Identification of candidate genes involved in Zika virus-induced reversible paralysis of mice.

Zika virus (ZIKV) causes a variety of peripheral and central nervous system complications leading to neurological symptoms such as limb weakness. We used a mouse model to identify candidate genes potentially involved in causation or recovery from ZIKV-induced acute flaccid paralysis. Using Zikv and Chat chromogenic and fluorescence in situ RNA hybridization, electron microscopy, immunohistochemistry, and ZIKV RT-qPCR, we determined that some paralyzed mice had infected motor neurons, but motor neurons are not reduced in number and the infection was not present in all paralyzed mice; hence infection of motor neurons were not strongly correlated with paralysis.

Differences in Susceptibility to SARS-CoV-2 Infection Among Transgenic hACE2-Hamster Founder Lines.

Animal models that are susceptible to SARS-CoV-2 infection and develop clinical signs like human COVID-19 are desired to understand viral pathogenesis and develop effective medical countermeasures. The golden Syrian hamster is important for the study of SARS-CoV-2 since hamsters are naturally susceptible to SARS-CoV-2. However, infected hamsters show only limited clinical disease and resolve infection quickly.

Adjusting susceptibilities of C57BL/6 mice to orthoflaviviruses for evaluation of antiviral drugs by altering the levels of interferon alpha/beta receptor function.

The purpose of this study was to optimize the infectivity of four different orthoflaviviruses in mice for evaluating antiviral drugs by using wild-type mice with intact interferon responses, type 1 interferon alpha/beta receptor knockout mice, or by injecting wild type C57BL/6 mice with varying doses of anti-type 1 interferon receptor antibody (MAR1-5A3) to optimize the infectivity and lethality. West Nile virus productively infected wild-type C57BL/6 mice to cause lethality, whereas Usutu virus required a complete absence of type 1 interferon receptor function. Deer tick virus (lineage 2 Powassan virus) and Japanese encephalitis viruses required a dampening of type 1 interferon responses by adjusting the doses of MAR1-5A3 antibody injections.

PI3Kγ inhibition circumvents inflammation and vascular leak in SARS-CoV-2 and other infections.

Virulent infectious agents such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and methicillin-resistant (MRSA) induce tissue damage that recruits neutrophils, monocyte, and macrophages, leading to T cell exhaustion, fibrosis, vascular leak, epithelial cell depletion, and fatal organ damage. Neutrophils, monocytes, and macrophages recruited to pathogen-infected lungs, including SARS-CoV-2-infected lungs, express phosphatidylinositol 3-kinase gamma (PI3Kγ), a signaling protein that coordinates both granulocyte and monocyte trafficking to diseased tissues and immune-suppressive, profibrotic transcription in myeloid cells. PI3Kγ deletion and inhibition with the clinical PI3Kγ inhibitor eganelisib promoted survival in models of infectious diseases, including SARS-CoV-2 and MRSA, by suppressing inflammation, vascular leak, organ damage, and cytokine storm.

Memantine treatment reduces the incidence of flaccid paralysis in a zika virus mouse model of temporary paralysis with similarities to Guillain-Barré syndrome.

Clinical evidence suggests that Zika virus contributes to Guillain-Barré syndrome that causes temporary paralysis. We utilized a recently described Zika virus mouse model of temporary flaccid paralysis to address the hypothesis that treatment with an -methyl-D-aspartate receptor antagonist, memantine, can reduce the incidence of paralysis. Aged interferon alpha/beta-receptor knockout mice were used because of their sublethal susceptibility to Zika virus infection.

Zika virus infection causes temporary paralysis in adult mice with motor neuron synaptic retraction and evidence for proximal peripheral neuropathy.

Clinical evidence is mounting that Zika virus can contribute to Guillain-Barré syndrome which causes temporary paralysis, yet the mechanism is unknown. We investigated the mechanism of temporary acute flaccid paralysis caused by Zika virus infection in aged interferon αβ-receptor knockout mice used for their susceptibility to infection. Twenty-five to thirty-five percent of mice infected subcutaneously with Zika virus developed motor deficits including acute flaccid paralysis that peaked 8-10 days after viral challenge.

Zika Virus Associated Pathology and Antigen Presence in the Testicle in the Absence of Sexual Transmission During Subacute to Chronic Infection in a Mouse Model.

Zika virus (ZIKV) is an arboviral infection that has been shown to be sexually transmitted. The study outlined herein aims to determine if accessory sex glands and epididymal epithelial cells are sources of viral persistence in subacute and chronic ZIKV infection, and if infection of these organs is important in sexual transmission during long-term (chronic) infection. Male interferon type I receptor knockout (Ifnar) mice were challenged with ZIKV and reproductive tissues were harvested 14 and 35 days post infection (DPI) for inoculation studies and 14, 35 and 70 DPI for histopathology.

Coitus-Free Sexual Transmission of Zika Virus in a Mouse Model.

Zika virus (ZIKV) is an arboviral infection that may be sexually transmitted. The present study aims to determine if accessory sex glands are a potential source of infectious virus and important in sexual transmission. Male interferon type I receptor knockout (Ifnar) mice were challenged subcutaneously with a Puerto Rican ZIKV isolate.

Consequences of in utero exposure to Zika virus in offspring of AG129 mice.

Zika virus (ZIKV) can cause various diseases in offspring after congenital infection. The purpose of this study was to identify disease phenotypes in pups exposed to ZIKV in utero. Female interferon-α/β, -γ receptor knockout mice (AG129) were infected intraperitoneally with ZIKV 7.

Zika virus-induced acute myelitis and motor deficits in adult interferon αβ/γ receptor knockout mice.

Zika virus (ZIKV) has received widespread attention because of its effect on the developing fetus. It is becoming apparent, however, that severe neurological sequelae, such as Guillian-Barrë syndrome (GBS), myelitis, encephalitis, and seizures can occur after infection of adults. This study demonstrates that a contemporary strain of ZIKV can widely infect astrocytes and neurons in the brain and spinal cord of adult, interferon α/β receptor knockout mice (AG129 strain) and cause progressive hindlimb paralysis, as well as severe seizure-like activity during the acute phase of disease.

Comparative Histopathologic Lesions of the Male Reproductive Tract during Acute Infection of Zika Virus in AG129 and Ifnar Mice.

An understanding of the pathogenesis of infection with the Zika virus in the male reproductive tract is vital for the development of vaccines and antivirals that will limit or prevent sexual transmission. Two common immunocompromised mouse strains used in transmission studies-male with genes encoding interferon types I and II receptor gene knockout (IFNAR/IFNGR; AG129) and with interferon type 1 receptor knockout (Ifnar) were infected with a Puerto Rican Zika virus isolate (PRVABC59), and pathology was assessed 5 to 11 days after infection. Virus was detected by immunohistochemistry and quantitative RT-PCR in the testicle and epididymis of AG129 and Ifnar mice, and by immunohistochemistry in the prostate and seminal vesicle of infected AG129 mice.

Causation of Acute Flaccid Paralysis by Myelitis and Myositis in Enterovirus-D68 Infected Mice Deficient in Interferon αβ/γ Receptor Deficient Mice.

Enterovirus D68 (EV-D68) caused a large outbreak in the summer and fall of 2014 in the United States. It causes serious respiratory disease, but causation of associated paralysis is controversial, because the virus is not routinely identified in cerebrospinal fluid. To establish clinical correlates with human disease, we evaluated EV-D68 infection in non-lethal paralysis mouse models.

Activity of nucleic acid polymers in rodent models of HBV infection.

Nucleic acid polymers (NAPs) block the release of HBsAg from infected hepatocytes. These compounds have been previously shown to have the unique ability to eliminate serum surface antigen in DHBV-infected Pekin ducks and achieve multilog reduction of HBsAg or HBsAg loss in patients with chronic HBV infection and HBV/HDV coinfection. In ducks and humans, the blockage of HBsAg release by NAPs occurs by the selective targeting of the assembly and/or secretion of subviral particles (SVPs).

Zika virus infection of adult and fetal STAT2 knock-out hamsters.

Zika virus (ZIKV) infection was investigated in adult and fetal STAT2 knock-out (KO) hamsters. Subcutaneous injection of ZIKV of adults resulted in morbidity, mortality, and infection of the uterus, placenta, brain, spinal cord, and testicles, thus providing an opportunity to evaluate congenital ZIKV infection in a second rodent species besides mice. ZIKV-infected cells with morphologies of Sertoli cells and spermatogonia were observed in the testes, which may have implications for sexual transmission and male sterility.

Efficacy of the broad-spectrum antiviral compound BCX4430 against Zika virus in cell culture and in a mouse model.

Zika virus (ZIKV) is currently undergoing pandemic emergence. While disease is typically subclinical, severe neurologic manifestations in fetuses and newborns after congenital infection underscore an urgent need for antiviral interventions. The adenosine analog BCX4430 has broad-spectrum activity against a wide range of RNA viruses, including potent in vivo activity against yellow fever, Marburg and Ebola viruses.

Phrenic nerve deficits and neurological immunopathology associated with acute West Nile virus infection in mice and hamsters.

Neurological respiratory deficits are serious outcomes of West Nile virus (WNV) disease. WNV patients requiring intubation have a poor prognosis. We previously reported that WNV-infected rodents also appear to have respiratory deficits when assessed by whole-body plethysmography and diaphragmatic electromyography.

The Synthetic Antiviral Drug Arbidol Inhibits Globally Prevalent Pathogenic Viruses.

Unlabelled: Arbidol (ARB) is a synthetic antiviral originally developed to combat influenza viruses. ARB is currently used clinically in several countries but not in North America. We have previously shown that ARB inhibits in vitro hepatitis C virus (HCV) by blocking HCV entry and replication.

Inhibition of West Nile virus by calbindin-D28k.

Evidence indicates that West Nile virus (WNV) employs Ca(2+) influx for its replication. Moreover, calcium buffer proteins, such as calbindin D28k (CB-D28k), may play an important role mitigating cellular destruction due to disease processes, and more specifically, in some neurological diseases. We addressed the hypothesis that CB-D28k inhibits WNV replication in cell culture and infected rodents.

BCX4430, a novel nucleoside analog, effectively treats yellow fever in a Hamster model.

No effective antiviral therapies are currently available to treat disease after infection with yellow fever virus (YFV). A Syrian golden hamster model of yellow fever (YF) was used to characterize the effect of treatment with BCX4430, a novel adenosine nucleoside analog. Significant improvement in survival was observed after treatment with BCX4430 at 4 mg/kg of body weight per day dosed intraperitoneally (i.

A molecularly cloned, live-attenuated japanese encephalitis vaccine SA14-14-2 virus: a conserved single amino acid in the ij Hairpin of the Viral E glycoprotein determines neurovirulence in mice.

Japanese encephalitis virus (JEV), a mosquito-borne flavivirus that causes fatal neurological disease in humans, is one of the most important emerging pathogens of public health significance. JEV represents the JE serogroup, which also includes West Nile, Murray Valley encephalitis, and St. Louis encephalitis viruses.

The use of plethysmography in determining the severity of lung pathology in a mouse model of minimally lethal influenza virus infection.

To characterize the impact on lung function, we assessed plethysmography parameters in a course of infection with mouse-adapted A/Pennsylvania/14/2010 (H3N2) influenza virus. Several parameters, represented by enhanced pause (penh) and ratio of inspiratory/expiratory time (Ti/Te), were observed that had early (1-7dpi) and robust changes regardless of virus challenge dose. Other parameters, characterized by tidal volume (TV), breathing frequency (freq) and end inspiratory pause (EIP), changed later (7-15dpi) during the course of infection and had a virus challenge dose effect.

Synergistic combinations of favipiravir and oseltamivir against wild-type pandemic and oseltamivir-resistant influenza A virus infections in mice.

Aim: Favipiravir and oseltamivir are antiviral compounds used for the treatment of influenza infections. We have aimed to investigate the efficacy of the compounds in combination to treat influenza H1N1 virus infections in mice.

Materials & Methods: Mice infected with pandemic influenza A/California/04/2009 (H1N1pdm) virus or an oseltamivir-resistant (H275Y neuraminidase mutation) influenza A/Mississippi/ 3/2001 (H1N1) virus were treated orally with inhibitors twice a day for 5 days starting 4 h after infection.

Humanized monoclonal antibody 2C9-cIgG has enhanced efficacy for yellow fever prophylaxis and therapy in an immunocompetent animal model.

Yellow fever virus (YFV) causes significant human disease and mortality in tropical regions of South and Central America and Africa, despite the availability of an effective vaccine. No specific therapy for YF is available. We previously showed that the humanized monoclonal antibody (MAb) 2C9-cIgG provided prophylactic and therapeutic protection from mortality in interferon receptor-deficient strain AG129 mice challenged with YF 17D-204 vaccine.

Autonomic deficit not the cause of death in West Nile virus neurological disease.

Introduction: Some West Nile virus (WNV)-infected patients have been reported to manifest disease signs consistent with autonomic dysfunction. Moreover, WNV infection in hamsters causes reduced electromyography amplitudes of the gastrointestinal tract and diaphragm, and they have reduced heart rate variability (HRV), a read-out for the parasympathetic autonomic function.

Methods: HRV was measured in both hamsters and mice using radiotelemetry to identify autonomic deficits.