Andrea L Graham

• Ph.D.
• Princeton University at Princeton University

Inbred mice used for biomedical research display an underdeveloped immune system compared with adult humans, which is attributed in part to the artificial laboratory environment. Despite representing a central component of adaptive immunity, the impact of the laboratory environment on the B cell compartment has not been investigated in detail. Here...

Estimating the durability of immunity from vaccination is complicated by unreported re-vaccination, and unobserved natural infection or reexposure, which could result in overestimation of protection longevity. We tested serial cross-sectional serum samples from 2005 to 2015 (N=2,530) for IgG to examine measles seroprevalence, spatiotemporal pattern...

Immune responses are induced by parasite exposure and can in turn reduce parasite burden. Despite such apparently simple rules of engagement, key drivers of within-host dynamics, including dose-dependence of defense and infection duration, have proven difficult to predict. Here, we model how varied inoculating doses interact with multi-tiered host...

Fundamental discoveries in many aspects of mammalian physiology have been made using laboratory mice as research models. These studies have been facilitated by the genetic tractability and inbreeding of such mice, the large set of immunological reagents that are available, and the establishment of environmentally controlled, high-throughput facilit...

Infection duration affects individual host fitness and between-host transmission. Whether an infection is cleared or becomes chronic depends on the complex interaction between host immune responses and parasite growth. Empirical and theoretical studies have suggested that there are critical thresholds of parasite dose that can determine clearance v...

The SARS-CoV-2 pandemic has generated a considerable number of infections and associated morbidity and mortality across the world. Recovery from these infections, combined with the onset of large-scale vaccination, have led to rapidly-changing population-level immunological landscapes. In turn, these complexities have highlighted a number of import...

High population density should drive individuals to more frequently share space and interact, producing better-connected spatial and social networks. Despite this widely-held assumption, it remains unconfirmed how local density generally drives individuals' positions within wild animal networks. We analysed 34 datasets of simultaneous spatial and s...

The study of immune phenotypes in wild animals is beset by numerous methodological challenges, with assessment of detailed aspects of phenotype difficult to impossible. This constrains the ability of disease ecologists and ecoimmunologists to describe immune variation and evaluate hypotheses explaining said variation. The development of simple appr...

The relative and synergistic contributions of genetics and environment to interindividual immune response variation remain unclear, despite implications in evolutionary biology and medicine. Here we quantify interactive effects of genotype and environment on immune traits by investigating C57BL/6, 129S1 and PWK/PhJ inbred mice, rewilded in an outdo...

The Almaco jack (Seriola rivoliana) is a marine fish maintained in mariculture systems and frequently infested by monogenean parasites like Neobenedenia sp. Severe infestations can lead to high mortalities and economic losses for farmers. This study evaluated the effects of temperature on the immune response on Almaco jack infested with Neobenedeni...

Environmental influences on immune phenotypes are well-documented, but our understanding of which elements of the environment affect immune systems, and how, remains vague. Behaviors, including socializing with others, are central to an individual’s interaction with its environment. We therefore tracked behavior of rewilded laboratory mice of three...

Due to a population bottleneck, northern elephant seals ( Mirounga angustirostris ) have very low genetic diversity, making them ideal model organisms for assessing the impact of genetic and non-genetic factors on the gut microbiome. In our study, we were especially interested in the role of sex given the northern elephant seal’s extreme sexual dim...

As the SARS-CoV-2 trajectory continues, the longer-term immuno-epidemiology of COVID-19, the dynamics of Long COVID, and the impact of escape variants are important outstanding questions. We examine these remaining uncertainties with a simple modelling framework that accounts for multiple (antigenic) exposures via infection or vaccination. If immun...

serosim is an open-source R package designed to aid inference from serological studies, by simulating data arising from user-specified vaccine and antibody kinetics processes using a random effects model. Serological data are used to assess population immunity by directly measuring individuals’ antibody titers. They uncover locations and/or populat...

The paucity of blood granulocyte populations such as neutrophils in laboratory mice is a notable difference between this model organism and humans, but the cause of this species-specific difference is unclear. We previously demonstrated that laboratory mice released into a seminatural environment, referred to as rewilding, display an increase in bl...

Immune responses are induced by parasite exposure and can in turn reduce parasite burden. Despite such apparently simple rules of engagement, key drivers of within-host dynamics, including dose-dependence of defence and infection duration, have proven difficult to predict. Here, we model how varied inoculating doses interact with host defences. Def...

Defending against novel, repeated, or unpredictable attacks, while avoiding attacks on the 'self', are the central problems of both mammalian immune systems and computer systems. Both systems have been studied in great detail, but with little exchange of information across the different disciplines. Here, we present a conceptual framework for struc...

The Almaco jack ( Seriola rivoliana ) is a marine fish maintained in mariculture systems and frequently infested by monogenean parasites like Neobenedenia sp. Severe infestations can lead to high mortalities and economic losses for farmers. This study evaluated the effects of temperature on the immune response on Almaco jack infested with Neobenede...

Raccoons are host to diverse gastrointestinal parasites, but little is known about the ecology of these parasites in terms of their interactions with each other during coinfections, their interactions with host physiology and environmental factors, and their impact on raccoon health and survival. As a first step, we investigated the patterns of par...

The relative and potentially synergistic contributions of genetics and environment to inter-individual immune response variation remain unclear, despite critical implications of such variation in both medicine and evolutionary biology. Here, we quantify interactive effects of genotype and environment on immune traits by investigating different inbr...

Environmental influences on immune phenotypes are well-documented, but our understanding of which elements of the environment affect immune systems, and how, remains vague. Behaviors, including socializing with others, are central to an individual's interaction with its environment. We tracked behavior of rewilded laboratory mice of three inbred st...

As the SARS-CoV-2 trajectory continues, the longer-term immuno-epidemiology of COVID-19, the dynamics of Long COVID, and the impact of escape variants are important outstanding questions. We examine these remaining uncertainties with a simple modelling framework that accounts for multiple (antigenic) exposures via infection or vaccination. If immun...

serosim is an open source R package designed to aid inference of serological surveys, by simulating data arising from user-specified vaccine and infection-generated antibody kinetics processes using a random effects model. Serological surveys are used to assess population immunity by directly measuring individuals’ antibody titers. They uncover loc...

Medical research reports that women often exhibit stronger immune responses than men, while pathogens tend to be more virulent in men. Current explanations cannot account for this pattern, creating an obstacle for our understanding of infectious-disease outcomes and the incidence of autoimmune diseases. We offer an alternative explanation that reli...

Microbes living within the mammalian gastrointestinal tract affect the metabolization and extraction of dietary nutrients; immune function; colonization by pathogens; and risk of autoimmune disease. While most microbiome studies focus on sequences of the 16S gene shared by Bacteria and Archaea, these are not the only regular inhabitants of mammalia...

Immune responses to pathogens and vaccination can be varied with some individuals inducing optimal responses while others do not. The host genetic profile, environment and previous microbial experience could influence an individual’s response, but the relative contribution, and interactions of these different factors remains largely unknown. Here,...

Various host and parasite factors interact to determine the outcome of infection. We investigated the effects of initial infectious dose and co-infection with a red blood cell-limiting helminth on the within-host dynamics of murine malaria. Using a time-series approach to model the within-host “epidemiology” of malaria, we found that increasing ini...

Hosts diverge widely in how, and how well, they defend themselves against infection and immunopathology. Why are hosts so heterogeneous? Both epidemiology and life history are commonly hypothesized to influence host immune strategy, but the relationship between immune strategy and each factor has commonly been investigated in isolation. Here, we sh...

The mammalian immune system packs serious punch against infection but can also cause harm: for example, coronavirus disease 2019 (COVID-19) made headline news of the simultaneous power and peril of human immune responses. In principle, natural selection leads to exquisite adaptation and therefore cytokine responsiveness that optimally balances the...

Stockpiling and control A triumph that has emerged from the catastrophe of the severe acute respiratory syndrome coronavirus 2 pandemic has been the rapid development of several potent vaccines. However, 18 months into the pandemic and more than 6 months after vaccine approval, wealthy countries remain the major beneficiaries. Wagner et al . model...

We explore the commonalities between methods for assuring the security of computer systems (cybersecurity) and the mechanisms that have evolved through natural selection to protect vertebrates against pathogens, and how insights derived from studying the evolution of natural defenses can inform the design of more effective cybersecurity systems. Mo...

Vaccines provide powerful tools to mitigate the enormous public health and economic costs that the ongoing SARS-CoV-2 pandemic continues to exert globally, yet vaccine distribution remains unequal between countries. To examine the potential epidemiological and evolutionary impacts of 'vaccine nationalism', we extend previous models to include simpl...

Various host and parasite factors interact to determine the outcome of infection. We investigated the effects of two factors on the within-host dynamics of malaria in mice: initial infectious dose and co-infection with a helminth that limits the availability of red blood cells (RBCs). Using a statistical, time-series approach to model the within-ho...

Epidemiology and life history are commonly hypothesized to influence host immune strategy, and the pairwise relationships between immune strategy and each factor have been extensively investigated. But the interaction of these two is rarely considered, despite evidence that this interaction might produce emergent effects on optimal immune strategy....

One dose or two? For two-dose vaccines against severe acute respiratory syndrome coronavirus 2, some jurisdictions have decided to delay the second dose to rapidly get the vaccine into more people. The consequences of deviating from manufacturer-prescribed dosing regimens are unknown but will depend on the strength of immune responses to the vaccin...

As the threat of Covid-19 continues and in the face of vaccine dose shortages and logistical challenges, various deployment strategies are being proposed to increase population immunity levels. How timing of delivery of the second dose affects infection burden but also prospects for the evolution of viral immune escape are critical questions. Both...

Laboratory mice have provided invaluable insight into mammalian immune systems. Yet the immune phenotypes of mice bred and maintained in conventional laboratory conditions often differ from the immune phenotypes of wild mammals. Recent work to naturalize the environmental experience of inbred laboratory mice—to take them where the wild things are (...

Individuals are often co-infected with several parasite species, yet measuring within-host interactions remains difficult in the wild. Consequently, the impacts of such interactions on host fitness and epidemiology are often unknown. We used anthelmintic drugs to experimentally reduce nematode infection and measured the effects on both nematodes an...

Health outcomes following infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) are remarkably variable. The way the virus spreads inside hosts, and how this spread interacts with host immunity and physiology, is likely to determine variation in health outcomes. Decades of data and dynamical analyses of how other viruses sprea...

Imperfect future immunity Humans are infected by several seasonal and cross-reacting coronaviruses. None provokes fully protective immunity, and repeat infections are the norm. Vaccines tend to be less efficient than natural infections at provoking immunity, and there are risks of adverse cross-reactions. Saad-Roy et al. used a series of simple mod...

Studies of controlled lab animals and natural populations represent two insightful extremes of microbiota research. We bridged these two approaches by transferring lab-bred female C57BL/6 mice from a conventional mouse facility to an acclimation room and then to an outdoor enclosure, to investigate how the gut microbiota changes with environment. M...

Individuals are often co-infected with several parasite species, yet measuring potential within-host interactions remains difficult in the wild. The impact of these relationships on host fitness and epidemiology is therefore often unknown. Here, we used anthelmintic drugs to experimentally reduce nematode infection and measured the effects on both...

In the animal kingdom, various forms of swarming enable groups of autonomous individuals to transform uncertain information into unified decisions which are probabilistically beneficial. Crossing scales from individual to group decisions requires dynamically accumulating signals among individuals. In striking parallel, the mammalian immune system i...

Uncertainty in the immune response to SARS-CoV-2 may have implications for future outbreaks. We use simple epidemiological models to explore estimates for the magnitude and timing of future Covid-19 cases given different impacts of the adaptive immune response to SARS-CoV-2 as well as its interaction with vaccines and nonpharmaceutical intervention...

Immune responses to vaccination are heterogeneous between individuals; the same vaccine that provides protection in one circumstance may be ineffective in another. One factor that could influence the response to vaccination is concurrent or prior infection with unrelated parasites. Here, we review both the experimental and epidemiological literatur...

The relative contributions of genetic and environmental factors to variation in immune responses are still poorly understood. Here, we performed a deep phenotypic analysis of immunological parameters of laboratory mice released into an outdoor enclosure, carrying susceptibility genes (Nod2 and Atg16l1) implicated in the development of inflammatory...

Free-living mammals, such as humans and wild mice, display heightened immune activation compared with artificially maintained laboratory mice. These differences are partially attributed to microbial exposure as laboratory mice infected with pathogens exhibit immune profiles more closely resembling that of free-living animals. Here, we examine how c...

The relative contributions of genetic and environmental factors to variation in immune responses are poorly understood. Here, we performed a phenotypic analysis of immunological parameters in laboratory mice carrying susceptibility genes implicated in inflammatory bowel disease (IBD) (Nod2 and Atg16l1) upon exposure to environmental microbes. Mice...

Bats host virulent zoonotic viruses without experiencing disease. A mechanistic understanding of the impact of bats' virus hosting capacities, including uniquely constitutive immune pathways, on cellular-scale viral dynamics is needed to elucidate zoonotic emergence. We carried out virus infectivity assays on bat cell lines expressing induced and c...

Ecoimmunological patterns and processes remain understudied in wild primates, in part because of the lack of noninvasive methods to measure immunity. Secretory immunoglobulin A (sIgA) is the most abundant antibody present at mammalian mucosal surfaces and provides an important first line of defense against pathogens. Recent studies show that sIgA c...

Please note: this is a book review, not the book itself. So please send any full text or reprint requests directly to the author, Prof Tauber. Thanks!

The immune system affects senescence (declines in probabilities of survival or reproduction with age), by shaping late age vulnerability to chronic inflammatory diseases and infections. It is also a dynamic interactive system that must balance competing demands across the life course. Thus, immune system function remains an important frontier in un...

The immune systems of free-living mammals such as humans and wild mice display a heightened degree of activation compared with laboratory mice maintained under artificial conditions. Here, we demonstrate that releasing inbred laboratory mice into an outdoor enclosure to mimic life in a natural environment alters the state of immunity. In addition t...

The relative contributions of genetic and environmental factors to variation in immune responses are still poorly understood. Here, we performed a deep phenotypic analysis of immunological parameters of laboratory mice released into an outdoor enclosure, carrying susceptibility genes ( Nod2 and Atg16l1 ) implicated in the development of inflammator...

Understanding the factors underpinning emergence and reemergence of virulent viral zoonoses is of critical importance. In particular, bats are known to host virulent zoonotic viruses without experiencing disease. Previous work suggests that bats' viral hosting capacities may partially result from uniquely constitutive immune capabilities, but the i...

Over a billion people on earth are infected with helminth parasites and show remarkable variation in parasite burden and chronicity. These parasite distributions are captured well by classic statistics, such as the negative binomial distribution. But the within-host processes underlying this variation are not well understood. In this study, we expl...

Current research on immunology are largely based on clean laboratory mice kept in specific pathogen free (SPF) environments. They have the advantage of being inbred, genetically homogeneous and can be manipulated genetically in disease models. However, humans as with all free-living mammals face a more complex environment and are exposed to various...

This cover image is based on the Research Article The effects of living in an outdoor enclosure on hippocampal plasticity and anxiety‐like behavior in response to nematode infection by Elise C. Cope et al., DOI: 10.1002/hipo.23033.

Sex differences in immunity are found in many species. Known immune mechanisms in birds and mammals suggest that pathogen detection may be amplified in females, whereas in males, pathogen killing is amplified. We show that these immunological profiles emerge as distinct peaks on a fitness landscape defined by sensitivity-specificity and infection-i...

The hippocampus of rodents undergoes structural remodeling throughout adulthood, including the addition of new neurons. Adult neurogenesis is sensitive to environmental enrichment and stress. Microglia, the brain's resident immune cells, are involved in adult neurogenesis by engulfing dying new neurons. While previous studies using laboratory envir...

The vertebrate gut teems with a large, diverse, and dynamic bacterial community that has pervasive effects on gut physiology, metabolism, and immunity. Under natural conditions, these microbes share their habitat with a similarly dynamic community of eukaryotes (helminths, protozoa, and fungi), many of which are well-known parasites. Both parasites...

Genetic and environmental factors shape host susceptibility to infection, but how and how rapidly environmental variation might alter the susceptibility of mammalian genotypes remains unknown. Here, we investigate the impacts of seminatural environments upon the nematode susceptibility profiles of inbred C57BL/6 mice. We hypothesized that natural e...

Albumin, total protein, and leptin levels in blood between infected and uninfected mice across all environments at 3 weeks and 4 weeks p.i. (A) Plasma albumin, total protein, and leptin levels in uninfected and infected mice across all environments at 3 weeks p.i. Sample sizes: Uninfected Lab mice: N = 2; Infected Lab mice: N = 8; Uninfected Short-...

Supporting information. (DOC)

Trichuris muris worm burdens and worm biomass in C57BL/6 mice residing in laboratory versus outdoor environments at 4 weeks p.i. (A) Worm burdens and (B) worm biomass from infected C57BL/6 mice residing in laboratory and outdoor environments at 4 weeks p.i. Lab: N = 7, Short-term Wild: N = 7, Long-term Wild: N = 8. Box centers show the medians, and...

Differences in the relative abundance of LPMC and MLN cytokines in mice living in laboratory and outdoor environments at 4 weeks p.i. (A) Proportion of CD4+ cells that are producing IL-13, IFNγ, IL-4, IL-10, IL-17, and TNFα in LPMCs of mice residing in laboratory and outdoor environments at 4 weeks p.i. Sample sizes: Uninfected Lab mice: N = 3; Inf...

Cytokine production in LPMCs of infected C57BL/6 and STAT6-/- mice residing outdoors for the short term. Proportion of CD4+ cells that are producing IL-4, IL-10, IL-17, and TNFα from LPMCs of infected C57BL/6 (N = 4) and STAT6-/- (N = 5) mice residing outdoors for the short term. Data on cytokine-positive lamina propria cells were log(x+1) transfor...

Effects of environmental variation and infection on host weight over time. Body weight in grams lost/gained over the course of the experiment from uninfected and infected mice residing in laboratory and outdoor environments. Data are means ± standard error mean. https://doi.org/10.5061/dryad.h9g697r. (TIF)

Outdoor environments alter the microbial and fungal communities of the gut. (A) Taxa summary plots at the phylum level showing the microbiota composition of individual Lab mice (N = 47) compared to Long-term Wild (N = 28) mice, which had been residing outdoors for two weeks. The Lab group includes both Lab and Short-term Wild mice, as both groups w...

Differences in the relative abundance of LPMC and MLN cytokines in mice living in laboratory and outdoor environments at 3 weeks p.i. (A) Representative gating strategy for CD4+ and CD8+ cytokine analyses from LPMCs of a laboratory mouse. (B) Proportion of CD4+ cells that are producing IL-4, IL-10, IL-17, and TNFα in LPMCs from mice residing in lab...

Statistical table showing blood albumin, total protein, and leptin levels at 3 weeks and 4 weeks p.i. Two-way ANOVA results for plasma albumin (g/dl), total protein (g/dl), and leptin (pg/ml) levels at 3 weeks and 4 weeks p.i., with location and infection as main factors. Nutritional data were log(x+1) transformed to meet assumptions of analysis. W...

Statistical table showing the alpha diversity of 16S microbiota data for fecal samples collected at 3 weeks and 4 weeks p.i. Two-way ANOVA results showing the alpha diversity as represented by the Shannon index of microbiota data for fecal samples at 3 weeks and 4 weeks p.i. When the interaction term is not significant, the main effect results come...

Statistical table showing LPMC and MLN cytokine production at 3 weeks and 4 weeks p.i. Two-way ANOVA results for CD4+ and CD8+ LPMC and MLN cytokine production at 3 weeks and 4 weeks p.i. with location and infection as main factors. Data on cytokine-positive lamina propria cells and in vitro cytokine secretion were log(x+1) transformed to meet assu...

Alterations in the composition, diversity, and density of the fecal microbiota with high-dose Trichuris muris infection. (A) Log2 fold change of OTUs that differ between infected and uninfected mice residing in laboratory and outdoor environments at 4 weeks p.i. using DESeq2. Data shown have been filtered to include OTUs that have a log2 fold chang...

Ecological theory suggests that co-infecting parasite species can interact within hosts directly, via host immunity and/or via resource competition. In mice, competition for red blood cells (RBCs) between malaria and bloodsucking helminths can regulate malaria population dynamics, but the importance of RBC competition in human hosts was unknown. We...

Resources are a core currency of species interactions and ecology in general (e.g., think of food webs or competition). Within parasite-infected hosts, resources are divided among the competing demands of host immunity and growth as well as parasite reproduction and growth. Effects of resources on immune responses are increasingly understood at the...

Interferon gamma (IFNg), interleukin 10 (IL10), and interleukin 17 (IL17) concentrations were higher in infected mice than uninfected mice (Wilcoxon tests; IFNg: W = 506, p = 0.046, IL10: W = 483, p = 0.010, IL17: W = 441, p = 0.0036), but did not vary with diet (IFNg: W = 843, p = 0.67, IL10: W = 929, p = 0.13, IL17: W = 899, p = 0.28).

Resources are a core currency of species interactions and ecology in general (e.g., think of food webs or competition). Within parasite-infected hosts, resources are divided among the competing demands of host immunity and growth as well as parasite reproduction and growth. Effects of resources on immune responses are increasingly understood at the...

Defense against infection incurs costs as well as benefits that are expected to shape the evolution of optimal defense strategies. In particular, many theoretical studies have investigated contexts favoring constitutive versus inducible defenses. However, even when one immune strategy is theoretically optimal, it may be evolutionarily unachievable....

The sooner the immune system launches, the greater the chances the host has of survival.

A fundamental challenge faced by the immune system is to discriminate contexts meriting activation from contexts in which activation would be harmful. Selection pressures on this ability are likely to be acute: the penalty of mis-identification of pathogens (therefore failure to attack them) is mortality or morbidity linked to infectious disease, w...

Over recent years, extensive phenotypic variability and plasticity have been revealed among the T-helper cells of the mammalian adaptive immune system, even within clonal lineages of identical antigen specificity. This challenges the conventional view that T-helper cells assort into functionally distinct subsets following differential instruction b...

Nutrient availability is predicted to interact with herbivore population densities. Competition for low quality food at high density may reduce summer food intake, and in turn winter survival. Conversely, low population density may favour physiological recovery through better access to better quality spring forage. Here, we take advantage of the lo...