Publications by authors named "David S Schneider"

56 Publications

Uncovering drivers of dose-dependence and individual variation in malaria infection outcomes.

PLoS Comput Biol 2020 10 8;16(10):e1008211. Epub 2020 Oct 8.

Department of Ecology & Evolutionary Biology, University of Toronto, Toronto, ON M5S 3B2, Canada.

To understand why some hosts get sicker than others from the same type of infection, it is essential to explain how key processes, such as host responses to infection and parasite growth, are influenced by various biotic and abiotic factors. In many disease systems, the initial infection dose impacts host morbidity and mortality. To explore drivers of dose-dependence and individual variation in infection outcomes, we devised a mathematical model of malaria infection that allowed host and parasite traits to be linear functions (reaction norms) of the initial dose. We fitted the model, using a hierarchical Bayesian approach, to experimental time-series data of acute Plasmodium chabaudi infection across doses spanning seven orders of magnitude. We found evidence for both dose-dependent facilitation and debilitation of host responses. Most importantly, increasing dose reduced the strength of activation of indiscriminate host clearance of red blood cells while increasing the half-life of that response, leading to the maximal response at an intermediate dose. We also explored the causes of diverse infection outcomes across replicate mice receiving the same dose. Besides random noise in the injected dose, we found variation in peak parasite load was due to unobserved individual variation in host responses to clear infected cells. Individual variation in anaemia was likely driven by random variation in parasite burst size, which is linked to the rate of host cells lost to malaria infection. General host vigour in the absence of infection was also correlated with host health during malaria infection. Our work demonstrates that the reaction norm approach provides a useful quantitative framework for examining the impact of a continuous external factor on within-host infection processes.
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http://dx.doi.org/10.1371/journal.pcbi.1008211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544130PMC
October 2020

Western diet regulates immune status and the response to LPS-driven sepsis independent of diet-associated microbiome.

Proc Natl Acad Sci U S A 2019 02 11;116(9):3688-3694. Epub 2019 Feb 11.

Department of Microbiology and Immunology, Stanford School of Medicine, Stanford University, Stanford, CA 94305;

Sepsis is a deleterious immune response to infection that leads to organ failure and is the 11th most common cause of death worldwide. Despite plaguing humanity for thousands of years, the host factors that regulate this immunological response and subsequent sepsis severity and outcome are not fully understood. Here we describe how the Western diet (WD), a diet high in fat and sucrose and low in fiber, found rampant in industrialized countries, leads to worse disease and poorer outcomes in an LPS-driven sepsis model in WD-fed mice compared with mice fed standard fiber-rich chow (SC). We find that WD-fed mice have higher baseline inflammation (metaflammation) and signs of sepsis-associated immunoparalysis compared with SC-fed mice. WD mice also have an increased frequency of neutrophils, some with an "aged" phenotype, in the blood during sepsis compared with SC mice. Importantly, we found that the WD-dependent increase in sepsis severity and higher mortality is independent of the microbiome, suggesting that the diet may be directly regulating the innate immune system through an unknown mechanism. Strikingly, we could predict LPS-driven sepsis outcome by tracking specific WD-dependent disease factors (e.g., hypothermia and frequency of neutrophils in the blood) during disease progression and recovery. We conclude that the WD is reprogramming the basal immune status and acute response to LPS-driven sepsis and that this correlates with alternative disease paths that lead to more severe disease and poorer outcomes.
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http://dx.doi.org/10.1073/pnas.1814273116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397595PMC
February 2019

The physiological basis of disease tolerance in insects.

Curr Opin Insect Sci 2018 10 14;29:133-136. Epub 2018 Nov 14.

Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, United States. Electronic address:

Immunology textbooks teach us about the ways hosts can recognize and kill microbes but leave out something important: the mechanisms used to survive infections. Survival depends on more than simply detecting and eliminating microbes; it requires that we prevent and repair the damage caused by pathogens and the immune response. Recent work in insects is helping to build our understanding of this aspect of pathology, called disease tolerance. Here we discuss papers that explore disease tolerance using theoretical, population genetics, and mechanistic approaches.
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http://dx.doi.org/10.1016/j.cois.2018.09.004DOI Listing
October 2018

Vector Immunity and Evolutionary Ecology: The Harmonious Dissonance.

Trends Immunol 2018 11 6;39(11):862-873. Epub 2018 Oct 6.

Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA. Electronic address:

Recent scientific breakthroughs have significantly expanded our understanding of arthropod vector immunity. Insights in the laboratory have demonstrated how the immune system provides resistance to infection, and in what manner innate defenses protect against a microbial assault. Less understood, however, is the effect of biotic and abiotic factors on microbial-vector interactions and the impact of the immune system on arthropod populations in nature. Furthermore, the influence of genetic plasticity on the immune response against vector-borne pathogens remains mostly elusive. Herein, we discuss evolutionary forces that shape arthropod vector immunity. We focus on resistance, pathogenicity and tolerance to infection. We posit that novel scientific paradigms should emerge when molecular immunologists and evolutionary ecologists work together.
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http://dx.doi.org/10.1016/j.it.2018.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218297PMC
November 2018

Predicting position along a looping immune response trajectory.

PLoS One 2018 8;13(10):e0200147. Epub 2018 Oct 8.

Department of Microbiology and Immunology, Stanford University, Stanford CA, United States of America.

When we get sick, we want to be resilient and recover our original health. To measure resilience, we need to quantify a host's position along its disease trajectory. Here we present Looper, a computational method to analyze longitudinally gathered datasets and identify gene pairs that form looping trajectories when plotted in the space described by these phases. These loops enable us to track where patients lie on a typical trajectory back to health. We analyzed two publicly available, longitudinal human microarray datasets that describe self-resolving immune responses. Looper identified looping gene pairs expressed by human donor monocytes stimulated by immune elicitors, and in YF17D-vaccinated individuals. Using loops derived from training data, we found that we could predict the time of perturbation in withheld test samples with accuracies of 94% in the human monocyte data, and 65-83% within the same cohort and in two independent cohorts of YF17D vaccinated individuals. We suggest that Looper will be useful in building maps of resilient immune processes across organisms.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0200147PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175499PMC
March 2019

Going to Bat(s) for Studies of Disease Tolerance.

Front Immunol 2018 20;9:2112. Epub 2018 Sep 20.

Australian Animal Health Laboratory, Health and Biosecurity Business Unit, Commonwealth Scientific and Industrial Research Organisation, Geelong, VIC, Australia.

A majority of viruses that have caused recent epidemics with high lethality rates in people, are zoonoses originating from wildlife. Among them are filoviruses (e.g., Marburg, Ebola), coronaviruses (e.g., SARS, MERS), henipaviruses (e.g., Hendra, Nipah) which share the common features that they are all RNA viruses, and that a dysregulated immune response is an important contributor to the tissue damage and hence pathogenicity that results from infection in humans. Intriguingly, these viruses also all originate from bat reservoirs. Bats have been shown to have a greater mean viral richness than predicted by their phylogenetic distance from humans, their geographic range, or their presence in urban areas, suggesting other traits must explain why bats harbor a greater number of zoonotic viruses than other mammals. Bats are highly unusual among mammals in other ways as well. Not only are they the only mammals capable of powered flight, they have extraordinarily long life spans, with little detectable increases in mortality or senescence until high ages. Their physiology likely impacted their history of pathogen exposure and necessitated adaptations that may have also affected immune signaling pathways. Do our life history traits make us susceptible to generating damaging immune responses to RNA viruses or does the physiology of bats make them particularly tolerant or resistant? Understanding what immune mechanisms enable bats to coexist with RNA viruses may provide critical fundamental insights into how to achieve greater resilience in humans.
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http://dx.doi.org/10.3389/fimmu.2018.02112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158362PMC
October 2019

Host Energy Source Is Important for Disease Tolerance to Malaria.

Curr Biol 2018 05 10;28(10):1635-1642.e3. Epub 2018 May 10.

Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA. Electronic address:

Pathologic infections are accompanied by a collection of short-term behavioral perturbations collectively termed sickness behaviors [1, 2]. These include changes in body temperature, reduced eating and drinking, and lethargy and mimic behaviors of animals in torpor and hibernation [1, 3-6]. Sickness behaviors are important, pathogen-specific components of the host response to infection [1, 3, 7-9]. In particular, host anorexia has been shown to be beneficial or detrimental depending on the infection [7, 8]. While these studies have illuminated the effects of anorexia on infection, they consider this behavior in isolation from other behaviors and from its effects on host metabolism and energy. Here, we explored the temporal dynamics of multiple sickness behaviors and their effect on host energy and metabolism throughout infection. We used the Plasmodium chabaudi AJ murine model of malaria as it causes severe pathology from which most animals recover. We found that infected animals did become anorexic, skewing their metabolism toward fatty acid oxidation and ketosis. Metabolism of fats requires oxygen for the production of ATP. In this model, animals also suffer severe anemia, limiting their ability to carry oxygen concurrent with their switch toward fatty acid metabolism. We reasoned that the combination of anorexia and anemia would increase pressure on glycolysis as a critical energy pathway because it does not require oxygen. Treating infected mice when anorexic with the glycolytic inhibitor 2-deoxyglucose (2DG) reduced survival; treating animals with glucose improved survival. Peak parasite loads were unchanged, demonstrating changes in disease tolerance. Parasite clearance was reduced with 2DG treatment, suggesting altered resistance.
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http://dx.doi.org/10.1016/j.cub.2018.04.009DOI Listing
May 2018

A Macrophage Colony-Stimulating-Factor-Producing γδ T Cell Subset Prevents Malarial Parasitemic Recurrence.

Immunity 2018 02 6;48(2):350-363.e7. Epub 2018 Feb 6.

Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, CA 94305, USA; Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA. Electronic address:

Despite evidence that γδ T cells play an important role during malaria, their precise role remains unclear. During murine malaria induced by Plasmodium chabaudi infection and in human P. falciparum infection, we found that γδ T cells expanded rapidly after resolution of acute parasitemia, in contrast to αβ T cells that expanded at the acute stage and then declined. Single-cell sequencing showed that TRAV15N-1 (Vδ6.3) γδ T cells were clonally expanded in mice and had convergent complementarity-determining region 3 sequences. These γδ T cells expressed specific cytokines, M-CSF, CCL5, CCL3, which are known to act on myeloid cells, indicating that this γδ T cell subset might have distinct functions. Both γδ T cells and M-CSF were necessary for preventing parasitemic recurrence. These findings point to an M-CSF-producing γδ T cell subset that fulfills a specialized protective role in the later stage of malaria infection when αβ T cells have declined.
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http://dx.doi.org/10.1016/j.immuni.2018.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5956914PMC
February 2018

Tracking Resilience to Infections by Mapping Disease Space.

PLoS Biol 2016 Apr 18;14(4):e1002436. Epub 2016 Apr 18.

Program in Immunology, Stanford University, Stanford, California, United States of America.

Infected hosts differ in their responses to pathogens; some hosts are resilient and recover their original health, whereas others follow a divergent path and die. To quantitate these differences, we propose mapping the routes infected individuals take through "disease space." We find that when plotting physiological parameters against each other, many pairs have hysteretic relationships that identify the current location of the host and predict the future route of the infection. These maps can readily be constructed from experimental longitudinal data, and we provide two methods to generate the maps from the cross-sectional data that is commonly gathered in field trials. We hypothesize that resilient hosts tend to take small loops through disease space, whereas nonresilient individuals take large loops. We support this hypothesis with experimental data in mice infected with Plasmodium chabaudi, finding that dying mice trace a large arc in red blood cells (RBCs) by reticulocyte space as compared to surviving mice. We find that human malaria patients who are heterozygous for sickle cell hemoglobin occupy a small area of RBCs by reticulocyte space, suggesting this approach can be used to distinguish resilience in human populations. This technique should be broadly useful in describing the in-host dynamics of infections in both model hosts and patients at both population and individual levels.
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http://dx.doi.org/10.1371/journal.pbio.1002436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4835107PMC
April 2016

How Many Parameters Does It Take to Describe Disease Tolerance?

PLoS Biol 2016 Apr 18;14(4):e1002435. Epub 2016 Apr 18.

Department of Microbiology and Immunology, Stanford University, Stanford, California, United States of America.

The study of infectious disease has been aided by model organisms, which have helped to elucidate molecular mechanisms and contributed to the development of new treatments; however, the lack of a conceptual framework for unifying findings across models, combined with host variability, has impeded progress and translation. Here, we fill this gap with a simple graphical and mathematical framework to study disease tolerance, the dose response curve relating health to microbe load; this approach helped uncover parameters that were previously overlooked. Using a model experimental system in which we challenged Drosophila melanogaster with the pathogen Listeria monocytogenes, we tested this framework, finding that microbe growth, the immune response, and disease tolerance were all well represented by sigmoid models. As we altered the system by varying host or pathogen genetics, disease tolerance varied, as we would expect if it was indeed governed by parameters controlling the sensitivity of the system (the number of bacteria required to trigger a response) and maximal effect size according to a logistic equation. Though either the pathogen or host immune response or both together could theoretically be the proximal cause of pathology that killed the flies, we found that the pathogen, but not the immune response, drove damage in this model. With this new understanding of the circuitry controlling disease tolerance, we can now propose better ways of choosing, combining, and developing treatments.
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http://dx.doi.org/10.1371/journal.pbio.1002435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4835111PMC
April 2016

What Can Vampires Teach Us about Immunology?

Trends Immunol 2016 Apr 9;37(4):253-6. Epub 2016 Mar 9.

Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA. Electronic address:

Speculative fiction examines the leading edge of science and can be used to introduce ideas into the classroom. For example, most students are already familiar with the fictional infectious diseases responsible for vampire and zombie outbreaks. The disease dynamics of these imaginary ailments follow the same rules we see for real diseases and can be used to remind students that they already understand the basic rules of disease ecology and immunology. By engaging writers of this sort of fiction in an effort to solve problems in immunology we may be able to perform a directed evolution experiment where we follow the evolution of plots rather than genetic traits.
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http://dx.doi.org/10.1016/j.it.2016.02.001DOI Listing
April 2016

Defining Resistance and Tolerance to Cancer.

Cell Rep 2015 Nov 22;13(5):884-7. Epub 2015 Oct 22.

Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA. Electronic address:

There are two ways to maintain fitness in the face of infection: resistance is a host's ability to reduce microbe load and disease tolerance is the ability of the host to endure the negative health effects of infection. Resistance and disease tolerance should be applicable to any insult to the host and have been explored in depth with regards to infection but have not been examined in the context of cancer. Here, we establish a framework for measuring and separating resistance and disease tolerance to cancer in Drosophila melanogaster. We plot a disease tolerance curve to cancer in wild-type flies and then compare this to natural variants, identifying a line with reduced cancer resistance. Quantitation of these two traits opens an additional dimension for analysis of cancer biology.
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http://dx.doi.org/10.1016/j.celrep.2015.09.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4761238PMC
November 2015

Drosophila melanogaster Natural Variation Affects Growth Dynamics of Infecting Listeria monocytogenes.

G3 (Bethesda) 2015 Oct 4;5(12):2593-600. Epub 2015 Oct 4.

Department of Microbiology and Immunology, Stanford University, California 94305-5124

We find that in a Listeria monocytogenes/Drosophila melanogaster infection model, L. monocytogenes grows according to logistic kinetics, which means we can measure both a maximal growth rate and growth plateau for the microbe. Genetic variation of the host affects both of the pathogen growth parameters, and they can vary independently. Because growth rates and ceilings both correlate with host survival, both properties could drive evolution of the host. We find that growth rates and ceilings are sensitive to the initial infectious dose in a host genotype-dependent manner, implying that experimental results differ as we change the original challenge dose within a single strain of host.
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http://dx.doi.org/10.1534/g3.115.022558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4683632PMC
October 2015

The genetics of immunity.

Genetics 2014 Jun;197(2):467-70

Department of Microbiology and Immunology, Stanford University, Palo Alto, CA, 94305.

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http://dx.doi.org/10.1534/genetics.114.165449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4063907PMC
June 2014

The genetics of immunity.

G3 (Bethesda) 2014 Jun 17;4(6):943-5. Epub 2014 Jun 17.

Department of Microbiology and Immunology, Stanford University, Palo Alto, CA, 94305.

In this commentary, Brian P. Lazzaro and David S. Schneider examine the topic of the Genetics of Immunity as explored in this month's issues of GENETICS and G3: Genes|Genomes|Genetics. These inaugural articles are part of a joint Genetics of Immunity collection (ongoing) in the GSA journals.
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http://dx.doi.org/10.1534/g3.114.011684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4065262PMC
June 2014

The Drosophila deubiquitinating enzyme dUSP36 acts in the hemocytes for tolerance to Listeria monocytogenes infections.

J Innate Immun 2014 23;6(5):632-8. Epub 2014 Apr 23.

Department of Microbiology and Immunology, Stanford University, Stanford, Calif., USA.

Listeria monocytogenes is a facultative intracellular pathogen which can infect Drosophila melanogaster. Upon infection, Drosophila mounts an immune response including antimicrobial peptide production and autophagy activation. A set of previously published results prompted us to study the role of the deubiquitinating enzyme dUSP36 in response to L. monocytogenes infections. We show in this report that flies with dUsp36-specific inactivation in hemocytes are susceptible to L. monocytogenes infections (as are flies with autophagy-deficient hemocytes) but are still able to control bacterial growth. Interestingly, flies with dUsp36-depleted hemocytes are not sensitized to infection by other pathogens. We conclude that dUsp36 plays a major role in hemocytes for tolerance to L. monocytogenes.
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http://dx.doi.org/10.1159/000360293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6741521PMC
May 2015

The ubiquitin ligase parkin mediates resistance to intracellular pathogens.

Nature 2013 Sep 4;501(7468):512-6. Epub 2013 Sep 4.

Department of Microbiology and Immunology Program in Microbial Pathogenesis and Host Defense, University of California, San Francisco, San Francisco, California 94158, USA.

Ubiquitin-mediated targeting of intracellular bacteria to the autophagy pathway is a key innate defence mechanism against invading microbes, including the important human pathogen Mycobacterium tuberculosis. However, the ubiquitin ligases responsible for catalysing ubiquitin chains that surround intracellular bacteria are poorly understood. The parkin protein is a ubiquitin ligase with a well-established role in mitophagy, and mutations in the parkin gene (PARK2) lead to increased susceptibility to Parkinson's disease. Surprisingly, genetic polymorphisms in the PARK2 regulatory region are also associated with increased susceptibility to intracellular bacterial pathogens in humans, including Mycobacterium leprae and Salmonella enterica serovar Typhi, but the function of parkin in immunity has remained unexplored. Here we show that parkin has a role in ubiquitin-mediated autophagy of M. tuberculosis. Both parkin-deficient mice and flies are sensitive to various intracellular bacterial infections, indicating parkin has a conserved role in metazoan innate defence. Moreover, our work reveals an unexpected functional link between mitophagy and infectious disease.
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http://dx.doi.org/10.1038/nature12566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3886920PMC
September 2013

Listeria monocytogenes infection causes metabolic shifts in Drosophila melanogaster.

PLoS One 2012 13;7(12):e50679. Epub 2012 Dec 13.

Department of Microbiology and Immunology, Stanford University, Stanford, California, United States of America.

Immunity and metabolism are intimately linked; manipulating metabolism, either through diet or genetics, has the power to alter survival during infection. However, despite metabolism's powerful ability to alter the course of infections, little is known about what being "sick" means metabolically. Here we describe the metabolic changes occurring in a model system when Listeria monocytogenes causes a lethal infection in Drosophila melanogaster. L. monocytogenes infection alters energy metabolism; the flies gradually lose both of their energy stores, triglycerides and glycogen, and show decreases in both intermediate metabolites and enzyme message for the two main energy pathways, beta-oxidation and glycolysis. L. monocytogenes infection also causes enzymatic reduction in the anti-oxidant uric acid, and knocking out the enzyme uric oxidase has a complicated effect on immunity. Free amino acid levels also change during infection, including a drop in tyrosine levels which may be due to robust L. monocytogenes induced melanization.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0050679PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3521769PMC
June 2013

How the fly balances its ability to combat different pathogens.

PLoS Pathog 2012 13;8(12):e1002970. Epub 2012 Dec 13.

Department of Microbiology and Immunology, Stanford University, Stanford, California, United States of America.

Health is a multidimensional landscape. If we just consider the host, there are many outputs that interest us: evolutionary fitness determining parameters like fecundity, survival and pathogen clearance as well as medically important health parameters like sleep, energy stores and appetite. Hosts use a variety of effector pathways to fight infections and these effectors are brought to bear differentially. Each pathogen causes a different disease as they have distinct virulence factors and niches; they each warp the health landscape in unique ways. Therefore, mutations affecting immunity can have complex phenotypes and distinct effects on each pathogen. Here we describe how two components of the fly's immune response, melanization and phagocytosis, contribute to the health landscape generated by the transcription factor ets21c (CG2914) and its putative effector, the signaling molecule wntD (CG8458). To probe the landscape, we infect with two pathogens: Listeria monocytogenes, which primarily lives intracellularly, and Streptococcus pneumoniae, which is an extracellular pathogen. Using the diversity of phenotypes generated by these mutants, we propose that survival during a L. monocytogenes infection is mediated by a combination of two host mechanisms: phagocytic activity and melanization; while survival during a S. pneumoniae infection is determined by phagocytic activity. In addition, increased phagocytic activity is beneficial during S. pneumoniae infection but detrimental during L. monocytogenes infection, demonstrating an inherent trade-off in the immune response.
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http://dx.doi.org/10.1371/journal.ppat.1002970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3521699PMC
May 2013

Where does innate immunity stop and adaptive immunity begin?

Cell Host Microbe 2012 Oct;12(4):394-5

The regulation of alternative splicing in the immune effector Dscam reported by Dong et al. (2012) in this issue of Cell Host & Microbe raises important questions about the nature of immune responses. Can we clearly define "adaptive" as being different from "innate" immunity, or is it time for a more flexible description?
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http://dx.doi.org/10.1016/j.chom.2012.10.004DOI Listing
October 2012

Infection-related declines in chill coma recovery and negative geotaxis in Drosophila melanogaster.

PLoS One 2012 13;7(9):e41907. Epub 2012 Sep 13.

Department of Microbiology and Immunology, Stanford University, Stanford, California, United States of America.

Studies of infection in Drosophila melanogaster provide insight into both mechanisms of host resistance and tolerance of pathogens. However, research into the pathways involved in these processes has been limited by the relatively few metrics that can be used to measure sickness and health throughout the course of infection. Here we report measurements of infection-related declines in flies' performance on two different behavioral assays. D. melanogaster are slower to recover from a chill-induced coma during infection with either Listeria monocytogenes or Streptococcus pneumoniae. L. monocytogenes infection also impacts flies' performance during a negative geotaxis assay, revealing a decline in their rate of climbing as part of their innate escape response after startle. In addition to providing new measures for assessing health, these assays also suggest pathological consequences of and metabolic shifts that may occur over the course of an infection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0041907PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3441536PMC
March 2013

Balancing resistance and infection tolerance through metabolic means.

Proc Natl Acad Sci U S A 2012 Aug 13;109(35):13886-7. Epub 2012 Aug 13.

Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.

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http://dx.doi.org/10.1073/pnas.1211724109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3435157PMC
August 2012

Immunity in society: diverse solutions to common problems.

PLoS Biol 2012 3;10(4):e1001297. Epub 2012 Apr 3.

Centre for Immunity, Infection and Evolution and Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, Scotland, United Kingdom.

Understanding how organisms fight infection has been a central focus of scientific research and medicine for the past couple of centuries, and a perennial object of trial and error by humans trying to mitigate the burden of disease. Vaccination success relies upon the exposure of susceptible individuals to pathogen constituents that do not cause (excessive) pathology and that elicit specific immune memory. Mass vaccination allows us to study how immunity operates at the group level; denser populations are more prone to transmitting disease between individuals, but once a critical proportion of the population becomes immune, "herd immunity" emerges. In social species, the combination of behavioural control of infection--e.g., segregation of sick individuals, disposal of the dead, quality assessment of food and water--and aggregation of immune individuals can protect non-immune members from disease. While immune specificity and memory are well understood to underpin immunisation in vertebrates, it has been somewhat surprising to find similar phenomena in invertebrates, which lack the vertebrate molecular mechanisms deemed necessary for immunisation. Indeed, reports showing alternative forms of immune memory are accumulating in invertebrates. In this issue of PLoS Biology, Konrad et al. present an example of fungus-specific immune responses in social ants that lead to the active immunisation of nestmates by infected individuals. These findings join others in showing how organisms evolved diverse mechanisms that fulfil common functions, namely the discrimination between pathogens, the transfer of immunity between related individuals, and the group-level benefits of immunisation.
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http://dx.doi.org/10.1371/journal.pbio.1001297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3317894PMC
August 2012

Disease tolerance as a defense strategy.

Science 2012 Feb;335(6071):936-41

Howard Hughes Medical Institute, Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510, USA.

The immune system protects from infections primarily by detecting and eliminating the invading pathogens; however, the host organism can also protect itself from infectious diseases by reducing the negative impact of infections on host fitness. This ability to tolerate a pathogen's presence is a distinct host defense strategy, which has been largely overlooked in animal and human studies. Introduction of the notion of "disease tolerance" into the conceptual tool kit of immunology will expand our understanding of infectious diseases and host pathogen interactions. Analysis of disease tolerance mechanisms should provide new approaches for the treatment of infections and other diseases.
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http://dx.doi.org/10.1126/science.1214935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3564547PMC
February 2012

Tolerance of infections.

Annu Rev Immunol 2012 3;30:271-94. Epub 2012 Jan 3.

Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA.

A host has two methods to defend against pathogens: It can clear the pathogens or reduce their impact on health in other ways. The first, resistance, is well studied. Study of the second, which ecologists call tolerance, is in its infancy. Tolerance measures the dose response curve of a host's health in reaction to a pathogen and can be studied in a simple quantitative manner. Such studies hold promise because they point to methods of treating infections that put evolutionary pressures on microbes different from antibiotics and vaccines. Studies of tolerance will provide an improved foundation to describe our interactions with all microbes: pathogenic, commensal, and mutualistic. One obvious mechanism affecting tolerance is the intensity of an immune response; an overly exuberant immune response can cause collateral damage through immune effectors and because of the energy allocated away from other physiological functions. There are potentially many other tolerance mechanisms, and here we systematically describe tolerance using a variety of animal systems.
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http://dx.doi.org/10.1146/annurev-immunol-020711-075030DOI Listing
July 2012

Pioneering immunology: insect style.

Curr Opin Immunol 2012 Feb 19;24(1):10-4. Epub 2011 Dec 19.

Department of Microbiology and Immunology Stanford University, United States.

Insects are a powerful tool for discovering and then dissecting interesting new immunology. Recent insect research has made productive forays into non-classical immune areas including tolerance, immune priming (trained immunity), and environmental effects on immunity. Environments which affect immunity not only include diet and metabolism, but also social interactions and the animal's microbiota. We argue that every process that affects immunity should be considered as part of the immune response and that it is the broad phenomena discovered in insects that will be translated to other organisms rather than fine mechanistic details.
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http://dx.doi.org/10.1016/j.coi.2011.11.003DOI Listing
February 2012

Tracing personalized health curves during infections.

PLoS Biol 2011 Sep 20;9(9):e1001158. Epub 2011 Sep 20.

Department of Microbiology and Immunology, Stanford University, Stanford, CA, United States of America.

It is difficult to describe host-microbe interactions in a manner that deals well with both pathogens and mutualists. Perhaps a way can be found using an ecological definition of tolerance, where tolerance is defined as the dose response curve of health versus parasite load. To plot tolerance, individual infections are summarized by reporting the maximum parasite load and the minimum health for a population of infected individuals and the slope of the resulting curve defines the tolerance of the population. We can borrow this method of plotting health versus microbe load in a population and make it apply to individuals; instead of plotting just one point that summarizes an infection in an individual, we can plot the values at many time points over the course of an infection for one individual. This produces curves that trace the course of an infection through phase space rather than over a more typical timeline. These curves highlight relationships like recovery and point out bifurcations that are difficult to visualize with standard plotting techniques. Only nine archetypical curves are needed to describe most pathogenic and mutualistic host-microbe interactions. The technique holds promise as both a qualitative and quantitative approach to dissect host-microbe interactions of all kinds.
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http://dx.doi.org/10.1371/journal.pbio.1001158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3176750PMC
September 2011

Reciprocal analysis of Francisella novicida infections of a Drosophila melanogaster model reveal host-pathogen conflicts mediated by reactive oxygen and imd-regulated innate immune response.

PLoS Pathog 2010 Aug 26;6(8):e1001065. Epub 2010 Aug 26.

Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, United States of America.

The survival of a bacterial pathogen within a host depends upon its ability to outmaneuver the host immune response. Thus, mutant pathogens provide a useful tool for dissecting host-pathogen relationships, as the strategies the microbe has evolved to counteract immunity reveal a host's immune mechanisms. In this study, we examined the pathogen Francisella novicida and identified new bacterial virulence factors that interact with different parts of the Drosophila melanogaster innate immune system. We performed a genome-wide screen to identify F. novicida genes required for growth and survival within the fly and identified a set of 149 negatively selected mutants. Among these, we identified a class of genes including the transcription factor oxyR, and the DNA repair proteins uvrB, recB, and ruvC that help F. novicida resist oxidative stress. We determined that these bacterial genes are virulence factors that allow F. novicida to counteract the fly melanization immune response. We then performed a second in vivo screen to identify an additional subset of bacterial genes that interact specifically with the imd signaling pathway. Most of these mutants have decreased resistance to the antimicrobial peptide polymyxin B. Characterization of a mutation in the putative transglutaminase FTN_0869 produced a curious result that could not easily be explained using known Drosophila immune responses. By using an unbiased genetic screen, these studies provide a new view of the Drosophila immune response from the perspective of a pathogen. We show that two branches of the fly's immunity are important for fighting F. novicida infections in a model host: melanization and an imd-regulated immune response, and identify bacterial genes that specifically counteract these host responses. Our work suggests that there may be more to learn about the fly immune system, as not all of the phenotypes we observe can be readily explained by its interactions with known immune responses.
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http://dx.doi.org/10.1371/journal.ppat.1001065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2928790PMC
August 2010

The lateral cutaneous nerve of the calf revisited.

PM R 2010 Jun;2(6):579-80

Lake Cook Orthopedic Associates, 27401 West Highway #22, Barrington, IL 60010, USA.

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http://dx.doi.org/10.1016/j.pmrj.2010.02.003DOI Listing
June 2010

The Drosophila TNF ortholog eiger is required in the fat body for a robust immune response.

J Innate Immun 2010 20;2(4):371-8. Epub 2010 May 20.

Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305-5124, USA.

Eiger is the sole TNF family member found in Drosophila melanogaster. This signaling molecule is induced during infection and is required for an appropriate immune response to many microbes; however, little is known about where eiger is produced. Here, we show that eiger is made in the fly's fat body during a Salmonella typhimurium infection. Using tissue-specific knockdown, we found that eiger expression in the fat body is required for all of the phenotypes we observed in eiger null mutant flies. This includes reduced melanization, altered antimicrobial peptide expression and reduced feeding rates. The effect of eiger on feeding rates alone may account for the entire phenotype seen in eiger mutants infected with S. typhimurium.
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http://dx.doi.org/10.1159/000315050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2968759PMC
October 2010