Loss of the TAM Receptor Axl Ameliorates Severe Zika Virus Pathogenesis and Reduces Apoptosis in Microglia

Hastings, Andrew K.; Hastings, Karen Taraszka; Uraki, Ryuta; Hwang, Jesse; Gaitsch, Hallie; Dhaliwal, Khushwant; Williamson, Eric; Fikrig, Erol

doi:10.1016/j.isci.2019.03.003

Cited by 23 publications

(18 citation statements)

References 55 publications

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“…Besides that, a more recent study showed that AXL expression may be important for ZIKV brain pathogenesis development due to an increased mice survival, decreased microglia apoptosis, and IL‐1β release in the absence of AXL and IFNAR. This evidences the role of AXL during ZIKV infection and its dependency on type I IFN response regulation …”

Section: Phosphatidyl Serine Receptorssupporting

confidence: 59%

“…This evidences the role of AXL during ZIKV infection and its dependency on type I IFN response regulation. 63 Although many reports have demonstrated the role of TAM receptors on flavivirus infection both in vitro and in vivo, intriguingly, some reports have shown opposite results. 53,64 For example, in vivo experimental approaches with ZIKV infection have demonstrated that viral replication in testis is independent on AXL expression.…”

Section: Phosphatidyl Serine Receptorsmentioning

confidence: 99%

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Viral receptors for flaviviruses: Not only gatekeepers

Oliveira

Peron²

2019

Journal of Leukocyte Biology

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Arboviruses have been a huge threat for human health since the discovery of yellow fever virus in 1901. Arboviruses are arthropod born viruses, mainly transmitted by mosquitoes and ticks, responsible for more than thousands of deaths annually. The Flavivirideae family is probably the most clinically relevant, as it is composed of very important agents, such as dengue, yellow fever, West Nile, Japanese encephalitis, and, recently, Zika virus. Intriguingly, despite their structural and genomic similarities, flaviviruses may cause conditions ranging from mild infections with fever, cutaneous rash, and headache, to very severe cases, such as hemorrhagic fever, encephalitis, Guillain‐Barré syndrome, and microcephaly. These differences may greatly rely on viral burden, tissue tropism, and mechanisms of immune evasion that may depend on both viral and host genetic factors. Unfortunately, very little is known about the biology of these factors, and how they orchestrate these differences. In this context, viral structural proteins and host cellular receptors may have a great relevance, as their interaction dictates not only viral tissue tropism, but also a plethora on intracellular mechanisms that may greatly account for either failure or success of infection. A great number of viral receptors have been described so far, although there is still a huge gap in understanding their overall role during infection. Here we discuss some important aspects triggered after the interaction of flaviviruses and host membrane receptors, and how they change the overall outcome of the infection.

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Section: Phosphatidyl Serine Receptorssupporting

confidence: 59%

Section: Phosphatidyl Serine Receptorsmentioning

confidence: 99%

Viral receptors for flaviviruses: Not only gatekeepers

Oliveira

Peron²

2019

Journal of Leukocyte Biology

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“…Although many studies have proposed that Axl serves as an entry receptor for several flaviviruses, accumulating evidence suggests that Axl plays unique roles in a virus type-dependent manner. For example, Axl mediates the entry of DENV ( 13 ), inhibits WNV neuroinvasion without affecting viral replication in target organs ( 14 ), and also enhances ZIKV pathogenesis in an age-dependent manner by exacerbating IL-1β production and apoptosis in microglia ( 18 ). Our results show that Axl impedes JEV neuroinvasion by antagonizing viral-induced pyroptosis in peritoneal macrophages and subsequent IL-1α release.…”

Section: Discussionmentioning

confidence: 99%

“…Although Axl promotes ZIKV infection in many cell types in vitro , its knockout has no impact on ZIKV replication or pathogenesis in mouse models, human neural progenitor cells, or cerebral organoids ( 15 – 17 ). Recently, Axl knockout mice were shown to be resistant to ZIKV pathogenesis in an age-dependent manner, corresponding to lower prointerleukin-1β (pro-IL-1β) production and decreased apoptosis in microglia ( 18 ). The complexity of the contributions of Axl to flaviviral infection is potentially associated with its versatile functions.…”

Section: Introductionmentioning

confidence: 99%

Axl Deficiency Promotes the Neuroinvasion of Japanese Encephalitis Virus by Enhancing IL-1α Production from Pyroptotic Macrophages

Wang

Zhen

Fan

et al. 2020

J Virol

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Japanese encephalitis virus (JEV) is a flavivirus that causes Japanese encephalitis (JE), which has an unclear pathogenesis. Despite vaccination, thousands of deaths attributed to JE are reported annually. In this study, we report that mice deficient for Axl, a receptor tyrosine kinase that plays multiple roles in flaviviral infection, displayed greater mortality upon JEV infection. The effect of Axl deficiency on JEV infection was mediated by markedly elevated serum interleukin-1α (IL-1α) levels, which devastated the blood-brain-barrier and promoted viral neuroinvasion within 24 h post infection. Using an in situ infection model, we showed that dead macrophages were the primary source of observed increased serum IL-1α levels. Axl deficiency enhanced cell death and caused pyroptosis in 80% of JEV-infected macrophages by disrupting PI3K-Akt signaling. Intriguingly, the primary effector released by pyroptotic macrophages in our model was IL-1α rather than IL-1β. Finally, we assessed the effect of an IL-1α antagonist and demonstrated that it effectively prevented the incidence of JE. Our results indicate that Axl plays a protective role in JEV infection, identify IL-1α released by pyroptotic macrophages as a crucial factor promoting JEV neuroinvasion, and suggest that an IL-1α antagonist may be a candidate for JE therapy. IMPORTANCE Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus that causes Japanese encephalitis (JE), the most commonly diagnosed viral encephalitis worldwide. The fatality rate of JE is 20%, and nearly half of the surviving patients develop neuropsychiatric sequelae. Axl is a receptor tyrosine kinase that plays multiple roles in flaviviral infections. Currently, the involvement of Axl in JEV infection remains enigmatic. In this study, we demonstrate that Axl impedes the pathogenesis of severe JE in mice by maintaining blood-brain-barrier (BBB) integrity and restricting viral neuroinvasion. Furthermore, serum IL-1α is a key mediator of this process and is primarily released by JEV-infected pyroptotic macrophages to elicit BBB breakdown, while an IL-1α antagonist can effectively reduce the incidence of severe JE. Our work uncovers the protective role of Axl in antagonizing severe JE and shows that the use of IL-1α antagonist may be a promising tactic to prevent severe JE.

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“…Countless studies showed that ZIKV infection causes cell death through several cell death mechanisms such as paraptosis and apoptosis [12,88] Apoptotic events in ZIKV-infected cells occur through both the intrinsic and extrinsic pathways based on the activation of pathway-specific caspase-9 and caspase-8, respectively [88,89]. Interestingly, ZIKV Env protein is sufficiently capable to induce pro-apoptotic expression profile that represents intrinsic apoptosis including elevated expression of tumor protein p53, which correspondingly mediates the expression and activity of its downstream targets by suppressing anti-apoptotic BCL-2 and facilitating expression of pro-apoptotic Bcl-2associated X (BAX) [90].…”

Section: Zikv-induced Er Stress Leads To Paraptosis-like Cell Deathmentioning

confidence: 99%

Endoplasmic reticulum: a focal point of Zika virus infection

et al. 2020

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Zika virus (ZIKV) belongs to the Flavivirus genus of the Flaviviridae family. It is an arbovirus that can cause congenital abnormalities and is sexually transmissible. A series of outbreaks accompanied by unexpected severe clinical complications have captured medical attention to further characterize the clinical features of congenital ZIKV syndrome and its underlying pathophysiological mechanisms. Endoplasmic reticulum (ER) and ER-related proteins are essential in ZIKV genome replication. This review highlights the subcellular localization of ZIKV to the ER and ZIKV modulation on the architecture of the ER. This review also discusses ZIKV interaction with ER proteins such as signal peptidase complex subunit 1 (SPCS1), ER membrane complex (EMC) subunits, and ER translocon for viral replication. Furthermore, the review covers several important resulting effects of ZIKV infection to the ER and cellular processes including ER stress, reticulophagy, and paraptosis-like death. Pharmacological targeting of ZIKVaffected ER-resident proteins and ER-associated components demonstrate promising signs of combating ZIKV infection and rescuing host organisms from severe neurologic sequelae.

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Loss of the TAM Receptor Axl Ameliorates Severe Zika Virus Pathogenesis and Reduces Apoptosis in Microglia

Cited by 23 publications

References 55 publications

Viral receptors for flaviviruses: Not only gatekeepers

Viral receptors for flaviviruses: Not only gatekeepers

Axl Deficiency Promotes the Neuroinvasion of Japanese Encephalitis Virus by Enhancing IL-1α Production from Pyroptotic Macrophages

Endoplasmic reticulum: a focal point of Zika virus infection

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