Inferring biomarkers for Mycobacterium avium subsp. paratuberculosis infection and disease progression in cattle using experimental data

Available diagnostic assays for Mycobacterium avium subsp. paratuberculosis (MAP) have poor sensitivities and cannot detect early stages of infection, therefore, there is need to find new diagnostic markers for early infection detection and disease stages. We analyzed longitudinal IFN-γ, ELISA-antibody and fecal shedding experimental sensitivity scores for MAP infection detection and disease progression. We used both statistical methods and dynamic mathematical models to (i) evaluate the empirical assays (ii) infer and explain biological mechanisms that affect the time evolution of the biomarkers, and (iii) predict disease stages of 57 animals that were naturally infected with MAP. This analysis confirms that the fecal test is the best marker for disease progression and illustrates that Th1/Th2 (IFN-γ/ELISA antibodies) assays are important for infection detection, but cannot reliably predict persistent infections. Our results show that the theoretical simulated macrophage-based assay is a potential good diagnostic marker for MAP persistent infections and predictor of disease specific stages. We therefore recommend specifically designed experiments to test the use of a based assay in the diagnosis of MAP infections

Modelling within Host Parasite Dynamics of Schistosomiasis

Schistosomiasis infection is characterized by the presence of adult worms in the portal and mesenteric veins of humans as part of a complex migratory cycle initiated by cutaneous penetration of the cercariae shed by infected freshwater snails. The drug praziquantel is not always effective in the treatment against schistosomiasis at larvae stage. However, our simulations show that it is effective against mature worms and eggs. As a result, the study and understanding of immunological responses is key in understanding parasite dynamics. We therefore introduce quantitative interpretations of human immunological responses of the disease to formulate mathematical models for the within-host dynamics of schistosomiasis. We also use numerical simulations to demonstrate that it is the level of T cells that differentiates between either an effective immune response or some degree of infection. These cells are responsible for the differentiation and recruitment of eosinophils that are instrumental in clearing the parasite. From the model analysis, we conclude that control of infection is much attributed to the value of a function f, a measure of the average number of larvae penetrating a susceptible individual having hatched from an egg released by an infected individual. This agrees with evidence that there is a close association between the ecology, the distribution of infection and the disease

Ceftazidime-avibactam has potent sterilizing activity against highly drug-resistant tuberculosis.

There are currently many patients with multidrug-resistant and extensively drug-resistant tuberculosis. Ongoing transmission of the highly drug-resistant strains and high mortality despite treatment remain problematic. The current strategy of drug discovery and development takes up to a decade to bring a new drug to clinical use. We embarked on a strategy to screen all antibiotics in current use and examined them for use in tuberculosis. We found that ceftazidime-avibactam, which is already used in the clinic for multidrug-resistant Gram-negative bacillary infections, markedly killed rapidly growing, intracellular, and semidormant Mycobacterium tuberculosis in the hollow fiber system model. Moreover, multidrug-resistant and extensively drug-resistant clinical isolates demonstrated good ceftazidime-avibactam susceptibility profiles and were inhibited by clinically achievable concentrations. Resistance arose because of mutations in the transpeptidase domain of the penicillin-binding protein PonA1, suggesting that the drug kills M. tuberculosis bacilli via interference with cell wall remodeling. We identified concentrations (exposure targets) for optimal effect in tuberculosis, which we used with susceptibility results in computer-aided clinical trial simulations to identify doses for immediate clinical use as salvage therapy for adults and young children. Moreover, this work provides a roadmap for efficient and timely evaluation of antibiotics and optimization of clinically relevant dosing regimens

Spatial Network Mapping of Pulmonary Multidrug-Resistant Tuberculosis Cavities Using RNA Sequencing.

Rationale: There is poor understanding about protective immunity and the pathogenesis of cavitation in patients with tuberculosis.Objectives: To map pathophysiological pathways at anatomically distinct positions within the human tuberculosis cavity.Methods: Biopsies were obtained from eight predetermined locations within lung cavities of patients with multidrug-resistant tuberculosis undergoing therapeutic surgical resection (n = 14) and healthy lung tissue from control subjects without tuberculosis (n = 10). RNA sequencing, immunohistochemistry, and bacterial load determination were performed at each cavity position. Differentially expressed genes were normalized to control subjects without tuberculosis, and ontologically mapped to identify a spatially compartmentalized pathophysiological map of the cavity. In silico perturbation using a novel distance-dependent dynamical sink model was used to investigate interactions between immune networks and bacterial burden, and to integrate these identified pathways.Measurements and Main Results: The median (range) lung cavity volume on positron emission tomography/computed tomography scans was 50 cm3 (15-389 cm3). RNA sequence reads (31% splice variants) mapped to 19,049 annotated human genes. Multiple proinflammatory pathways were upregulated in the cavity wall, whereas a downregulation "sink" in the central caseum-fluid interface characterized 53% of pathways including neuroendocrine signaling, calcium signaling, triggering receptor expressed on myeloid cells-1, reactive oxygen and nitrogen species production, retinoic acid-mediated apoptosis, and RIG-I-like receptor signaling. The mathematical model demonstrated that neuroendocrine, protein kinase C-θ, and triggering receptor expressed on myeloid cells-1 pathways, and macrophage and neutrophil numbers, had the highest correlation with bacterial burden (r > 0.6), whereas T-helper effector systems did not.Conclusions: These data provide novel insights into host immunity to Mycobacterium tuberculosis-related cavitation. The pathways defined may serve as useful targets for the design of host-directed therapies, and transmission prevention interventions

Modelling the immmunopathogenesis of HIV-1 infection and the effect of multidrug therapy: the role of fusion inhibitors in HAART

The role of fusion inhibitors in HAART,There is currently tremendous e?ort being directed at developing potent, highly active antiretroviral therapies that can e?ectively control HIV- 1 infection without the need for continuous, lifelong use of these drugs. In the ongoing search for powerful antiretroviral agents that can a?ect sustained control for HIV infection, mathematical models can help in assessing both the correlates of protective immunity and the clinical role of a given drug regimen as well as in understanding the e?cacy of drug therapies administered at di?erent stages of the disease. In this study, we develop a new mathematical model of the immuno-pathogenesis of HIV-1 infection, which we use to assess virological responses to both intracellular and extracellular antiretroviral drugs. We ?rst develop a basic mathematical model of the immuno-pathogenesis of HIV-1 infection that incorporates three distinct stages in the infection cycle of HIV-1: entry of HIV-1 into the cytoplasm of CD4+ T cells, transcription of HIV-1 RNA to DNA within CD4+ T cells, and production of HIV-1 viral particles within CD4+ T cells. Then we extend the basic model to incorporate the e?ect of three major categories of anti-HIV-1 drugs: fusion/entry inhibitors (FIs), reverse transcriptase inhibitors (RTIs), and protease inhibitors (PIs). Model analysis establishes that the actual drug e?cacy of FIs, ? and of PIs, ? is the same as their e?ective e?cacies while the e?ective drug e?cacy for the RTIs, r?, is dependent on the rate of transcription of the HIV-1 RNA to DNA, and the lifespan of infected CD4+ T cells where virions have only entered the cytoplasm and that this e?ective e?cacy is less than the actual e?cacy, ?. Our studies suggest that, of the three anti-HIV drug categories (FIs, RTIs, and PIs), any drug combination of two drugs that includes RTIs is the weakest in the control of HIV-1 infection

Modelling the human immune response mechanisms to mycobacterium tuberculosis infection in the lungs

Human immune response mechanisms to TB infection,This work elaborates on the e?ects of cytotoxic lymphocytes (CTLs) and other immune mechanisms in determining whether a TB-infected individ- ual will develop active or latent TB. It answers one intriguing question: why do individuals infected with Mycobacterium tuberculosis (Mtb) experience dif- ferent clinical outcomes? In addressing this question, we have developed a model that captures the e?ects of CTLs and the combined e?ects of CD4+ helper T cells (Th1 and Th2) immune response mechanisms to TB infection. The occurrence of active or latent infection is shown to depend on a number of factors that include e?ector function and levels of CTLs. We use the model to predict disease progression scenarios, including primary, latency or clearance. Model analysis shows that occurrence of active disease is much attributed to the Mtb pathogen ability to persist outside the intracellular environment and that high levels of CTLs result in latent TB, while low levels of CTLs result in active TB. This is attributed to the CTLs' ability to directly kill infected macrophages and the bacteria inside the infected macrophages. The study suggests directions for further basic studies and potential new treatment strategies

Optimal control of malaria chemotherapy

We present an intra-host mathematical model of malaria that describes the interaction of the immune system with the blood stage malaria merozoites. The model is modified by incorporating the effects of malaria drugs that target blood stage parasites. The optimal control represents a percentage effect of the chemotherapy of chloroquine in combination with chlorpheniramine on the reproduction of merozoites in erythrocytes. First we maximise the benefit based on the immune cells, and minimise the systemic cost based on the percentage of chemotherapies given and the population of merozoites. An objective functional to minimise merozite reproduction and treatment systemic costs is then built. The existence and uniqueness results for the optimal control are established. The optimality system is derived and the Runge–Kutta fourth order scheme is used to numerically simulate different therapy efforts. Our results indicate that highly toxic drugs with the compensation of high infection suppression have the potential of yeilding better treatment results than less toxic drugs with less infection suppression potential or high toxic drugs with less infection suppression potential. In addition, we also observed that a treatment protocol with drugs with high adverse effects and with a high potential of merozoite suppression can be beneficial to patients. However, an optimal control strategy that seeks to maximise immune cells has no potential to improve the treatment of blood stage malaria.</jats:p

Modeling the TB/HIV-1 Co-Infection and the Effects of Its Treatment

Modeling the interaction of Tuberculosis (TB) and AIDS (HIV) drugs in the treatment of the TB/HIV co-infection shows that the treatment of Mtb (Mycobacterium tuberculosis) and AIDS improves. The administration of HIV drugs without TB drugs during co-infection favors the treatment of HIV, but the patient will eventually die of the Mtb opportunistic infection. Reducing the interaction of TB and HIV drugs and increasing the performance (efficiency of inhibition) of Reverse Transcriptase Inhibitors (RTIs) in CD4+ T cells improves the treatment of HIV and leads to the preferential replication of HIV particles in macrophages. The simultaneous administration of TB and HIV drugs is to be recommended for it prevents patients from dying of the Mtb opportunistic infection.AIDS, co-infection, highly active anti-retroviral therapy (HAART), Mycobacterium tuberculosis, TB chemotherapy,

Competition for antigen between Th1 and Th2 responses determines the timing of the immune response switch during Mycobaterium avium subspecies paratuberulosis infection in ruminants.

Johne's disease (JD), a persistent and slow progressing infection of ruminants such as cows and sheep, is caused by slow replicating bacilli Mycobacterium avium subspecies paratuberculosis (MAP) infecting macrophages in the gut. Infected animals initially mount a cell-mediated CD4 T cell response against MAP which is characterized by the production of interferon gamma (Th1 response). Over time, Th1 response diminishes in most animals and antibody response to MAP antigens becomes dominant (Th2 response). The switch from Th1 to Th2 response occurs concomitantly with disease progression and shedding of the bacteria in feces. Mechanisms controlling this Th1/Th2 switch remain poorly understood. Because Th1 and Th2 responses are known to cross-inhibit each other, it is unclear why initially strong Th1 response is lost over time. Using a novel mathematical model of the immune response to MAP infection we show that the ability of extracellular bacteria to persist outside of macrophages naturally leads to switch of the cellular response to antibody production. Several additional mechanisms may also contribute to the timing of the Th1/Th2 switch including the rate of proliferation of Th1/Th2 responses at the site of infection, efficiency at which immune responses cross-inhibit each other, and the rate at which Th1 response becomes exhausted over time. Our basic model reasonably well explains four different kinetic patterns of the Th1/Th2 responses in MAP-infected sheep by variability in the initial bacterial dose and the efficiency of the MAP-specific T cell responses. Taken together, our novel mathematical model identifies factors of bacterial and host origin that drive kinetics of the immune response to MAP and provides the basis for testing the impact of vaccination or early treatment on the duration of infection