Infection is a complex and dynamic process involving a population of invading microbes, the host and its responses, aimed at controlling the situation. Depending on the purpose and level of ...organization, infection at the organism level can be described by a process as simple as a coin toss, or as complex as a multi-factorial dynamic model; the former, for instance, may be adequate as a component of a population model, while the latter is necessary for a thorough description of the process beginning with a challenge with an infectious inoculum up to establishment or elimination of the pathogen. Experimental readouts in the laboratory are often static, snapshots of the process, assayed under some convenient experimental condition, and therefore cannot comprehensively describe the system. Different from the discrete treatment of infection in population models, or the descriptive summarized accounts of typical lab experiments, in this manuscript, infection is treated as a dynamic process dependent on the initial conditions of the infectious challenge, viral growth, and the host response along time. Here, experimental data is generated for multiple doses of type 1 dengue virus, and pathogen levels are recorded at different points in time for two populations of mosquitoes: either carrying endosymbiont bacteria Wolbachia or not. A dynamic microbe/host-response mathematical model is used to describe pathogen growth in the face of a host response like the immune system, and to infer model parameters for the two populations of insects, revealing a slight-but potentially important-protection conferred by the symbiont.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Wolbachia has been introduced into Aedes aegypti mosquitoes to control the spread of arboviruses, such as dengue, chikungunya and Zika. Studies showed that certain Wolbachia strains (such as wMel) ...reduce replication of dengue viruses in the laboratory, prompting the release of mosquitoes carrying the bacterium into the field, where vectorial capacity can be realistically assessed in relation to native non-carriers. Here we apply a new analysis to two published datasets, and show that wMel increases the mean and the variance in Ae. aegypti susceptibility to dengue infection when introgressed into Brazil and Vietnam genetic backgrounds. In the absence of other processes, higher mean susceptibility should lead to enhanced viral transmission. The increase in variance, however, widens the basis for selection imposed by unexplored natural forces, retaining the potential for reducing transmission overall.
Sensing light is the fundamental property of visual systems, with vision in animals being based almost exclusively on opsin photopigments 1. Rhodopsin also acts as a photoreceptor linked to ...phototaxis in green algae 2, 3 and has been implicated by chemical means as a light sensor in the flagellated swimming zoospores of the fungus Allomyces reticulatus 4; however, the signaling mechanism in these fungi remains unknown. Here we use a combination of genome sequencing and molecular inhibition experiments with light-sensing phenotype studies to examine the signaling pathway involved in visual perception in the closely related fungus Blastocladiella emersonii. Our data show that in these fungi, light perception is accomplished by the function of a novel gene fusion (BeGC1) of a type I (microbial) rhodopsin domain and guanylyl cyclase catalytic domain. Photobleaching of rhodopsin function prevents accumulation of cGMP levels and phototaxis of fungal zoospores exposed to green light, whereas inhibition of guanylyl cyclase activity negatively affects fungal phototaxis. Immunofluorescence microscopy localizes the BeGC1 protein to the external surface of the zoospore eyespot positioned close to the base of the swimming flagellum 4, 5, demonstrating this is a photoreceptive organelle composed of lipid droplets. Taken together, these data indicate that Blastocladiomycota fungi have a cGMP signaling pathway involved in phototaxis similar to the vertebrate vision-signaling cascade but composed of protein domain components arranged as a novel gene fusion architecture and of distant evolutionary ancestry to type II rhodopsins of animals.
•A rhodopsin-guanylate cyclase gene fusion is involved in B. emersonii phototaxis•The rhodopsin fusion protein BeGC1 is localized to the zoospore eyespot apparatus•Endogenous retinal substitution by retinalA1 reconstitutes green light phototaxis•Zoospore phototaxis uses cGMP as a second messenger similar to vertebrate vision
Avelar et al. use genome sequencing, molecular inhibition, and light-sensing phenotype experiments, combined with immunolocalization data, to show that a type I rhodopsin-guanylyl cyclase fusion protein localizes to the “eyespot” and is involved in green light phototaxis in zoospores of the Blastocladiomycete fungus Blastocladiella emersonii.
Abstract
Although less well-recognized than for other infectious diseases, heterogeneity is a defining feature of tuberculosis (TB) epidemiology. To advance toward TB elimination, this heterogeneity ...must be better understood and addressed. Drivers of heterogeneity in TB epidemiology act at the level of the infectious host, organism, susceptible host, environment, and distal determinants. These effects may be amplified by social mixing patterns, while the variable latent period between infection and disease may mask heterogeneity in transmission. Reliance on notified cases may lead to misidentification of the most affected groups, as case detection is often poorest where prevalence is highest. Assuming that average rates apply across diverse groups and ignoring the effects of cohort selection may result in misunderstanding of the epidemic and the anticipated effects of control measures. Given this substantial heterogeneity, interventions targeting high-risk groups based on location, social determinants, or comorbidities could improve efficiency, but raise ethical and equity considerations.
Heterogeneity in tuberculosis burden is driven by the organism, host, environment, and distal determinants. More reliable data are needed given inconsistent case ascertainment. Targeting high-risk groups is an important consideration in designing interventions, but raises equity and efficiency issues.
Any infectious processes must depend in some fashion on dose, and empirical evidence exists for an effect of exposure dose on the probability of transmission to mumps-vaccinated hosts 1, the ...case-fatality ratio of measles 2, and the probability of infection and, given infection, of symptoms in cholera 3. Simulated sets of dose-infectivity data were generated and used to estimate model parameters (Figure S2), assuming the host susceptibility of the intervention group described by a beta distribution, , with shape parameters positioned as a grid in a square neighborhood of the uniform distribution, .
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Understanding the causes of vaccine failure is important for predicting disease dynamics in vaccinated populations and planning disease interventions. Pathogen exposure dose and heterogeneity in host ...susceptibility have both been implicated as important factors that may reduce overall vaccine efficacy and cause vaccine failure. Here, we explore the effect of pathogen dose and heterogeneity in host susceptibility in reducing efficacy of vaccines. Using simulation-based methods, we find that increases in pathogen exposure dose decrease vaccine efficacy, but this effect is modified by heterogeneity in host susceptibility. In populations where the mode of vaccine action is highly polarized, vaccine efficacy decreases more slowly with exposure dose than in populations with less variable protection. We compared these theoretical results to empirical estimates from a systematic literature review of vaccines tested over multiple exposure doses. We found that few studies (nine of 5,389) tested vaccine protection against infection over multiple pathogen challenge doses, with seven studies demonstrating a decrease in vaccine efficacy with increasing exposure dose. Our research demonstrates that pathogen dose has potential to be an important determinant of vaccine failure, although the limited empirical data highlight a need for additional studies to test theoretical predictions on the plausibility of reduced host susceptibility and high pathogen dose as mechanisms responsible for reduced vaccine efficacy in high transmission settings.
Global stakeholders including the World Health Organization rely on predictive models for developing strategies and setting targets for tuberculosis care and control programs. Failure to account for ...variation in individual risk leads to substantial biases that impair data interpretation and policy decisions. Anticipated impediments to estimating heterogeneity for each parameter are discouraging despite considerable technical progress in recent years. Here we identify acquisition of infection as the single process where heterogeneity most fundamentally impacts model outputs, due to selection imposed by dynamic forces of infection. We introduce concrete metrics of risk inequality, demonstrate their utility in mathematical models, and pack the information into a risk inequality coefficient (RIC) which can be calculated and reported by national tuberculosis programs for use in policy development and modeling.
We first study an SIR system of differential equations with periodic coefficients describing an epidemic in a seasonal environment. Unlike in a constant environment, the final epidemic size may not ...be an increasing function of the basic reproduction number ℛ₀ or of the initial fraction of infected people. Moreover, large epidemics can happen even if ℛ₀<1. But like in a constant environment, the final epidemic size tends to 0 when ℛ₀<1 and the initial fraction of infected people tends to 0. When ℛ₀>1, the final epidemic size is bigger than the fraction 1−1/ℛ₀ of the initially nonimmune population. In summary, the basic reproduction number ℛ₀ keeps its classical threshold property but many other properties are no longer true in a seasonal environment. These theoretical results should be kept in mind when analyzing data for emerging vector-borne diseases (West-Nile, dengue, chikungunya) or air-borne diseases (SARS, pandemic influenza); all these diseases being influenced by seasonality.
Abstract Mathematical models are increasingly adopted for setting disease prevention and control targets. As model-informed policies are implemented, however, the inaccuracies of some forecasts ...become apparent, for example overprediction of infection burdens and intervention impacts. Here, we attribute these discrepancies to methodological limitations in capturing the heterogeneities of real-world systems. The mechanisms underpinning risk factors of infection and their interactions determine individual propensities to acquire disease. These factors are potentially so numerous and complex that to attain a full mechanistic description is likely unfeasible. To contribute constructively to the development of health policies, model developers either leave factors out (reductionism) or adopt a broader but coarse description (holism). In our view, predictive capacity requires holistic descriptions of heterogeneity which are currently underutilised in infectious disease epidemiology, in comparison to other population disciplines, such as non-communicable disease epidemiology, demography, ecology and evolution.
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