Multiscale Modeling of Toxoplasma gondii

Toxoplasma gondii is a potentially deadly parasite that uses a very unique way of manipulating the cell and immune systems. To investigate the mechanics of how the parasite spreads within hosts, several interwoven topics related to the study of within-host dynamics of Toxoplasma gondii are presented here. Understanding the complicated methods of how the parasite grows, dies, invades, replicates, and evades the host immune response is the critical aim of this independent research. Understanding the processes of acute and chronic infection are studied independently, followed by modeling the two processes in the same model. Finally, the dynamic models are simulated within a 3D mesh representation of a mouse brain to visualize the infection spreading during the acute and chronic phase. The results presented shed light onto the effects of the immune response, cyst volume growth, and the dependence of multiple stages in the dissemination of the parasite within a host

Evaluación de la actividad antimalárica de preparaciones tradicionales obtenidas de dos especies promisorias usadas por una comunidad en zona endémica y profundización en el estudio de su actividad farmacológica

Se trabajó con la comunidad Ciudad Hitoma de la ciudad de Leticia, obteniéndose información de tres plantas usadas para el tratamiento de la malaria por parte del médico tradicional. Las preparaciones fueron evaluadas en los modelos de actividad antiplasmodial (Ensayo de inhibición de la invasión y desarrollo de P. falciparum cepa FCB2) y en el modelo de actividad antimalárica in vivo, ratones infectados con P. berghei. De las cinco preparaciones evaluadas, solamente la preparación obtenida de Curarea. toxicofera mostró una actividad buena a moderada en el ensayo in vitro (CI50 de 1.1 a 10 μg/mL) y actividad buena a moderada (Inhibición de la parasitemia de 50 a 90%) en los ensayos in vivo. Mediante perfiles de CCD (Cromatografía en capa delgada) se encontró cualitativamente la presencia de compuestos de tipo alcaloidal principalmente y de tipo esteroideo y/o triterpénico en esta preparación. Las otras preparaciones evaluadas, obtenidas de Abuta grandifolia y Aspidosperma excelsum, mostraron muy poca actividad (CI50 de 26 a 50 μg/mL) en los ensayos in vitro e inactivas en las condiciones del ensayo in vivo. Se detectó la presencia de flavonoides en estas mismas preparaciones. / Abstract. We worked with the community “Ciudad Hitoma” of the Leticia, obtaining information from three plants used for the treatment of malaria by the traditional healer. Preparations were evaluated in antiplasmodial activity (Test of inhibition of invasion and development of P. falciparum strain FCB 2) and the model of antimalarial activity in vivo, mice infected with P.berghei. Of the five preparations tested, only the preparation obtained from Curarea. Toxicofera showed a good activity to moderate in vitro assay (CI50 of 1.1 to 10 mg / mL) and good to moderate activity (inhibition of parasitemia of 50 to 90%) in vivo testing. By TLC profiles (thin layer chromatography) showed qualitatively the presence of compounds mainly type and type alkaloidal steroid and / or triterpenes in this preparation. The other preparations tested obtained from Abuta grandifolia and Aspidosperma excelsum showed very little activity (CI50 of 26 to 50 mg / mL) in the inactive in vitro and in vivo test conditions.Maestrí

Prevalence of molecular markers associated with chloroquine, sulphadoxine-pyrimethamine and lumefantrine resistance following the deployment of artemether-lumefantrine as first-line treatment for uncomplicated falciparum malaria in Gaza Province, Mozambique.

M. Sc. University of KwaZulu-Natal, Pietermaritzburg 2013.Antimalarial drug resistance is a major contributing factor to the sustained malaria burden in sub-Saharan Africa. Under extreme drug pressure, drug resistant parasites have a selective fitness advantage over wild-type parasites. However this selective advantage is negated once the drug pressure is removed. Over the past decade, malaria treatment policy in Mozambique has changed at least twice. In 2006 the monotherapy chloroquine (CQ) was replaced by artemisinin-based combination therapy artesunate plus sulphadoxine-pyrimethamine (SP) which in turn was replaced by artemether-lumefantrine in 2008. This study investigates the effect these changes in drug pressure had on the prevalence of molecular markers associated with CQ, SP and lumefantrine resistance in Gaza Province, Mozambique. Finger prick filter paper blood samples were collected from malaria rapid diagnostic test positive children at 20 sentinel sites during annual cross-sectional malaria prevalence surveys in 2010 and 2011. Chelex extracted parasite DNA confirmed as being P. falciparum positive using quantitative and nested PCR methods was subjected to mutational analysis using nested PCR and RFLP protocols to determine the prevalence of molecular markers associated with SP,CQ and lumefantrine resistance. Over the study period, the prevalence of SP resistance markers were nearing fixation, while all samples analysed had a single copy of the pfmdr1 gene. Despite the reduction of SP drug pressure since 2008, the prevalence of SP resistance markers were still high suggesting that SP pressure still exists in the region, raising concerns over the efficacy of intermittent preventative treatment using SP. This study supports the change from artesunate plus SP to artemether-lumefantrine in Gaza Province The prevalence of CQ resistance markers in the pfcrt gene increased over the study period whilst a decrease was observed in the pfmdr1 gene. These results suggest that CQ could still be in use in Gaza Province probably due to a lack of ACTs and availability of CQ. Whilst markers of artemisinin resistance have yet to be identified, the selection of the pfmdr1 86N allele, indicative of lumefantrine resistance, suggests that the pfmdr1 gene is under selection because of CQ withdrawal and raises concern for the continued use of the drug combination in the region. Further studies, using other markers of artemether-lumefantrine resistance are required. The pfmdr1 86Y marker was found to be associated with the pfcrt CVIET haplotype and the SP quintuple marker prevalence with residence influencing this association. This study contributes to the body of knowledge regarding drug resistance markers in Gaza Province which could be used to inform drug policy in the future

Backward bifurcation and reinfection in mathematical models of tuberculosis

Mathematical models are widely used for understanding the transmission mechanisms and control of infectious diseases. Numerous infectious diseases such as those caused by bacterial and viral infections do not confer life long immunity after recovering from the first episode. Consequently, they are characterized by partial or complete loss of immunity and subsequent reinfection. This thesis explores the epidemiological implications of loss of immunity using simple and complex mathematical models. First, a simple basic model mimicking transmission mechanisms of tuberculosis (TB) is proposed with the aim of correcting problems that are often repeated by mathematical modellers when determining underlying bifurcation structures. Specifically, the model makes transparent the problems that may arise if one aggregates all the bifurcation parameters when computing backward bifurcation thresholds and structures. The backward bifurcation phenomenon is an important concept for public health and disease management. This is because backward bifurcation signals that disease will not be eliminated even when the basic reproduction number R0 is decreased below unity; rather, for the disease to be eliminated, R0 has to be reduced below another critical threshold. I provide conditions to find the threshold correctly. Secondly, the simple basic TB model is extended to incorporate epidemiological and biological aspects pertinent to TB transmission such as recurrent TB, which is defined as a second episode of TB following successful recovery from a previous episode. I study the conditions for backward bifurcation in this extended model that features recurrent TB. Mathematical techniques based on the center manifold approach, are used to derive an exact backward bifurcation threshold. Furthermore, both analytical and numerical findings reveal that recurrent TB is capable of inducing a new and rare hysteresis effect where TB will persist when the basic reproduction number is below unity even though there is no backward bifurcation. Moreover, when the reinfection pathway among latently infected individuals is switched off, leaving only recurrent TB, the model analysis indicates that recurrent TB can independently induce a backward bifurcation. However, this will only occur if recurrent TB transmission exceeds a certain threshold. Although this threshold seems to be relatively high when realistic parameters are used, it falls within the recent range estimated in the relevant literature. The second TB model is extended by dividing the latent compartment into two: fast (early latent) and slow (late latent) latent compartments, to enhance realism. Individuals in both early and late compartments are subjected to treatment. The proposed TB model is used to investigate how heterogeneity in host susceptibility influences the effectiveness of treatment. It is found that making the assumption that individuals treated with preventive therapy and recovered individuals (previously treated for active TB) acquire equal levels of protection after initial infection, and are therefore reinfected at the same rate, may obscure dynamics that are imperative when designing intervention strategies. Comparison of reinfection rates between cohorts treated with preventive therapy and recovered individuals who were previously treated from active TB provides important epidemiological insights. That is, the reinfection parameter accounting for the relative rate of reinfection of the cohort treated with preventive therapy is the one that plays the key role in generating qualitative changes in TB dynamics. In contrast, the parameter accounting for the risk of reinfection among recovered individuals (previously treated for active TB) does not play a significant role. The study shows that preventive treatment during early latency is always beneficial regardless of the level of susceptibility to reinfection. And if patients have greater immunity following treatment for late latent infection, then treatment is again beneficial. However, if susceptibility increases following treatment for late latent infection, the effect of treatment depends on the epidemiological setting: (a) for (very) low burden settings, the effect on reactivation predominates and burden declines; (b) for high burden settings, the effect on reinfection predominates and burden increases. This is mostly observed between the two reinfection thresholds, RT2 and RT1, respectively associated with individuals being treated with preventive therapy and individuals with untreated late latent TB infection. Finally, a mathematical model that examines how heroin addiction spreads in society is formulated. The model has many commonalities with the TB model. The global stability properties of the proposed model are analysed using both the Lyapunov direct method and the geometric approach by Li and Muldowney. It is shown that even for a four dimensional model, the use of two well known nonlinear stability techniques becomes nontrivial. When all the parameters of the model are accounted for, it is difficult if not impossible, to design a Lyapunov function. Here I apply the geometric approach to establish a global condition that accounts for all model parameters. If the condition is satisfied, then heroin persistence within the community is globally stable. However, if the global condition is not satisfied heroin users can oscillate periodically in number. Numerical simulations are also presented to give a more complete representation of the model dynamics. Sensitivity analysis performed by Latin hypercube sampling (LHS) suggests that the effective contact rate in the population, the relapse rate of heroin users undergoing treatment, and the extent of saturation of heroin users, are the key mechanisms fuelling heroin epidemic proliferation. However, in the long term, relapse of heroin users undergoing treatment back to a heroin using career, has the most significant impact