Kellie Ann Jurado

Zika virus causes testicular atrophy

Zika virus replicates in mouse testes and causes testicular atrophy, with implication on sexual transmission and male fertility. Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that has recently been found to cause fetal infection and neonatal abnormalities, including microcephaly and neurological dysfunction. ZIKV persists in the semen months after the acute viremic phase in humans. To further understand the consequences of ZIKV persistence in males, we infected Ifnar1−/− mice via subcutaneous injection of a pathogenic but nonlethal ZIKV strain. ZIKV replication persists within the testes even after clearance from the blood, with interstitial, testosterone-producing Leydig cells supporting virus replication. We found high levels of viral RNA and antigen within the epididymal lumen, where sperm is stored, and within surrounding epithelial cells. Unexpectedly, at 21 days post-infection, the testes of the ZIKV-infected mice were significantly smaller compared to those of mock-infected mice, indicating progressive testicular atrophy. ZIKV infection caused a reduction in serum testosterone, suggesting that male fertility can be affected. Our findings have important implications for nonvector-borne vertical transmission, as well as long-term potential reproductive deficiencies, in ZIKV-infected males.

Nlrp9b inflammasome restricts rotavirus infection in intestinal epithelial cells

Rotavirus, a leading cause of severe gastroenteritis and diarrhoea in young children, accounts for around 215,000 deaths annually worldwide. Rotavirus specifically infects the intestinal epithelial cells in the host small intestine and has evolved strategies to antagonize interferon and NF-κB signalling, raising the question as to whether other host factors participate in antiviral responses in intestinal mucosa. The mechanism by which enteric viruses are sensed and restricted in vivo, especially by NOD-like receptor (NLR) inflammasomes, is largely unknown. Here we uncover and mechanistically characterize the NLR Nlrp9b that is specifically expressed in intestinal epithelial cells and restricts rotavirus infection. Our data show that, via RNA helicase Dhx9, Nlrp9b recognizes short double-stranded RNA stretches and forms inflammasome complexes with the adaptor proteins Asc and caspase-1 to promote the maturation of interleukin (Il)-18 and gasdermin D (Gsdmd)-induced pyroptosis. Conditional depletion of Nlrp9b or other inflammasome components in the intestine in vivo resulted in enhanced susceptibility of mice to rotavirus replication. Our study highlights an important innate immune signalling pathway that functions in intestinal epithelial cells and may present useful targets in the modulation of host defences against viral pathogens.

Zika virus infection of Hofbauer cells

Recent studies have linked antenatal infection with Zika virus (ZIKV) with major adverse fetal and neonatal outcomes, including microcephaly. There is a growing consensus for the existence of a congenital Zika syndrome (CZS). Previous studies have indicated that non‐placental macrophages play a key role in the replication of dengue virus (DENV), a closely related flavivirus. As the placenta provides the conduit for vertical transmission of certain viruses, and placental Hofbauer cells (HBCs) are fetal—placental macrophages located adjacent to fetal capillaries, it is not surprising that several recent studies have examined infection of HBCs by ZIKV. In this review, we describe congenital abnormalities associated with ZIKV infection, the role of HBCs in the placental response to infection, and evidence for the susceptibility of HBCs to ZIKV infection. We conclude that HBCs may contribute to the spread of ZIKV in placenta and promote vertical transmission of ZIKV, ultimately compromising fetal and neonatal development and function. Current evidence strongly suggests that further studies are warranted to dissect the specific molecular mechanism through which ZIKV infects HBCs and its potential impact on the development of CZS.

Type I interferons instigate fetal demise after Zika virus infection

After Zika virus infection, fetal type I interferon signaling is responsible for abnormal placental development and fetal resorption. The interferon boomerang Interferon-α/β receptor (IFNAR)–deficient mice are highly susceptible to viruses, including Zika virus (ZIKV). Previous studies modeled ZIKV infection during pregnancy in mice by crossing Ifnar1−/− females to wild-type males, generating Ifnar1+/− fetuses that retain type I interferon (IFN) responsiveness. Yockey et al. have directly examined the role of fetal type I IFN signaling in protection in this context, by crossing Ifnar1−/− females to Ifnar1+/− males. Although Ifnar1−/− fetuses had higher ZIKV titers as compared with Ifnar1+/− fetuses, Ifnar1−/− fetuses survived longer. Furthermore, they found that activation of type I IFN signaling in the placentas of Ifnar1+/− fetuses led to fetal hypoxia, demise, and resorption. Beyond ZIKV infection, the study calls for closer examination of the role of IFNs in pregnancy-associated complications. Zika virus (ZIKV) infection during pregnancy is associated with adverse fetal outcomes, including microcephaly, growth restriction, and fetal demise. Type I interferons (IFNs) are essential for host resistance against ZIKV, and IFN-α/β receptor (IFNAR)–deficient mice are highly susceptible to ZIKV infection. Severe fetal growth restriction with placental damage and fetal resorption is observed after ZIKV infection of type I IFN receptor knockout (Ifnar1−/−) dams mated with wild-type sires, resulting in fetuses with functional type I IFN signaling. The role of type I IFNs in limiting or mediating ZIKV disease within this congenital infection model remains unknown. In this study, we challenged Ifnar1−/− dams mated with Ifnar1+/− sires with ZIKV. This breeding scheme enabled us to examine pregnant dams that carry a mixture of fetuses that express (Ifnar1+/−) or do not express IFNAR (Ifnar1−/−) within the same uterus. Virus replicated to a higher titer in the placenta of Ifnar1−/− than within the Ifnar1+/− concepti. Yet, rather unexpectedly, we found that only Ifnar1+/− fetuses were resorbed after ZIKV infection during early pregnancy, whereas their Ifnar1−/− littermates continue to develop. Analyses of the fetus and placenta revealed that, after ZIKV infection, IFNAR signaling in the conceptus inhibits development of the placental labyrinth, resulting in abnormal architecture of the maternal-fetal barrier. Exposure of midgestation human chorionic villous explants to type I IFN, but not type III IFNs, altered placental morphology and induced cytoskeletal rearrangements within the villous core. Our results implicate type I IFNs as a possible mediator of pregnancy complications, including spontaneous abortions and growth restriction, in the context of congenital viral infections.

Fetal Growth Restriction Caused by Sexual Transmission of Zika Virus in Mice

Zika virus (ZIKV) can be transmitted by mosquito bite or sexual contact. Using mice that lack the type I interferon receptor, we examined sexual transmission of ZIKV. Electron microscopy analyses showed association of virions with developing sperm within testes as well as with mature sperm within epididymis. When ZIKV-infected male mice were mated with naive female mice, the weight of fetuses at embryonic day 18.5 was significantly reduced compared with the control group. Additionally, we found ocular deformities in a minority of the fetuses. These results suggest that ZIKV causes fetal abnormalities after female mating with an infected male.

Antiviral CD8 T cells induce Zika-virus-associated paralysis in mice

Zika virus (ZIKV) is an emerging, mosquito-borne RNA virus. The rapid spread of ZIKV within the Americas has unveiled microcephaly1 and Guillain–Barré syndrome2,3 as ZIKV-associated neurological complications. Recent reports have also indicated other neurological manifestations to be associated with ZIKV, including myelitis4, meningoencephalitis5 and fatal encephalitis6. Here, we investigate the neuropathogenesis of ZIKV infection in type I interferon receptor IFNAR knockout (Ifnar1−/−) mice, an infection model that exhibits high viral burden within the central nervous system. We show that systemic spread of ZIKV from the site of infection to the brain requires Ifnar1 deficiency in the haematopoietic compartment. However, spread of ZIKV within the central nervous system is supported by Ifnar1-deficient non-haematopoietic cells. Within this context, ZIKV infection of astrocytes results in breakdown of the blood–brain barrier and a large influx of CD8+ effector T cells. We also find that antiviral activity of CD8+ T cells within the brain markedly limits ZIKV infection of neurons, but, as a consequence, instigates ZIKV-associated paralysis. Taken together, our study uncovers mechanisms underlying ZIKV neuropathogenesis within a susceptible mouse model and suggests blood–brain barrier breakdown and T-cell-mediated neuropathology as potential underpinnings of ZIKV-associated neurological complications in humans.Zika virus infection of astrocytes in Ifnar–/– mice results in breakdown of the blood–brain barrier and CD8+ effector T-cell infiltration, which limits neuron infection but leads to Zika-virus-associated paralysis.

An Antiviral Branch of the IL-1 Signaling Pathway Restricts Immune-Evasive Virus Replication

Virulent pathogens often cause the release of host-derived damage-associated molecular patterns (DAMPs) from infected cells. During encounters with immune-evasive viruses that block inflammatory gene expression, preformed DAMPs provide backup inflammatory signals that ensure protective immunity. Whether DAMPs exhibit additional backup defense activities is unknown. Herein, we report that viral infection of barrier epithelia (keratinocytes) elicits the release of preformed interleukin-1 (IL-1) family cytokines, including the DAMP IL-1α. Mechanistic studies revealed that IL-1 acts on skin fibroblasts to induce an interferon (IFN)-like state that restricts viral replication. We identified a branch in the IL-1 signaling pathway that induces IFN-stimulated gene expression in infected cells and found that IL-1 signaling is necessary to restrict viral replication in human skin explants. These activities are most important to control immune-evasive virus replication in fibroblasts and other barrier cell types. These findings highlight IL-1 as an important backup antiviral system to ensure barrier defense.

Zika virus targets blood monocytes

Two studies identify circulating monocytes as the primary cellular target of Zika virus infection in human blood. Monocytes are an ideal target as they have the potential to be used as a Trojan horse to infiltrate immune-sheltered tissues, including placenta, testes and the brain, to spread Zika virus.

Genetics of War and Truce between Mosquitos and Emerging Viruses

Arboviruses have made unexpected reappearances in recent years. Unlike viruses that undergo direct transmission, arboviruses utilize an arthropod vector (e.g., mosquitos, sandflies, and ticks) to spread throughout human populations. Here, we provide a snapshot of mosquito susceptibility to viral infection using flaviviruses, alphaviruses, and bunyaviruses as examples of emerging pathogens of global health relevance.

Publisher Correction: Antiviral CD8 T cells induce Zika-virus-associated paralysis in mice

In the version of this Letter originally published, technical problems led to errors in Figs. 3e and 4f. In Fig. 3e, the bottom right graph had an incorrect title of ‘CD8+ T cells’; it should have instead been ‘CD4+ T cells’. In Fig. 4f, the bottom panels had an incorrect title of ‘CD8 competent Ifnar–/–7 d.p.i. cerebral cortex’; it should have instead been ‘CD8 depleted Ifnar–/– 7 d.p.i. cerebral cortex’. These errors have now been corrected in all versions of the Letter.