Equine Polyclonal Antibodies Prevent Acute Chikungunya Virus Infection in Mice

Chikungunya virus (CHIKV) is a mosquito-transmitted pathogen that causes chikungunya disease (CHIK); the disease is characterized by fever, muscle ache, rash, and arthralgia. This arthralgia can be debilitating and long-lasting, seriously impacting quality of life for years. Currently, there is no specific therapy available for CHIKV infection. We have developed a despeciated equine polyclonal antibody (CHIKV-EIG) treatment against CHIKV and evaluated its protective efficacy in mouse models of CHIKV infection. In immunocompromised (IFNAR−/−) mice infected with CHIKV, daily treatment for five consecutive days with CHIKV-EIG administered at 100 mg/kg starting on the day of infection prevented mortality, reduced viremia, and improved clinical condition as measured by body weight loss. These beneficial effects were seen even when treatment was delayed to 1 day after infection. In immunocompetent mice, CHIKV-EIG treatment reduced virus induced arthritis (including footpad swelling), arthralgia-associated cytokines, viremia, and tissue virus loads in a dose-dependent fashion. Collectively, these results suggest that CHIKV-EIG is effective at preventing CHIK and could be a viable candidate for further development as a treatment for human disease

Vascular Leak and Hypercytokinemia Associated with Severe Fever with Thrombocytopenia Syndrome Virus Infection in Mice

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging viral hemorrhagic fever (VHF) endemic to China, South Korea, Japan, and Vietnam. Here we characterize the pathogenesis and natural history of disease in IFNAR-/- mice challenged with the HB29 strain of SFTS virus (SFTSV) and demonstrate hallmark features of VHF such as vascular leak and high concentrations of proinflammatory cytokines in blood and tissues. Treatment with FX06, a natural plasmin digest product of fibrin in clinical development as a treatment for vascular leak, reduced vascular permeability associated with SFTSV infection but did not significantly improve survival outcome. Further studies are needed to assess the role of vascular compromise in the SFTS disease process modeled in IFNAR-/- mice

Amelioration of Chikungunya through Inhibition of the Inflammatory Response

Chikungunya (CHIK) is an emerging viral disease, which causes significant morbidity and mortality throughout tropical/subtropical areas of the world, including a recent outbreak in the Americas. Disease typically includes fever, rash, and arthritis. Joint involvement is generally self-limiting, but infection with Chikungunya virus (CHIKV) can lead to chronic debilitating arthritis that can last for months to years. With no vaccine and no licensed treatment, suitable animal models of CHIKV are needed to test intervention strategies. We developed a model of CHIK in DBA1/J mice that develop joint swelling, increase in inflammatory cytokines and splenomegaly in mice, which include important symptoms of disease seen in infected humans. We used this model to test the hypothesis that treatment with immune-modulatory compounds would ameliorate disease. GP1681, which suppresses TNF-α, IL-1β, and IL-6, exacerbated CHIK as indicated by increased footpad swelling and viral load. Prophylactic treatment with mDEF201, an adenovirus-vectored interferon, reduced disease, including joint swelling, virus titers at the site of virus challenge and inflammatory cytokines (IL-6, MCP-1, MIP-1α, and RANTES), although efficacy waned as treatment initiation was extended beyond virus challenge. Methotrexate treatment was also effective at ameliorating joint swelling and other disease parameters. Actemra (ACT), an anti-IL-6 antibody, reduced IL-6 levels to baseline, although the resulting improvement in footpad swelling was not significant. Combination therapy with methotrexate and ACT resulted in reduced footpad swelling. Based on our results, immune modulators have potential for the treatment of CHIKV and some of the compounds tested might have potential for clinical developmental

Protection Against Chikungunya Virus Induced Arthralgia Following Prophylactic Treatment With Adenovirus Vectored Interferon (Mdef201)

Recent outbreaks of Chikungunya virus (CHIKV) infection have resulted in millions of cases of disease with significant morbidity. No approved antiviral treatments exist for the prevention or treatment of this viral disease. Infection with CHIKV results in a high rate of symptomatic disease that primarily includes a debilitating arthralgia. To model this cardinal disease manifestation, adult DBA/1J mice were challenged with CHIKV by footpad injection. Viremia and hind limb virus titers increased ∼100-fold while spleen virus increased \u3e1000-fold within 1 day post-virus infection (dpi). Footpad swelling was measured over a 10-day period, with peak swelling observed between 6 and 7 dpi. Histology of the hind leg at the site of virus challenge showed evidence of myositis and synovitis starting on 5 dpi. Cytokine profiling of the hind limb at the site of inoculation revealed a biphasic inflammatory response represented by an increase in IL-6, MCP-1, IFN-γ, MIP-1α, RANTES, and IL-17. To investigate the prophylactic capacity of IFN, mice were treated with mDEF201, an adenovirus-vectored IFN-α. Intranasal administration of a single 107 pfu/ml dose of mDEF201 administered 21 days to 24 h prior to infection, significantly reduced footpad swelling, virus titers in the hind leg and spleen, and several inflammatory cytokines. Efficacy was not observed when treatment was initiated 24 h after virus challenge. This arthralgia model of CHIKV recapitulates relevant disease features commonly observed in human disease making it applicable to preclinical testing of therapies that target both viral replication and the associated joint disease

The attitudes and behaviors of school officials and how they engage parents in trusting relationships in high achieving Title I schools

This study was conducted to understand the behaviors and attitudes displayed by school officials in building trusting relationship with parents in successful Title I schools. Four school sites within the same school district were chosen for this study. The study was a qualitative action research study. Four participants were interviewed at each school site (a total of sixteen participants were interviewed). All interviews were transcribed and coded for common themes. Based on the results of the study, recommendations were made for school officials and school organizations who seek to building trusting relationships with parents. (Published By University of Alabama Libraries

Vascular Leak and Hypercytokinemia Associated with Severe Fever with Thrombocytopenia Syndrome Virus Infection in Mice

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging viral hemorrhagic fever (VHF) endemic to China, South Korea, Japan, and Vietnam. Here we characterize the pathogenesis and natural history of disease in IFNAR-/- mice challenged with the HB29 strain of SFTS virus (SFTSV) and demonstrate hallmark features of VHF such as vascular leak and high concentrations of proinflammatory cytokines in blood and tissues. Treatment with FX06, a natural plasmin digest product of fibrin in clinical development as a treatment for vascular leak, reduced vascular permeability associated with SFTSV infection but did not significantly improve survival outcome. Further studies are needed to assess the role of vascular compromise in the SFTS disease process modeled in IFNAR-/- mice

A Computationally Designed Hemagglutinin Stem-Binding Protein Provides In Vivo Protection from Influenza Independent of a Host Immune Response.

Broadly neutralizing antibodies targeting a highly conserved region in the hemagglutinin (HA) stem protect against influenza infection. Here, we investigate the protective efficacy of a protein (HB36.6) computationally designed to bind with high affinity to the same region in the HA stem. We show that intranasal delivery of HB36.6 affords protection in mice lethally challenged with diverse strains of influenza independent of Fc-mediated effector functions or a host antiviral immune response. This designed protein prevents infection when given as a single dose of 6.0 mg/kg up to 48 hours before viral challenge and significantly reduces disease when administered as a daily therapeutic after challenge. A single dose of 10.0 mg/kg HB36.6 administered 1-day post-challenge resulted in substantially better protection than 10 doses of oseltamivir administered twice daily for 5 days. Thus, binding of HB36.6 to the influenza HA stem region alone, independent of a host response, is sufficient to reduce viral infection and replication in vivo. These studies demonstrate the potential of computationally designed binding proteins as a new class of antivirals for influenza