Mathematical model of a three-stage innate immune response to a pneumococcal lung infection

ManuscriptPneumococcal pneumonia is a leading cause of death and a major source of human morbidity. The initial immune response plays a central role in determining the course and outcome of pneumococcal disease. We combine bacterial titer measurements from mice infected with Streptococcus pneumoniae with mathematical modeling to investigate the coordination of immune responses and the effects of initial inoculum on outcome. To evaluate the contributions of individual components, we systematically build a mathematical model from three subsystems that describe the succession of defensive cells in the lung: resident alveolar macrophages, neutrophils and monocyte-derived macrophages. The alveolar macrophage response, which can be modeled by a single differential equation, can by itself rapidly clear small initial numbers of pneumococci. Extending the model to include the neutrophil response required additional equations for recruitment cytokines and host cell status and damage. With these dynamics, two outcomes can be predicted: bacterial clearance or sustained bacterial growth. Finally, a model including monocyte-derived macrophage recruitment by neutrophils suggests that sustained bacterial growth is possible even in their presence. Our model quantifies the contributions of cytotoxicity and immune-mediated damage in pneumococcal pathogenesis

Lullaby

I have been investigating the way in which my mind has altered my memories, especially from childhood. The more a moment is recalled, the less precise it becomes. The most inaccurate memories from childhood are the ones I have fixated on. Bedrooms are spaces where dreaming, sleeping and reverie take place leading to even more fragmenting. The intimate space of a bedroom allows me to represent the personal distorted recollections. The bedroom furniture is missing parts, shifted in height and placement or combined together. By making doubles of furniture, a direct comparison can be made from the real piece to the made imagined work. A counterpart can be a defense against loss, by having multiples of the same. Through dwelling on the past I have lost most of the original content and am left with disintegrating parts

TBK1 and IKKε act redundantly to mediate STING-induced NF-κB responses in myeloid cells

Stimulator of Interferon Genes (STING) is a critical component of host innate immune defense but can contribute to chronic autoimmune or autoinflammatory disease. Once activated, the cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP) synthase (cGAS)-STING pathway induces both type I interferon (IFN) expression and nuclear factor-κB (NF-κB)-mediated cytokine production. Currently, these two signaling arms are thought to be mediated by a single upstream kinase, TANK-binding kinase 1 (TBK1). Here, using genetic and pharmacological approaches, we show that TBK1 alone is dispensable for STING-induced NF-κB responses in human and mouse immune cells, as well as in vivo. We further demonstrate that TBK1 acts redundantly with IκB kinase ε (IKKε) to drive NF-κB upon STING activation. Interestingly, we show that activation of IFN regulatory factor 3 (IRF3) is highly dependent on TBK1 kinase activity, whereas NF-κB is significantly less sensitive to TBK1/IKKε kinase inhibition. Our work redefines signaling events downstream of cGAS-STING. Our findings further suggest that cGAS-STING will need to be targeted directly to effectively ameliorate the inflammation underpinning disorders associated with STING hyperactivity

Building bacterial knowledge: Games as teaching aides for higher-order thinking skills

Bacteria Builder is a videogame designed to teach student nurses about bacterial form and function within the context of a university fundamental science module. It challenges players to design and build bacteria with appropriate structures for surviving in different environments. This paper describes two studies undertaken to explore the most effective way to use the game as part of teaching on the module. 152 student nurses took part in the first evaluation, which used a control group to compare learning gains for a) only the game b) only the lecture and c) the game plus a reflective activity. All three conditions demonstrated improvements over the control, but there were no significant differences in learning gains between the experimental conditions. In a second evaluation, 124 student nurses took part in a study which compared the lecture on its own to the lecture and game together. Learning gains were found to be over 50% higher in the lecture and game condition, and subsequent analysis showed that the nurses who had played the game made greater improvements in questions designed to test higher-order thinking skills. The design and motivation behind the Bacteria Builder game is described and the results of these studies are discussed with respect to the role of teaching in maximising the effectiveness of game-based learning. Correlations between interaction data for different parts of the game are explored with respect to learning outcomes, and implications for the design of future studies are discussed

Country of origin, culture, self-esteem and intimate partner violence among community dwelling Hispanic women

The purpose of this study was to explore variations in demographics, culture, self-esteem and intimate partner violence among Hispanic women according to country of origin, and to identify factors that are associated with differences in intimate partner violence. Baseline data from a randomized control trial testing the efficacy of an HIV prevention program was used. Path analyses were conducted to describe relationships between variables and identify potential mediators. Differences between Colombian women and women from other Central/South American countries were noted for intimate partner violence. Self-esteem was the only factor that was associated with these differences. Interventions that address the unique needs of Hispanic sub-groups and promote self-esteem are needed

Influenza Virus Infection Model With Density Dependence Supports Biphasic Viral Decay

Mathematical models that describe infection kinetics help elucidate the time scales, effectiveness, and mechanisms underlying viral growth and infection resolution. For influenza A virus (IAV) infections, the standard viral kinetic model has been used to investigate the effect of different IAV proteins, immune mechanisms, antiviral actions, and bacterial coinfection, among others. We sought to further define the kinetics of IAV infections by infecting mice with influenza A/PR8 and measuring viral loads with high frequency and precision over the course of infection. The data highlighted dynamics that were not previously noted, including viral titers that remain elevated for several days during mid-infection and a sharp 4–5 log10 decline in virus within 1 day as the infection resolves. The standard viral kinetic model, which has been widely used within the field, could not capture these dynamics. Thus, we developed a new model that could simultaneously quantify the different phases of viral growth and decay with high accuracy. The model suggests that the slow and fast phases of virus decay are due to the infected cell clearance rate changing as the density of infected cells changes. To characterize this model, we fit the model to the viral load data, examined the parameter behavior, and connected the results and parameters to linear regression estimates. The resulting parameters and model dynamics revealed that the rate of viral clearance during resolution occurs 25 times faster than the clearance during mid-infection and that small decreases to this rate can significantly prolong the infection. This likely reflects the high efficiency of the adaptive immune response. The new model provides a well-characterized representation of IAV infection dynamics, is useful for analyzing and interpreting viral load dynamics in the absence of immunological data, and gives further insight into the regulation of viral control

A Mouse Model of Zika Virus Pathogenesis

SummaryThe ongoing Zika virus (ZIKV) epidemic and unexpected clinical outcomes, including Guillain-Barré syndrome and birth defects, has brought an urgent need for animal models. We evaluated infection and pathogenesis with contemporary and historical ZIKV strains in immunocompetent mice and mice lacking components of the antiviral response. Four- to six-week-old Irf3−/− Irf5−/− Irf7−/− triple knockout mice, which produce little interferon α/β, and mice lacking the interferon receptor (Ifnar1−/−) developed neurological disease and succumbed to ZIKV infection, whereas single Irf3−/−, Irf5−/−, and Mavs−/− knockout mice exhibited no overt illness. Ifnar1−/− mice sustained high viral loads in the brain and spinal cord, consistent with evidence that ZIKV causes neurodevelopmental defects in human fetuses. The testes of Ifnar1−/− mice had the highest viral loads, which is relevant to sexual transmission of ZIKV. This model of ZIKV pathogenesis will be valuable for evaluating vaccines and therapeutics as well as understanding disease pathogenesis