Pathogenesis Of Zika Virus Infection Research Articles

In vitro and in vivo inhibition of the host TRPC4 channel attenuates Zika virus infection

Zika virus (ZIKV) infection may lead to severe neurological consequences, including seizures, and early infancy death. However, the involved mechanisms are still largely unknown. TRPC channels play an important role in regulating nervous system excitability and are implicated in seizure development. We investigated whether TRPCs might be involved in the pathogenesis of ZIKV infection. We found that ZIKV infection increases TRPC4 expression in host cells via the interaction between the ZIKV-NS3 protein and CaMKII, enhancing TRPC4-mediated calcium influx. Pharmacological inhibition of CaMKII decreased both pCREB and TRPC4 protein levels, whereas the suppression of either TRPC4 or CaMKII improved the survival rate of ZIKV-infected cells and reduced viral protein production, likely by impeding the replication phase of the viral life cycle. TRPC4 or CaMKII inhibitors also reduced seizures and increased the survival of ZIKV-infected neonatal mice and blocked the spread of ZIKV in brain organoids derived from human-induced pluripotent stem cells. These findings suggest that targeting CaMKII or TRPC4 may offer a promising approach for developing novel anti-ZIKV therapies, capable of preventing ZIKV-associated seizures and death.

Revealing the characteristics of ZIKV infection through tissue-specific transcriptome sequencing analysis

BackgroundRecently, Zika virus (ZIKV) re-emerged in India and was potentially associated with microcephaly. However, the molecular mechanisms underlying ZIKV pathogenesis remain to be explored.ResultsHerein, we performed a comprehensive RNA-sequencing analysis on ZIKV-infected JEG-3, U-251 MG, and HK-2 cells versus corresponding uninfected controls. Combined with a series of functional analyses, including gene annotation, pathway enrichment, and protein–protein interaction (PPI) network analysis, we defined the molecular characteristics induced by ZIKV infection in different tissues and invasion time points. Data showed that ZIKV infection and replication in each susceptible organ commonly stimulated interferon production and down-regulated metabolic-related processes. Also, tissue-specific immune responses or biological processes (BPs) were induced after ZIKV infection, including GnRH signaling pathway in JEG-3 cells, MAPK signaling pathway in U-251 MG cells, and PPAR signaling pathway in HK-2 cells. Of note, ZIKV infection induced delayed antiviral interferon responses in the placenta-derived cell lines, which potentially explains the molecular mechanism by which ZIKV replicates rapidly in the placenta and subsequential vertical transmission occurs.ConclusionsTogether, these data may provide a systemic insight into the pathogenesis of ZIKV infection in distinct human tissue-derived cell lines, which is likely to help develop prophylactic and therapeutic strategies against ZIKV infection.

SARM1 Depletion Slows Axon Degeneration in a CNS Model of Neurotropic Viral Infection.

Zika virus (ZIKV) is a neurotropic flavivirus recently linked to congenital ZIKV syndrome in children and encephalitis and Guillain-Barré syndrome in adults. Neurotropic viruses often use axons to traffic to neuronal or glial cell somas where they either remain latent or replicate and proceed to infect new cells. Consequently, it has been suggested that axon degeneration could represent an evolutionarily conserved mechanism to limit viral spread. Whilst it is not known if ZIKV transits in axons, we previously reported that ZIKV infection of glial cells in a murine spinal cord-derived cell culture model of the CNS is associated with a profound loss of neuronal cell processes. This, despite that postmitotic neurons are relatively refractory to infection and death. Here, we tested the hypothesis that ZIKV-associated degeneration of neuronal processes is dependent on activation of Sterile alpha and armadillo motif-containing protein 1 (SARM1), an NADase that acts as a central executioner in a conserved axon degeneration pathway. To test this, we infected wild type and Sarm1 homozygous or heterozygous null cell cultures with ZIKV and examined NAD+ levels as well as the survival of neurons and their processes. Unexpectedly, ZIKV infection led to a rapid SARM1-independent reduction in NAD+. Nonetheless, the subsequent profound loss of neuronal cell processes was SARM1-dependent and was preceded by early changes in the appearance of β-tubulin III staining. Together, these data identify a role for SARM1 in the pathogenesis of ZIKV infection, which may reflect SARM1's conserved prodegenerative function, independent of its NADase activity.

Human host genetics and susceptibility to ZIKV infection.

Managing emerging infectious diseases is a current challenge in the fields of microbiology and epidemiology. Indeed, among other environmental and human-related factors, climate change and global warming favor the emergence of new pathogens. The recent Zika virus (ZIKV) epidemic, of which the large and rapid spread surprised the scientific community, is a reminder of the importance to study viruses currently responsible for sporadic infections. Increasing our knowledge of key factors involved in emerging infections is essential to implement specific monitoring that can be oriented according to the pathogen, targeted population, or at-risk environment. Recent technological developments, such as high-throughput sequencing, genome-wide association studies and CRISPR screenings have allowed the identification of human single nucleotide polymorphisms (SNPs) involved in infectious disease outcome. This review focuses on the human genetic host factors that have been identified and shown to be associated with the pathogenesis of ZIKV infection and candidate SNP targets.

Zika virus infection of glia leads to secondary injury to axons and dendrites

Zika virus infection was recently linked to microcephaly and peripheral neuropathy (GBS) in Zika virus epidemic areas. Building on our previous work (Cumberworth et al, 2017) we investigated, in a time-course study, how the viral infection and the injury of cell processes of oligodendrocytes and neurons are related to each other in the same in vitro model. We generated CNS myelinating cultures from a reporter mouse (Thy1-YFP) on the Ifnar1 -/-background. A proportion of neurons and their processes are positive for YFP in those cultures, which enabled us to visualise single neurons. Cultures were infected with the Brazilian Zika virus strain (PE243) at an MOI of 0.3 and cultured for up to 6 days post infection. We observed that the neuronal cell processes were affected as early as the appearance of the first clusters of infected glial cells. To analyse the interrelation of neurons and myelin further, cultures were labeled with an antibody recognising proteolipid protein. We found that the myelin got injured as early as neuronal processes. These results suggest that the injury to neuronal processes might be a consequence of the infection of the primary target of Zika virus: oligodendroglia. These data help us to understand disease pathogenesis of Zika virus infection of the CNS, and whether there is a time-window to intervene therapeutically. Furthermore, this gives an insight as to how viral infection of glial cells can affect neuronal processes such as axons.

Zika Virus Infection in Tupaia belangeri Causes Dermatological Manifestations and Confers Protection against Secondary Infection.

Animal models of Zika virus (ZIKV) infection have recently been established in mice, guinea pigs, and nonhuman primates. Tree shrews (Tupaia belangeri) are an emerging experimental animal in biomedical applications, but their susceptibility to ZIKV infection has not been explored. In the present study, we show that subcutaneous inoculation of ZIKV led to rapid viremia and viral secretion in saliva, as well as to typical dermatological manifestations characterized by massive diffuse skin rash on the trunk. Global transcriptomic sequencing of peripheral blood mononuclear cells isolated from ZIKV-infected animals revealed systematic gene expression changes related to the inflammatory response and dermatological manifestations. Importantly, ZIKV infection readily triggered the production of high-titer neutralizing antibodies, thus preventing secondary homologous infection in tree shrews. However, neonatal tree shrews succumbed to ZIKV challenge upon intracerebral infection. The tree shrew model described here recapitulates the most common dermatological manifestations observed in ZIKV-infected patients and may greatly facilitate the elucidation of ZIKV pathogenesis and the development of novel vaccines and therapeutics.IMPORTANCE The reemergence of Zika virus (ZIKV) has caused a global public health crisis since 2016, and there are currently no vaccines or antiviral drugs to prevent or treat ZIKV infection. However, considerable advances have been made in understanding the biology and pathogenesis of ZIKV infection. In particular, various animal models have been successfully established to mimic ZIKV infection and its associated neurological diseases and to evaluate potential countermeasures. However, the clinical symptoms in these mouse and nonhuman primate models are different from the common clinical manifestations seen in human ZIKV patients; in particular, dermatological manifestations are rarely recapitulated in these animal models. Here, we developed a new animal model of ZIKV infection in tree shrews, a rat-sized, primate-related mammal. In vitro and in vivo characterization of ZIKV infection in tree shrews established a direct link between ZIKV infection and the immune responses and dermatological manifestations. The tree shrew model described here, as well as other available animal models, provides a valuable platform to study ZIKV pathogenesis and to evaluate vaccines and therapeutics.

Role of Gas6, TAM receptors ligand, in the pathogenesis of Zika virus infection

Zika virus (ZIKV) represents a public health challenge to Brazil and the rest of the world, especially because ZIKV infection has been linked to neurological sequelae, such as congenital fetal syndrome. Here, we aim to verify the role of Gas6 in the pathogenesis of ZIKV infection, by evaluating the expression of Gas6 and TAM receptors in patients infected by the virus with different degrees of disease severity, and infection of different human cells in vitro.

Disruption of glial cell development by Zika virus contributes to severe microcephalic newborn mice

The causal link between Zika virus (ZIKV) infection and microcephaly has raised alarm worldwide. Microglial hyperplasia, reactive gliosis, and myelination delay have been reported in ZIKV-infected microcephalic fetuses. However, whether and how ZIKV infection affects glial cell development remain unclear. Here we show that ZIKV infection of embryos at the later stage of development causes severe microcephaly after birth. ZIKV infects the glial progenitors during brain development. Specifically, ZIKV infection disturbs the proliferation and differentiation of the oligodendrocyte progenitor cells and leads to the abolishment of oligodendrocyte development. More importantly, a single intraperitoneal injection of pregnant mice with a human monoclonal neutralizing antibody provides full protection against ZIKV infection and its associated damages in the developing fetuses. Our results not only provide more insights into the pathogenesis of ZIKV infection, but also present a new model for the preclinical test of prophylactic and therapeutic agents against ZIKV infection.

Relationship between microcephaly and Zika virus during pregnancy: a review.

the present study analysed the association between Zika-virus and microcephaly during the gestational period of women in Brazil. Systematic reviews of intervention research, current publications of clinical investigations were used systematic search strategies in three electronic databases PubMed, SciELO and Google academic. The following keywords were used: Microcephaly, gestation, Zika-virus to perform the search, and 1020 articles were obtained after exclusion, 45 were left and 35 were eligible. The collection period was from 2004 to 2017. Epidemiological data suggest a temporal association between the quantitative increase and the Zika-virus epidemic, especially in Northeast Brazil. It is not consensual to measure the cephalic perimeter curve to be considered. Given this, the application of techniques to accurately diagnose the relationship between causes and effects in the pathogenesis of Zika virus infection in the central nervous system should be prioritized.

T Cell Immunity to Zika and Dengue Viral Infections.

The 2015-2016 Zika virus (ZIKV) outbreak in the Americas has brought this relatively unknown flavivirus into the spotlight as the etiologic agent of congenital Zika syndrome in newborns and, potentially, of Guillain-Barré syndrome in adults. ZIKV shares a high degree of amino acid sequence homology with the closely related flavivirus Dengue virus (DENV). Due to the paucity of research investigating T cell-mediated immune responses to ZIKV, the precise roles of T cells in protection against and pathogenesis of ZIKV infection are unclear. Nevertheless, knowledge gained from studies of T cell responses to other flaviviruses, such as the four DENV serotypes, provides a framework for investigating and understanding anti-ZIKV T cell responses. In this review, we summarize our current understanding of how T cells respond to primary and secondary infections with DENV and ZIKV. A thorough understanding of the role of ZIKV-specific and DENV cross-reactive T cells in controlling infection is essential for developing ZIKV- and DENV-specific vaccines with maximal safety and efficacy.

IL-22 signaling contributes to modulate the pathogenesis of Zika virus infection

Abstract The recent outbreaks of Zika virus (ZIKV) in multiple countries are linked to increased risk of neurological disorders and congenital defects. However, host immunity and immune-mediated pathogenesis in ZIKV infection are not well understood. Interleukin-22 (IL-22) is a crucial cytokine for regulating host immunity in infectious diseases. Whether IL-22 plays a role in ZIKV infection is entirely unknown. Here, we infected 3-week-old Ifnar1−/− mice with ZIKV (Cambodian isolate, 1.0×105 pfu/mouse), and found that ZIKV infection resulted in weight loss, paralysis, and mortality at 5 to 6 days post-infection (dpi). This was accompanied by tissue injuries, neutrophil influx, and CD8+ T cell expansion in multiple organs, especially in the brain. The infection significantly up-regulated gene expression of multiple inflammatory cytokines, including IL-6, IL-1β, and TNF-α. Importantly, ZIKV infection elicited a tenfold increase in IL-22 production from non-T cells compared with that of uninfected animals. To investigate the effects of IL-22 on ZIKV infection, we challenged 1-day-old WT and IL-22−/− mice with ZIKV (4.0×103 pfu/mouse). WT mice began to develop weight loss, staggered steps, bilateral hind limb paralysis, weakness at 10 dpi, and ultimately succumbed to the infection on 16–19 dpi. Surprisingly, IL-22 deficiency lessened the weight loss, moderated the systemic inflammatory response, and greatly reduced the incidence of neurological disorders and mortality. In fact, around 90% of the IL-22−/− mice recovered from the insult on the nervous system at 20 dpi. Thus, our data revealed an obvious systemic inflammation in multiple organs induced by ZIKV, and demonstrated a novel role of IL-22 in determining the disease outcome.