Dissecting the determinants of malaria chronicity: why within-host models struggle to reproduce infection dynamics

The duration of infection is fundamental to the epidemiological behaviour of any infectious disease, but remains one of the most poorly understood aspects of malaria. In endemic areas, the malaria parasite Plasmodium falciparum can cause both acute, severe infections and asymptomatic, chronic infections through its interaction with the host immune system. Frequent superinfection and massive parasite genetic diversity make it extremely difficult to accurately measure the distribution of infection lengths, complicating the estimation of basic epidemiological parameters and the prediction of the impact of interventions. Mathematical models have qualitatively reproduced parasite dynamics early during infection, but reproducing long-lived chronic infections remains much more challenging. Here, we construct a model of infection dynamics to examine the consequences of common biological assumptions for the generation of chronicity and the impact of co-infection. We find that although a combination of host and parasite heterogeneities are capable of generating chronic infections, they do so only under restricted parameter choices. Furthermore, under biologically plausible assumptions, co-infection of parasite genotypes can alter the course of infection of both the resident and co-infecting strain in complex non-intuitive ways. We outline the most important puzzles for within-host models of malaria arising from our analysis, and their implications for malaria epidemiology and control.

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The impact of resource provisioning on the epidemiological responses of different parasites

10.1101/2021.05.22.445253 ◽

2021 ◽

Author(s):

Diana Erazo ◽

Amy B Pedersen ◽

Andy Fenton

Keyword(s):

Infectious Diseases ◽

Anthropogenic Activities ◽

Resource Provisioning ◽

Transmission Mode ◽

Host Susceptibility ◽

Host Immune System ◽

Trade Offs ◽

Duration Of Infection ◽

Host Parasite ◽

The Impact

Events such as anthropogenic activities and periodic tree masting can alter resource provisioning in the environment, directly affecting animals, and potentially impacting the spread of infectious diseases in wildlife. The effect of these supplemental resources on infectious diseases can manifest through different pathways, affecting host susceptibility, transmission and host demography. To date however, empirical research has tended to examine these different pathways in isolation, for example by quantifying the effects of provisioning on host behaviour in the wild or changes in immune responses in controlled laboratory studies. Further, while theory has investigated the interactions between these pathways, thus far this work has focussed on a narrow subset of pathogen types, typically directly-transmitted microparasites. Given the diverse ways that provisioning can affect host susceptibility, contact patterns or host demography, we may expect the epidemiological consequences of provisioning to depend on key aspects of parasite life-history, such as the duration of infection and transmission mode. We developed a suite of generic epidemiological models to compare how resource provisioning alters responses for different parasites that vary in their biology (micro- and macro-parasite), transmission mode (direct, environmental, and vector transmitted) and duration of infection (acute, latent, and chronic). Next, we parameterised these different parasite types using data from the diverse parasite community of wild wood mice as a case study. We show there are common epidemiological responses to host resource provisioning across all parasite types examined. In particular, the response to provisioning could be driven in opposite directions, depending on which host pathways (contact rate, susceptibility or host demography) are most altered by the addition of resources to the environment. Broadly, these responses were qualitatively consistent across all parasite types, emphasising the importance of identifying general trade-offs between provisioning-altered parameters. Despite the qualitative consistency in responses to provisioning across parasite types, we found notable quantitative differences between parasites, suggesting specific epidemiological outcomes could strongly depend on parasite type, infection duration and permanency of recovery, and whether the parasite is directly, environmentally, or vector transmitted. These analyses therefore highlight the importance of knowing key specific aspects of host-parasite biology, such as host contact behaviours, parasite interactions with the host immune system, and how resource availability shapes host demographics, in order to understand and predict epidemiological responses to provisioning for any specific host-parasite system.

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Environmental reservoir dynamics predict global infection patterns and population impacts for the fungal disease white-nose syndrome

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1914794117 ◽

2020 ◽

Vol 117 (13) ◽

pp. 7255-7262 ◽

Cited By ~ 9

Author(s):

Joseph R. Hoyt ◽

Kate E. Langwig ◽

Keping Sun ◽

Katy L. Parise ◽

Aoqiang Li ◽

...

Keyword(s):

Disease Outbreaks ◽

Population Declines ◽

Pseudogymnoascus Destructans ◽

White Nose Syndrome ◽

Infection Dynamics ◽

Environmental Reservoir ◽

Severe Infections ◽

Seasonal Epidemics ◽

Host Infection ◽

The Impact

Disease outbreaks and pathogen introductions can have significant effects on host populations, and the ability of pathogens to persist in the environment can exacerbate disease impacts by fueling sustained transmission, seasonal epidemics, and repeated spillover events. While theory suggests that the presence of an environmental reservoir increases the risk of host declines and threat of extinction, the influence of reservoir dynamics on transmission and population impacts remains poorly described. Here we show that the extent of the environmental reservoir explains broad patterns of host infection and the severity of disease impacts of a virulent pathogen. We examined reservoir and host infection dynamics and the resulting impacts of Pseudogymnoascus destructans, the fungal pathogen that causes white-nose syndrome, in 39 species of bats at 101 sites across the globe. Lower levels of pathogen in the environment consistently corresponded to delayed infection of hosts, fewer and less severe infections, and reduced population impacts. In contrast, an extensive and persistent environmental reservoir led to early and widespread infections and severe population declines. These results suggest that continental differences in the persistence or decay of P. destructans in the environment altered infection patterns in bats and influenced whether host populations were stable or experienced severe declines from this disease. Quantifying the impact of the environmental reservoir on disease dynamics can provide specific targets for reducing pathogen levels in the environment to prevent or control future epidemics.

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Study of the effectiveness of partial quarantines applied to control the spread of the Covid-19 virus

10.1101/2021.04.03.21254727 ◽

2021 ◽

Author(s):

Alejandro Leon

Keyword(s):

Theoretical Model ◽

Cellular Automaton ◽

Spatial Region ◽

Free Zone ◽

Individual Mobility ◽

Infection Dynamics ◽

The World ◽

Effectiveness And Efficiency ◽

And Control ◽

The Impact

In Chile and in many countries of the world, partial quarantines have been used as part of the strategy to contain and control the Covid-19 virus. However, there is no certainty of its effectiveness and efficiency due to the lack of comparison with similar scenarios. In this work, we formulated a theoretical model of individual mobility, which also incorporates the infection dynamics of Covid-19. The model is based on a cellular automaton, which includes individuals moving through the represented spatial region and interacting according to the dynamics of Covid-19. In addition, we include mobile and partial health barriers, and different mobility regimes. Our results show that, partial quarantines would not be effective in general, to reduce the peak of active individuals infected with the virus, except for some proportions of territorial area involved in the division of the global region. Another interesting result of our research is that the passage restrictions in a sanitary barrier would not be relevant to the impact of the pandemic indicators in a sanitary quarantine regime. A possible explanation for the ineffectiveness of partial quarantines lies in the fact that the sanitary barriers are permeable to infected individuals and therefore when one of these individuals passes, an outbreak occurs in the virus-free zone that is independent of the original one.

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Card9 mediates susceptibility to intestinal pathogens through microbiota modulation and control of bacterial virulence

Gut ◽

10.1136/gutjnl-2017-314195 ◽

2017 ◽

Vol 67 (10) ◽

pp. 1836-1844 ◽

Cited By ~ 12

Author(s):

Bruno Lamas ◽

Marie-Laure Michel ◽

Nadine Waldschmitt ◽

Hang-Phuong Pham ◽

Vassiliki Zacharioudaki ◽

...

Keyword(s):

Humoral Response ◽

Pcr Analysis ◽

Host Immune System ◽

Independent Manner ◽

Pathogen Virulence ◽

Infection Susceptibility ◽

Intestinal Pathogens ◽

Human Infections ◽

And Control ◽

The Impact

ObjectiveIn association with innate and adaptive immunity, the microbiota controls the colonisation resistance against intestinal pathogens. Caspase recruitment domain 9 (CARD9), a key innate immunity gene, is required to shape a normal gut microbiota. Card9–/– mice are more susceptible to the enteric mouse pathogen Citrobacter rodentium that mimics human infections with enteropathogenic and enterohaemorrhagic Escherichia coli. Here, we examined how CARD9 controls C. rodentium infection susceptibility through microbiota-dependent and microbiota-independent mechanisms.DesignC. rodentium infection was assessed in conventional and germ-free (GF) wild-type (WT) and Card9–/– mice. To explore the impact of Card9–/–microbiota in infection susceptibility, GF WT mice were colonised with WT (WT→GF) or Card9–/– (Card9–/–→GF) microbiota before C. rodentium infection. Microbiota composition was determined by 16S rDNA gene sequencing. Inflammation severity was determined by histology score and lipocalin level. Microbiota–host immune system interactions were assessed by quantitative PCR analysis.ResultsCARD9 controls pathogen virulence in a microbiota-independent manner by supporting a specific humoral response. Higher susceptibility to C. rodentium-induced colitis was observed in Card9–/–→GF mice. The microbiota of Card9–/– mice failed to outcompete the monosaccharide-consuming C. rodentium, worsening the infection severity. A polysaccharide-enriched diet counteracted the ecological advantage of C. rodentium and the defective pathogen-specific antibody response in Card9–/– mice.ConclusionsCARD9 modulates the susceptibility to intestinal infection by controlling the pathogen virulence in a microbiota-dependent and microbiota-independent manner. Genetic susceptibility to intestinal pathogens can be overridden by diet intervention that restores humoural immunity and a competing microbiota.

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A Mathematical Model of Treatment and Vaccination Interventions of Pneumococcal Pneumonia Infection Dynamics

Journal of Applied Mathematics ◽

10.1155/2018/2539465 ◽

2018 ◽

Vol 2018 ◽

pp. 1-16 ◽

Cited By ~ 4

Author(s):

Mohammed Kizito ◽

Julius Tumwiine

Keyword(s):

Reproduction Number ◽

Control Strategies ◽

The Elderly ◽

Infection Dynamics ◽

And Control ◽

Long Term Behavior ◽

The Impact ◽

Globally Stable ◽

Disease Free

Streptococcus pneumoniae is one of the leading causes of serious morbidity and mortality worldwide, especially in young children and the elderly. In this study, a model of the spread and control of bacterial pneumonia under public health interventions that involve treatment and vaccination is formulated. It is found out that the model exhibits the disease-free and endemic equilibria. The disease-free equilibrium is stable if and only if the basic reproduction number R0<1 and the disease will be wiped out of the population. For R0≥1, the endemic equilibrium is globally stable and the disease persists. We infer the effect of these interventions on the dynamics of the pneumonia through sensitivity analysis on the effective reproduction number Re, from which it is revealed that treatment and vaccination interventions combined can eradicate pneumonia infection. Numerical simulation to illustrate the analytical results and establish the long term behavior of the disease is done. The impact of pneumonia infection control strategies is investigated. It is revealed that, with treatment and vaccination interventions combined, pneumonia can be wiped out. However, with treatment intervention alone, pneumonia persists in the population.

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Electron Microscopy of a Herpesvirus Isolated from Marek's Disease in Duck and Chicken Embryo Fibroblast Cultures

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100100858 ◽

1968 ◽

Vol 26 ◽

pp. 222-223 ◽

Cited By ~ 1

Author(s):

Keyvan Nazerian

Keyword(s):

Inclusion Bodies ◽

Chicken Embryo Fibroblast ◽

Marek's Disease ◽

Marek’S Disease ◽

Duck Embryo Fibroblast ◽

Multinucleated Cells ◽

Viral Particles ◽

Infected Cells ◽

And Control ◽

Do So

A herpes-like virus has been isolated from duck embryo fibroblast (DEF) cultures inoculated with blood from Marek's disease (MD) infected birds. Cultures which contained this virus produced MD in susceptible chickens while virus negative cultures and control cultures failed to do so. This and other circumstantial evidence including similarities in properties of the virus and the MD agent implicate this virus in the etiology of MD.Histochemical studies demonstrated the presence of DNA-staining intranuclear inclusion bodies in polykarocytes in infected cultures. Distinct nucleo-plasmic aggregates were also seen in sections of similar multinucleated cells examined with the electron microscope. These aggregates are probably the same as the inclusion bodies seen with the light microscope. Naked viral particles were observed in the nucleus of infected cells within or on the edges of the nucleoplasmic aggregates. These particles measured 95-100mμ, in diameter and rarely escaped into the cytoplasm or nuclear vesicles by budding through the nuclear membrane (Fig. 1). The enveloped particles (Fig. 2) formed in this manner measured 150-170mμ in diameter and always had a densely stained nucleoid. The virus in supernatant fluids consisted of naked capsids with 162 hollow, cylindrical capsomeres (Fig. 3). Enveloped particles were not seen in such preparations.

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Suppressed, but Not Forgotten

Swiss Journal of Psychology ◽

10.1024/1421-0185/a000033 ◽

2011 ◽

Vol 70 (1) ◽

pp. 5-11 ◽

Cited By ~ 8

Author(s):

Beat Meier ◽

Anja König ◽

Samuel Parak ◽

Katharina Henke

Keyword(s):

Memory Trace ◽

Thought Suppression ◽

Test Phase ◽

Indirect Test ◽

Final Test ◽

Test Experiment ◽

And Control ◽

Cue Words ◽

The Impact

This study investigates the impact of thought suppression over a 1-week interval. In two experiments with 80 university students each, we used the think/no-think paradigm in which participants initially learn a list of word pairs (cue-target associations). Then they were presented with some of the cue words again and should either respond with the target word or avoid thinking about it. In the final test phase, their memory for the initially learned cue-target pairs was tested. In Experiment 1, type of memory test was manipulated (i.e., direct vs. indirect). In Experiment 2, type of no-think instructions was manipulated (i.e., suppress vs. substitute). Overall, our results showed poorer memory for no-think and control items compared to think items across all experiments and conditions. Critically, however, more no-think than control items were remembered after the 1-week interval in the direct, but not in the indirect test (Experiment 1) and with thought suppression, but not thought substitution instructions (Experiment 2). We suggest that during thought suppression a brief reactivation of the learned association may lead to reconsolidation of the memory trace and hence to better retrieval of suppressed than control items in the long term.

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Research Participation Experiences of Informants of Suicide and Control Cases

Crisis ◽

10.1027/0227-5910/a000025 ◽

2010 ◽

Vol 31 (5) ◽

pp. 238-246 ◽

Cited By ~ 9

Author(s):

Paul W. C. Wong ◽

Wincy S. C. Chan ◽

Philip S. L. Beh ◽

Fiona W. S. Yau ◽

Paul S. F. Yip ◽

...

Keyword(s):

Ethical Issues ◽

Research Participation ◽

Self Report ◽

Initial Contact ◽

Psychological Autopsy ◽

Autopsy Study ◽

The People ◽

And Control ◽

The Impact

Background: Ethical issues have been raised about using the psychological autopsy approach in the study of suicide. The impact on informants of control cases who participated in case-control psychological autopsy studies has not been investigated. Aims: (1) To investigate whether informants of suicide cases recruited by two approaches (coroners’ court and public mortuaries) respond differently to the initial contact by the research team. (2) To explore the reactions, reasons for participation, and comments of both the informants of suicide and control cases to psychological autopsy interviews. (3) To investigate the impact of the interviews on informants of suicide cases about a month after the interviews. Methods: A self-report questionnaire was used for the informants of both suicide and control cases. Telephone follow-up interviews were conducted with the informants of suicide cases. Results: The majority of the informants of suicide cases, regardless of the initial route of contact, as well as the control cases were positive about being approached to take part in the study. A minority of informants of suicide and control cases found the experience of talking about their family member to be more upsetting than expected. The telephone follow-up interviews showed that none of the informants of suicide cases reported being distressed by the psychological autopsy interviews. Limitations: The acceptance rate for our original psychological autopsy study was modest. Conclusions: The findings of this study are useful for future participants and researchers in measuring the potential benefits and risks of participating in similar sensitive research. Psychological autopsy interviews may be utilized as an active engagement approach to reach out to the people bereaved by suicide, especially in places where the postvention work is underdeveloped.

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