N. E. Yun ◽

A. L. Poussard ◽

J. N. Smith ◽

J. K. Smith ◽

...

Keyword(s):

Virus Infection ◽

Guinea Pigs ◽

Junin Virus ◽

Junín Virus

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Role of the chaperone protein 14-3-3ε in the regulation of influenza A virus-activated beta interferon

Journal of Virology ◽

10.1128/jvi.00231-21 ◽

2021 ◽

Author(s):

Ee-Hong Tam ◽

Yen-Chin Liu ◽

Chian-Huey Woung ◽

Helene Minyi Liu ◽

Guan-Hong Wu ◽

...

Keyword(s):

Virus Infection ◽

Influenza A Virus ◽

Influenza A ◽

Critical Role ◽

Type I ◽

Type I Ifn ◽

Ns1 Protein ◽

Chaperone Protein ◽

Influenza A Virus Infection

The NS1 protein of the influenza A virus plays a critical role in regulating several biological processes in cells, including the type I interferon (IFN) response. We previously profiled the cellular factors that interact with the NS1 protein of influenza A virus and found that the NS1 protein interacts with proteins involved in RNA splicing/processing, cell cycle regulation, and protein targeting processes, including 14-3-3ε. Since 14-3-3ε plays an important role in RIG-I translocation to MAVS to activate type I IFN expression, the interaction of the NS1 and 14-3-3ε proteins may prevent the RIG-I-mediated IFN response. In this study, we confirmed that the 14-3-3ε protein interacts with the N-terminal domain of the NS1 protein and that the NS1 protein inhibits RIG-I-mediated IFN-β promoter activation in 14-3-3ε-overexpressing cells. In addition, our results showed that knocking down 14-3-3ε can reduce IFN-β expression elicited by influenza A virus and enhance viral replication. Furthermore, we found that threonine in the 49 th amino acid position of the NS1 protein plays a role in the interaction with 14-3-3ε. Influenza A virus expressing C-terminus-truncated NS1 with T49A mutation dramatically increases IFN-β mRNA in infected cells and causes slower replication than that of virus without the T-to-A mutation. Collectively, this study demonstrates that 14-3-3ε is involved in influenza A virus-initiated IFN-β expression and that the interaction of the NS1 protein and 14-3-3ε may be one of the mechanisms for inhibiting type I IFN activation during influenza A virus infection. IMPORTANCE Influenza A virus is an important human pathogen causing severe respiratory disease. The virus has evolved several strategies to dysregulate the innate immune response and facilitate its replication. We demonstrate that the NS1 protein of influenza A virus interacts with the cellular chaperone protein 14-3-3ε, which plays a critical role in RIG-I translocation that induces type I IFN expression, and that NS1 protein prevents RIG-I translocation to mitochondrial membrane. The interaction site for 14-3-3ε is the RNA-binding domain (RBD) of the NS1 protein. Therefore, this research elucidates a novel mechanism by which the NS1 RBD mediates IFN-β suppression to facilitate influenza A viral replication. Additionally, the findings reveal the antiviral role of 14-3-3ε during influenza A virus infection.

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

Bioscience Reports ◽

10.1042/bsr20192769 ◽

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.

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