In the early 1970s, a trial was conducted in Beagles comparing an irradiated spherule vaccine for Valley Fever against a control vaccine. The results did not show a significant difference between the vaccinated and the control dogs. Reactions to the vaccine were significant.

In the early 1970s, a trial was conducted in Beagles comparing an irradiated spherule vaccine for Valley Fever against a control vaccine. The results did not show a significant difference between the vaccinated and the control dogs. Reactions to the vaccine were significant.

In the early 1970s, a trial was conducted in Beagles comparing an irradiated spherule vaccine for Valley Fever against a control vaccine. The results did not show a significant difference between the vaccinated and the control dogs. Reactions to the vaccine were significant.

In the early 1970s, a trial was conducted in Beagles comparing an irradiated spherule vaccine for Valley Fever against a control vaccine. The results did not show a significant difference between the vaccinated and the control dogs. Reactions to the vaccine were significant.

In the early 1970s, a trial was conducted in Beagles comparing an irradiated spherule vaccine for Valley Fever against a control vaccine. The results did not show a significant difference between the vaccinated and the control dogs. Reactions to the vaccine were significant.

No description available.

Rift Valley Fever is a zoonotic, arthropod-borne disease that adversely affects ungulates and people. The etiologic agent, Rift Valley fever virus (RVFV; Bunyaviridae, Phlebovirus), is primarily transmitted through mosquito bites, yet can be transmitted by exposure to infectious aerosols. Presently, there are no licensed vaccines or therapeutics to prevent or treat severe RVFV infection in humans. We have previously reported on the activity of favipiravir (T-705) against the MP-12 vaccine strain of RVFV and other bunyaviruses in cell culture. Additionally, efficacy has been documented in mouse and hamster models of infection with the related Punta Toro virus. Here, we characterize a hamster RVFV challenge model and use it to evaluate the activity of favipiravir against the highly pathogenic ZH501 strain of the virus. Subcutaneous RVFV challenge resulted in substantial serum and tissue viral loads and caused severe disease and mortality within 2-3 days after infection. Oral favipiravir (200 mg/kg/day) prevented mortality in 60% or greater in hamsters challenged with RVFV when administered within 6 h post-exposure and reduced RVFV titers in serum and tissues relative to the time of treatment initiation. In contrast, although ribavirin (75 mg/kg/day) was effective at protecting animals from the peracute RVFV disease, most ultimately succumbed from a delayed-onset neurologic disease associated with high RVFV burden in the brain observed in moribund animals. When combined, T-705 and ribavirin treatment started 24 h post-infection significantly improved survival outcome and reduced serum and tissue virus titers compared to monotherapy. Our findings demonstrate significant post-RVFV exposure efficacy with favipiravir against both peracute disease and delayed-onset neuroinvasion, and suggest added benefit when combined with ribavirin.

Valley fever, or coccidioidomycosis, is a disease caused by the Coccidioides immitis and Coccidioides posadasii fungal species that dwell in the soil but can become airborne and infect a human or mammalian host through their respiratory tract. Disease rates in the western U.S. have significantly increased over the past two decades, creating an emerging public health burden. Studies have been conducted that attempt to elucidate the association between environmental conditions and the growth and dispersal of the pathogen, yet the specific ecology of and environmental precursors to the disease remain uncertain. This research project investigates the relationship between environmental variables and valley fever by modeling the spatial and temporal dynamics of the disease using varying techniques. Chapter 1 discusses relevant literature before discussing the challenges associated with studying valley fever. Chapter 2 analyzes the temporal relationships between valley fever and climatic variables, focusing on Kern County, California, an understudied region in the U.S. where valley fever is highly endemic. Chapter 3 focuses on a regional spatial analysis using ecological niche modeling to better understand the environmental factors that influence the overall spatial distribution of valley fever in the U.S. Finally, combining both spatial and temporal components, Chapter 4 uses a hierarchical Bayesian spatio-temporal model to investigate the patterns and drivers of this disease, focusing on state of California, which saw an approximate 200% increase in cases from 2014 to 2018. Cumulatively, this work offers new insights on relationships between climate, landcover, and valley fever disease risk. Significant findings include climate variables explaining up to 76% of valley fever variability in Kern County, California, the significance of both climatic and landcover variables in characterizing the geographic distribution of the disease, and identification of patterns increasing risk in geographic regions of California not currently considered highly endemic. These findings advance scholarly understandings of valley fever's environmental disease drivers. The results of this research can be applied by public health officials in the allocation of surveillance and public education resources, focusing upon regions that are most likely to encounter the illness. / Doctor of Philosophy / Valley fever is a fungal disease that causes illness in over ten thousand people in the western U.S. every year. Disease rates have been increasing for the past two decades for unknown reasons, although previous research suggests that climatic variations are likely contributing factors. This research evaluated environmental factors with hypothesized relationships to valley fever disease rates. First, this dissertation explored time-series relationships between climatic factors and valley fever incidence in an understudied county in California. Research findings identified that climatic factors including precipitation from previous seasons and temperature were significantly associated with valley fever incidence in this county. Second, this dissertation assessed where valley fever is found in the western U.S. The likely spatial distribution for the disease was mapped and environmental variables influential to this distribution were identified; they included both climate and landcover variables. Finally, a model was developed to analyze patterns of disease risk in California that considered both space and time, and environmental risk factors potentially contributing to the observed patterns were assessed. Counties with increased risk were identified and significant environmental relationships with valley fever risk were confirmed. The results of this research can be applied by public health officials in allocating surveillance and public education resources, focusing upon regions that are most likely to encounter the illness.

Thesis (Ph.D. (Biochemistry)) -- University of Limpopo, 2021 / Introduction: Rift Valley fever virus (RVFV) is an arthropod-born RNA zoonotic virus causing Rift Valley fever (RVF) disease. RVFV is prevalent across sub-Saharan Africa and the Arabian Peninsula with no existing effective and approved antiviral remedies for humans or animals. RVFV has developed mechanisms to hide from immune recognition and induce anti-apoptosis processes to keep the infected host cells viable in an attempt to advance their viral progeny. RVFV is a single-stranded enveloped RNA genome virus composed of 3 segments; the L, M and S segments. The S segment is known to encode a non-structural protein (NSs) identified to be the main virulence factor promoting viral replication through immune suppression. RVFV elicits a set of diverse symptoms ranging from a febrile illness to more severe symptoms that usually culminate in life-threatening haemorrhagic fever with high fatality rates. Thus, this study was designed to investigate the efficacy of lithium as a potential drug for reduction of RVFV load and amelioration of imbalanced and dysregulated inflammatory responses observed in Huvec and Raw 264.7 macrophages infected with this virus. Methods and results: The MTT and Cyquant viability assays were used to demonstrate that lithium exerts no cytotoxic effects on non-infected Raw 264.7 macrophage cells but rather promotes cell growth and proliferation. Conversely, lithium was shown to significantly induce cell death in RVFV-infected Raw 264.7 macrophages. The Annexin-V/PI apoptosis assay was employed to demonstrate that RVFV induces apoptosis as a mode of cell death on Raw 264.7 cells. RVFV-induced apoptosis was accompanied by antagonistic Bax/Bcl-2 protein expression ratios. RVFV-infected cells treated with lithium resulted in higher levels of apoptosis signals compared to untreated RVFV-infected cells. Analysis of apoptosis stages using the real-time cell analyser (RTCA) also revealed that lithium induced early forms of apoptosis in RVFV-infected cells. Interestingly, induction of early apoptosis in these cells corresponds with lower viral load, probably as a result of early inhibition of viral progeny replication, as determined using viral titration assay. Immune response profiles elicited in Raw 264.7 macrophages infected with RVFV and treated with lithium were monitored. An ELISA assay was used to determine the effect of lithium on cytokines and chemokine production in this cell model. The results obtained showed that lithium significantly stimulated production of IFN-γ as RVFV-infected lithium-treated cells produced high levels of IFN-γ compared to lithium-free RVFV-infected control cells. Furthermore, in the same setting, the secondary pro-inflammatory cytokine, IL-6, and chemokine, RANTES, were stimulated by lithium 12 hrs post-infection (pi). Lithium was shown to significantly stimulate TNF-α production as early as 3 hrs pi. In addition to TNF-α expression, the expression of the regulatory cytokine, IL-10, was significantly stimulated by lithium with the highest expression peak at 12 hrs pi. As determined using the H2DCF-DA and DAF-2 DA florigenic assays, reduced production of the ROS and RNS was observed in RVFV-infected lithium-treated cells as opposed to untreated RVFV-infected controls. This was further supported by the Western blot assay results that showed low expression of the iNOS while upregulating expression of heme oxygenase and IκB in RVFV-infected lithium-treated cells. Results from immunocytochemistry and Western blot assays revealed that lithium inhibits NF-κB nuclear translocation in RVFV-infected cells compared to lithium-free RVFV-infected cells and 5 mg/ml LPS controls. This study hypothesises persistent and deregulated inflammation as the central phenomenon responsible for endothelial damage and haemorrhagic fever in RVFV pathogenesis. Supernatants were collected from RVFV-infected macrophage cells treated with lithium and their effects on the integrity of endothelial cells were evaluated. The xcelligence real-time cell analyser system (RTCA) and transwell assay that measure endothelial monolayer integrity were used to demonstrate that lithium protects endothelial cells from RVFV-induced cellular damage. Moreover, lithium was shown to upregulate expression of cytoplasmic molecules such as α and β-catenins involved in attaching the cadherin molecules to the actin cytoskeleton on the endothelial cell. Expression of α-catenins, talins, zyxins and vinculins that attach integrins to the extracellular matrix and to other cells were observed to be upregulated by supernatants from RVFV-infected Raw 264.7 macrophage cells treated with lithium. Endothelial cell monolayer exposed to supernatants from RVFV-infected lithium-treated Raw 264.7 cells displayed upregulated expression of transmembrane molecules such as E-cadherins and N-cadherins. However, expression of VE-cadherins was observed to be lower compared to those treated with supernatants from lithium-free RVFV-infected Raw 264.7 control cells. Conclusion: These findings propose that lithium limits viral replication and viral load in macrophages by inducing early apoptosis in RVFV-infected cells. Since lithium was shown to promote Raw 264.7 macrophage proliferation, it is thus suggested that the use of lithium as an RVFV antiviral drug is less likely to elicit leukocytopenia. Lithium seems to regulate excessive inflammation in RVFV-infected Raw 264.7 macrophages by modulating the NF-kB signalling pathway. The endothelial integrity observed in the permeability assays has been supported by the expression of the molecules involved in keeping the cell to cell adhesion intact. This study links endothelial integrity patterns exerted by lithium with lowered production of inflammatory mediators such as ROS and RNS as these molecules are involved in destabilisation of cell junctions. Results from this study point towards the use of lithium as a potential treatment for RVFV infections by limiting viral replication, restricting viral spread and restoring the inflammation-regulating machinery. Key words. Lithium, Rift Valley fever virus, NF-kB, endothelial integrity, inflammation and apoptosis / Poliomyelitis Research foundation and National Research Foundation

Rift Valley fever virus (RVFV) is a mosquito-borne virus which has the ability to infect a large variety of animals including humans in Africa and Arabian Peninsula. The abortion rate among these animals are close to 100%, and young animals develop severe disease which often are lethal. In humans, Rift Valley fever (RVF) presents in most cases as a mild illness with influenza-like symptoms. However, in about 8% of the cases it progresses into a more severe disease with a high case fatality rate. Since there is such a high abortion rate among infected animals, a link between human miscarriage and RVFV has been suggested, but never proven. We could in paper I for the first time show an association between acute RVFV infection and miscarriage in humans. We observed an increase in pregnant women arriving at the Port Sudan Hospital with fever of unknown origin, and several of the patients experienced miscarriage. When we analysed their blood samples for several viral diseases we found that many had an acute RVFV infection and of these, 54% experienced a miscarriage. The odds of having a miscarriage was 7 times higher for RVFV patients compared to the RVFV negative women of which only 12% miscarried. These results indicated that RVFV infection could be a contributing factor to miscarriage. RVFV is an enveloped virus containing the viral glycoproteins n and c (Gn and Gc respectively), where Gn most likely is responsible for the initial cellular contact. The protein DC-SIGN on dendritic cells and the glycosaminoglycan heparan sulfate has been suggested as cellular receptors for RVFV, however other mechanisms are probably also involved in binding and entry. Charge is a driving force for molecular interaction and has been shown to be important for cellular attachment of several viruses, and in paper II we could show that when the charge around the cells was altered, the infection was affected. We also showed that Gn most likely has a positive charge at a physiological pH. When we added negatively charged molecules to the viral particles before infection, we observed a decreased infection efficiency, which we also observed after removal of carbohydrate structures from the cell surface. Our results suggested that the cellular interaction partner for initial attachment is a negatively charged carbohydrate. Further investigations into the mechanisms of RVFV cellular interactions has to be undertaken in order to understand, and ultimately prevent, infection and disease. There is currently no vaccine approved for human use and no specific treatments for RVF, so there is a great need for developing safe effective drugs targeting this virus. We designed a whole-cell based high-throughput screen (HTS) assay which we used to screen libraries of small molecular compounds for anti-RVFV properties. After dose-response and toxicity analysis of the initial hits, we identified six safe and effective inhibitors of RVFV infection that with further testing could become drug candidates for treatment of RVF. This study demonstrated the application of HTS using a whole-cell virus replication reporter gene assay as an effective method to identify novel compounds with potential antiviral activity against RVFV.