Jonathan J. Miner

A Mouse Model of Zika Virus Pathogenesis

The ongoing Zika virus (ZIKV) epidemic and unexpected clinical outcomes, including Guillain-Barré syndrome and birth defects, has brought an urgent need for animal models. We evaluated infection and pathogenesis with contemporary and historical ZIKV strains in immunocompetent mice and mice lacking components of the antiviral response. Four- to six-week-old Irf3(-/-)Irf5(-/-)Irf7(-/-) triple knockout mice, which produce little interferon α/β, and mice lacking the interferon receptor (Ifnar1(-/-)) developed neurological disease and succumbed to ZIKV infection, whereas single Irf3(-/-), Irf5(-/-), and Mavs(-/-) knockout mice exhibited no overt illness. Ifnar1(-/-) mice sustained high viral loads in the brain and spinal cord, consistent with evidence that ZIKV causes neurodevelopmental defects in human fetuses. The testes of Ifnar1(-/-) mice had the highest viral loads, which is relevant to sexual transmission of ZIKV. This model of ZIKV pathogenesis will be valuable for evaluating vaccines and therapeutics as well as understanding disease pathogenesis.

Zika Virus Infection in Mice Causes Panuveitis with Shedding of Virus in Tears.

Zika virus (ZIKV) is an emerging flavivirus that causes congenital abnormalities and Guillain-Barré syndrome. ZIKV infection also results in severe eye disease characterized by optic neuritis, chorioretinal atrophy, and blindness in newborns and conjunctivitis and uveitis in adults. We evaluated ZIKV infection of the eye by using recently developed mouse models of pathogenesis. ZIKV-inoculated mice developed conjunctivitis, panuveitis, and infection of the cornea, iris, optic nerve, and ganglion and bipolar cells in the retina. This phenotype was independent of the entry receptors Axl or Mertk, given that Axl(-/-), Mertk(-/-), and Axl(-/-)Mertk(-/-) double knockout mice sustained levels of infection similar to those of control animals. We also detected abundant viral RNA in tears, suggesting that virus might be secreted from lacrimal glands or shed from the cornea. This model provides a foundation for studying ZIKV-induced ocular disease, defining mechanisms of viral persistence, and developing therapeutic approaches for viral infections of the eye.

A CRISPR screen defines a signal peptide processing pathway required by flaviviruses

Flaviviruses infect hundreds of millions of people annually, and no antiviral therapy is available. We performed a genome-wide CRISPR/Cas9-based screen to identify host genes that, when edited, resulted in reduced flavivirus infection. Here, we validated nine human genes required for flavivirus infectivity, and these were associated with endoplasmic reticulum functions including translocation, protein degradation, and N-linked glycosylation. In particular, a subset of endoplasmic reticulum-associated signal peptidase complex (SPCS) proteins was necessary for proper cleavage of the flavivirus structural proteins (prM and E) and secretion of viral particles. Loss of SPCS1 expression resulted in markedly reduced yield of all Flaviviridae family members tested (West Nile, dengue, Zika, yellow fever, Japanese encephalitis, and hepatitis C viruses), but had little impact on alphavirus, bunyavirus, or rhabdovirus infection or the surface expression or secretion of diverse host proteins. We found that SPCS1 dependence could be bypassed by replacing the native prM protein leader sequences with a class I major histocompatibility complex (MHC) antigen leader sequence. Thus, SPCS1, either directly or indirectly via its interactions with host proteins, preferentially promotes the processing of specific protein cargo, and Flaviviridae have a unique dependence on this signal peptide processing pathway. SPCS1 and other signal processing pathway members could represent pharmacological targets for inhibiting infection by the expanding number of flaviviruses of medical concern.

Zika Virus Pathogenesis and Tissue Tropism

Although Zika virus (ZIKV) was isolated approximately 70 years ago, few experimental studies had been published prior to 2016. The recent spread of ZIKV to countries in the Western Hemisphere is associated with reports of microcephaly, congenital malformations, and Guillain-Barré syndrome. This has resulted in ZIKV being declared a public health emergency and has greatly accelerated the pace of ZIKV research and discovery. Within a short time period, useful mouse and non-human primate disease models have been established, and pre-clinical evaluation of therapeutics and vaccines has begun. Unexpectedly, ZIKV exhibits a broad tropism and persistence in body tissues and fluids, which contributes to the clinical manifestations and epidemiology that have been observed during the current epidemic. In this Review, we highlight recent advances in our understanding of ZIKV pathogenesis, tissue tropism, and the resulting pathology and discuss areas for future investigation.

Brief Report: Chikungunya Viral Arthritis in the United States: A Mimic of Seronegative Rheumatoid Arthritis

Chikungunya virus (CHIKV) is an arthritogenic mosquito‐transmitted alphavirus that spread to the Caribbean in 2013 and to the US in 2014. CHIKV‐infected patients develop inflammatory arthritis that can persist for months or years, but little is known about the rheumatologic and immunologic features of CHIKV‐related arthritis in humans, particularly as compared to rheumatoid arthritis (RA). The purpose of this study was to describe these features in a group of 10 American travelers who were nearly simultaneously infected while visiting Haiti in June 2014.

The TAM receptor Mertk protects against neuroinvasive viral infection by maintaining blood-brain barrier integrity

The TAM receptors Tyro3, Axl and Mertk are receptor tyrosine kinases that dampen host innate immune responses following engagement with their ligands Gas6 and Protein S, which recognize phosphatidylserine on apoptotic cells. In a form of apoptotic mimicry, many enveloped viruses display phosphatidylserine on the outer leaflet of their membranes, enabling TAM receptor activation and downregulation of antiviral responses. Accordingly, we hypothesized that a deficiency of TAM receptors would enhance antiviral responses and protect against viral infection. Unexpectedly, mice lacking Mertk and/or Axl, but not Tyro3, exhibited greater vulnerability to infection with neuroinvasive West Nile and La Crosse encephalitis viruses. This phenotype was associated with increased blood-brain barrier permeability, which enhanced virus entry into and infection of the brain. Activation of Mertk synergized with interferon-β to tighten cell junctions and prevent virus transit across brain microvascular endothelial cells. Because TAM receptors restrict pathogenesis of neuroinvasive viruses, these findings have implications for TAM antagonists that are currently in clinical development.

Cardiac manifestations of systemic lupus erythematosus.

The heart is one of the most frequently affected organs in SLE. Any part of the heart can be affected, including the pericardium, myocardium, coronary arteries, valves, and the conduction system. In addition to pericarditis and myocarditis, a high incidence of CAD has become increasingly recognized as a cause of mortality, especially in older adult patients and those with long-standing SLE. Many unanswered questions remain in terms of understanding the pathogenesis of cardiac manifestations of SLE. It is not currently possible to predict the patients who are at greatest risk for the various types of cardiac involvement. However, with the rapid advancement of basic science and translational research approaches, it is now becoming easier to identify specific mutations associated with SLE. A better understanding of these genetic factors may eventually allow clinicians to categorize and predict the patients who are at risk for specific cardiac manifestations of SLE.

Chikungunya virus: an update on the biology and pathogenesis of this emerging pathogen

Re-emergence of chikungunya virus, a mosquito-transmitted pathogen, is of serious public health concern. In the past 15 years, after decades of infrequent, sporadic outbreaks, the virus has caused major epidemic outbreaks in Africa, Asia, the Indian Ocean, and more recently the Caribbean and the Americas. Chikungunya virus is mainly transmitted by Aedes aegypti mosquitoes in tropical and subtropical regions, but the potential exists for further spread because of genetic adaptation of the virus to Aedes albopictus, a species that thrives in temperate regions. Chikungunya virus represents a substantial health burden to affected populations, with symptoms that include severe joint and muscle pain, rashes, and fever, as well as prolonged periods of disability in some patients. The inflammatory response coincides with raised levels of immune mediators and infiltration of immune cells into infected joints and surrounding tissues. Animal models have provided insights into disease pathology and immune responses. Although host innate and adaptive responses have a role in viral clearance and protection, they can also contribute to virus-induced immune pathology. Understanding the mechanisms of host immune responses is essential for the development of treatments and vaccines. Inhibitory compounds targeting key inflammatory pathways, as well as attenuated virus vaccines, have shown some success in animal models, including an attenuated vaccine strain based on an isolate from La Reunion incorporating an internal ribosome entry sequence that prevents the virus from infecting mosquitoes and a vaccine based on virus-like particles expressing envelope proteins. However, immune correlates of protection, as well as the safety of prophylactic and therapeutic candidates, are important to consider for their application in chikungunya infections. In this Review, we provide an update on chikungunya virus with regard to its epidemiology, molecular virology, virus-host interactions, immunological responses, animal models, and potential antiviral therapies and vaccines.

Chikungunya viral arthritis in the United States: a mimic of seronegative rheumatoid arthritis.

Chikungunya virus (CHIKV) is an arthritogenic mosquito‐transmitted alphavirus that spread to the Caribbean in 2013 and to the US in 2014. CHIKV‐infected patients develop inflammatory arthritis that can persist for months or years, but little is known about the rheumatologic and immunologic features of CHIKV‐related arthritis in humans, particularly as compared to rheumatoid arthritis (RA). The purpose of this study was to describe these features in a group of 10 American travelers who were nearly simultaneously infected while visiting Haiti in June 2014.

Mechanisms of restriction of viral neuroinvasion at the blood-brain barrier.

Abstract The blood–brain barrier (BBB) consists of highly specialized cells including brain microvascular endothelial cells, astrocytes, microglia, pericytes, and neurons, which act in concert to restrict the entry of pathogens, immune cells, and soluble molecules into the central nervous system (CNS). If pathogens manage to cross the BBB and establish infection within the CNS, the BBB can open in a regulated manner to allow leukocyte transmigration into the CNS so that microbes, infected cells, and debris can be cleared. This review highlights how different inflammatory cytokines or signaling pathways disrupt or enhance BBB integrity in a way that regulates entry of neurotropic viruses into the CNS.