Influence of Chronic Exposure to Simulated Shift Work on Disease and Longevity in Disease-Prone Inbred Mice.

Shift work (SW) is viewed as a risk factor for the development of many serious health conditions, yet prospective studies that document such risks are rare. The current study addressed this void by testing the hypothesis that long-term exposure to repeated diurnal phase shifts, mimicking SW, will accelerate disease onset or death in inbred mice with genetic risk of developing cancer, diabetes, or autoimmune disease. The data indicate that 1) life-long exposure to simulated SW accelerates death in female cancerprone AKR/J mice; 2) a significant proportion of male NON/ShiLtJ mice, which have impaired glucose tolerance but do not normally progress to type 2 diabetes, develop hyperglycemia, consistent with diabetes (that is, blood glucose 250 mg/dL or greater) after exposure to simulated SW for 8 wk; and 3) MRL/MpJ mice, which are prone to develop autoimmune disease, showed sex-related acceleration of disease development when exposed to SW as compared with mice maintained on a stable photocycle. Thus, longterm exposure to diurnal phase shifts that mimic SW reduces health or longevity in a wide variety of disease models. Our approach provides a simple way to assess the effect of chronic diurnal disruption in disease development in at-risk genotypes.

Effects of Chronic Diurnal Disruption and Acute Inflammatory Challenge on Mice with Latent Murine Gammaherpesvirus Infection.

People who engage in shift work (SW) have increased risk of developing illnesses, including infectious diseases and various inflammatory conditions. We hypothesized that exposure to repeated cycles of diurnal disruption, mimicking SW, influences viral clearance, latent viral load, or viral reactivation from latency in mice infected with murine gammaherpesvirus (MuGHV). To test this idea, we inoculated BALB/cByJ and C.129S7(B6)-Ifng tm1Ts/J (IFNgKO) mice with MuGHV and housed them under either a stable light:dark (LD) cycle or one mimicking SW. Compared with BALB/cByJ mice, IFNgKO mice generally had higher levels of lytic virus during the 6-wk period after inoculation. In addition, more IFNgKO mice were positive for replicating virus than were BALB/cByJ mice. Exposure to SW did not alter these measures consistently. After the virus had entered the latent phase of infection, mice received either LPS or pyrogen-free saline intraperitoneally. Mice exposed to SW and then injected with LPS during latent infection had greater viral loads and more replicating virus in the lung at 7 d after injection than did either mice that received pyrogen-free saline or those exposed to LD and then treated with LPS. Some cytokine and chemokine concentrations were changed in lung collected 1 d after but not at 7 d after LPS administration. These findings suggest that exposure to repeated chronic diurnal disruption and an acute inflammatory challenge during latent MuGHV infection, in the context of impaired host immune competence, contribute to enhanced viral reactivity and an increased viral load that might trigger 'sickness behavior' symptoms of infectious disease and perhaps contribute to chronic fatigue syndrome.

Interactions Between Housing Density and Ambient Temperature in the Cage Environment: Effects on Mouse Physiology and Behavior.

To determine how housing density and ambient temperature interact to influence the physiology and behavior of mice, we systematically varied housing density (1 to 5 mice per cage) and ambient temperature (22, 26, or 30 °C) and measured effects on body weight, food intake, diurnal patterns of locomotor activity and core temperature, fecal corticosterone, and serum cytokine and adipokine panels. Temperatures inside cages housing 5 mice were 1 to 2 °C higher than the ambient temperature. As the housing density decreased, in-cage temperatures began to fall at a density of 2 or 3 mice per cage and did not differ from ambient temperature at 1 mouse per cage. Ambient temperature, but not housing density, significantly affected food intake. Although neither ambient temperature nor housing density affected core temperature or activity, hyperthermia and behavioral activation occurred during the 12-h period after cage change. Fecal concentrations of corticosterone metabolites and serum cytokines, chemokines, insulin, and leptin were not influenced by cage density and were only sporadically influenced by ambient temperature. Our data document that the number of mice housed per cage influences the intracage environmental conditions and that ambient temperature influences food intake even when temperatures are within or near recommended or thermoneutral ranges. We conclude that investigators should be cautious when changing the number of mice housed in a cage over the course of a study, because doing so significantly alters the cage environment to which remaining mice are exposed.

Effects of Sleep Fragmentation and Chronic Latent Viral Infection on Behavior and Inflammation in Mice.

Many chronic diseases are associated with both fatigue and disrupted or nonrestorative sleep. In addition, so-called 'sickness behaviors' (for example, anorexia, anhedonia, reduced social interaction, fatigue) are common during infectious and inflammatory disease and have been linked to facets of the immune response. To study these relationships, we used murine gammaherpesvirus (MuGHV), a natural pathogen of wild rodents that provides an experimental model for studying the pathophysiology of an Epstein-Barr (EBV)-like γ-herpesvirus infection in mice. We exposed male and female C57BL/6J mice that were either uninfected or latently infected with MuGHV to either sleep fragmentation (SF) or control conditions and measured the effects on behavior and markers of inflammation. Exposure of infected male mice to SF during the normal somnolent (light) phase significantly reduced locomotor activity during the subsequent active phase, despite an intervening 6-h rest period. Infection was associated with significant increases in lung IFNγ and CXC motif ligand (CXCL) 10 in both male and female mice. In both infected and uninfected male mice, exposure to SF was associated with lower levels of IL1ß and C-C motif ligand (CCL) 3 in lung. Exposure of infected female mice to SF led to reductions in lung IL2, CXCL1, and CCL 3. Thus, compared with control conditions, SF was generally associated with lower concentrations of various cytokines in lung. These findings, together with our previous work, indicate that complex interactions among several host factors likely contribute to the behavioral and inflammatory changes associated with viral infection and sleep disruption even in a well-controlled mouse model.

Behavioral perturbation and sleep in healthy and virus-infected inbred mice.

Murine gammaherpesvirus (MuGHV) is a natural pathogen of wild rodents that has been studied extensively in terms of host immune responses to herpesviruses during acute infection, latency, and reactivation from latency. Although herpesvirus infections in people can be associated with fatigue and excessive sleepiness during both acute and latent infection, MuGHV has not been assessed extensively as a model for studying the behavioral consequences of chronic latent herpesvirus infections. To assess MuGHV infection as a model for evaluating fatigue and assessing potential mechanisms that underlie the exacerbation of fatigue during chronic viral disease, we evaluated sleep, temperature, and activity after exposure of healthy and latently MuGHV-infected mice to sleep fragmentation and social interaction. Neither treatment nor infection significantly affected temperature. However, at some time points, latently infected mice that underwent sleep fragmentation had less locomotor activity and more slow-wave sleep than did mice exposed to social interaction. In addition, delta-wave amplitude during slow-wave sleep was lower in infected mice exposed to sleep fragmentation compared with uninfected mice exposed to the same treatment. Both reduced locomotor activity and increased time asleep could indicate fatigue in infected mice after sleep fragmentation; reduced delta-wave amplitude during slow-wave sleep indicates a light plane of sleep from which subjects would be aroused easily. Identifying the mechanisms that underlie sleep responses of mice with chronic latent MuGHV infection may increase our understanding of fatigue during infec- tions and eventually contribute to improving the quality of life for people with chronic viral infections.

Effects of sleep fragmentation on sleep and markers of inflammation in mice.

Many people in our society experience curtailment and disruption of sleep due to work responsibilities, care-giving, or life style choice. Delineating the health effect of acute and chronic disruptions in sleep is essential to raising awareness of and creating interventions to manage these prevalent concerns. To provide a platform for studying the health impact and underlying pathophysiologic mechanisms associated with inadequate sleep, we developed and characterized an approach to creating chronic disruption of sleep in laboratory mice. We used this method to evaluate how 3 durations of sleep fragmentation (SF) affect sleep recuperation and blood and lung analyte concentrations in male C57BL/6J mice. Mice housed in environmentally controlled chambers were exposed to automated SF for periods of 6, 12, or 24 h or for 12 h daily during the light (somnolent) phase for 4 sequential days. Sleep time, slow-wave amplitude, or bout lengths were significantly higher when uninterrupted sleep was permitted after each of the 3 SF durations. However, mice did not recover all of the lost slow-wave sleep during the subsequent 12- to 24-h period and maintained a net loss of sleep. Light-phase SF was associated with significant changes in serum and lung levels of some inflammatory substances, but these changes were not consistent or sustained. The data indicate that acute light-phase SF can result in a sustained sleep debt in mice and may disrupt the inflammatory steady-state in serum and lung.

Mapping complex traits using families of recombinant inbred strains: an overview and example of mapping susceptibility to Candida albicans induced illness phenotypes.

This overview and data-based example indicate how large families of recombinant inbred (RI) strains can be used to identify genetic loci and genes that underlie complex phenotypic differences among inbred mice. The RI approach requires no a priori expectations or assumptions about mechanisms that influence the phenotype, other than that variability is partly heritable. RI strains, which are produced by inbreeding the F2 progeny of two parental strains for at least 20 generations, have two major advantages. First, numerous subjects with identical genotypes can be analyzed to determine the average phenotype associated with that genotype, and second, it becomes practical to systematically accumulate large genome and phenome data sets for entire RI families, including sequence data, transcriptomes for many organs, and cell types and extensive data on gene-by-pathogen interactions. This enables the construction of far more sophisticated models of disease cause and progression. To illustrate the use of the systems genetics approach to infectious disease, we designed a simple study using three complementary families of RI strains (CXB, BXD, and AXB/BXA) that are differentially susceptible to intravenous challenge with the yeast Candida albicans.

Environmental perturbation, inflammation and behavior in healthy and virus-infected mice.

The development of so-called "sickness behaviors" (e.g., anorexia, anhedonia, reduced social interaction, fatigue) during infectious and inflammatory disease has been linked to facets of the immune response. Such problems can be particularly troublesome during chronic latent infection, as the host immune system must employ continual vigilance to maintain viral latency. Epstein-Barr virus (EBV) is a ubiquitous human gamma-herpesvirus that causes acute disease and establishes life-long latency in people. Murine gammaherpesvirus (MuGHV) is a natural pathogen of wild rodents that provides an experimental model for studying the pathophysiology of an EBV-like gamma-herpesvirus in mice. To evaluate this model with regard to sickness behavior and its exacerbation during a chronic latent viral disease, we exposed uninfected and MuGHV-infected C57BL/6J and BALB/cByJ mice to novel and potentially stressful environmental perturbations and measured the impact of these challenges on behavior and markers of inflammation. The data indicate that exposure of mice to environmental perturbations during the normal somnolent phase is associated with reduced activity during the subsequent active phase, despite an intervening rest period. Effects on inflammatory mediators were complex due to independent and interactive effects of infection status, mouse strain, and exposure to stressful environment. However, GCSF and MCP1 were consistently elevated in lung both immediately after and 12h after exposure to a "dirty" cage containing the resident mouse (DCR); this increase occurred in both C57BL/6J and BALB/cByJ mice and was independent of infection status. At 12h after DCR, IL1ß and IP10 were also consistently elevated in lung. In response to DCR, BALB/cByJ mice showed a greater number of significant cytokine effects than did C57BL/6J mice. With regard to infection status, IP10 was consistently elevated in lung at both time points regardless of mouse strain or DCR exposure. Several analytes were affected by mouse strain in serum or lung at one or both time points, with most strain differences present in serum at E18. Taken together, the data show that exposure of mice to environmental perturbations is associated with systemic inflammation that is in part independent of genetic background or latent MuGHV infection and with reduced activity that could represent fatigue, depression, or other facets of sickness behavior.

Cytokine and chemokine responses of lung exposed to surrogate viral and bacterial infections.

The use of in vitro models of complex in vivo systems has yielded many insights into the molecular mechanisms that underlie normal and pathologic physiology. However although the reduced complexity of these models is advantageous with regard to some research questions, the simplification may obscure or eliminate key influences that occur in vivo. We sought to examine this possibility with regard to the lung's response to infection, which may be inherent to resident lung cells or related to the systemic response to pulmonary infection. We used the inbred mouse strains C57BL/6J, DBA/2J, and B6.129S2-IL6(tm1Kopf), which differ in their response to inflammatory and infectious challenges, to assess in vivo responses of lung to surrogate viral and bacterial infection and compared these with responses of cultured lung slices and human A549 cells. Pulmonary cytokine concentrations were measured both after in vivo inoculation of mice and in vitro exposure of lung slices and A549 cells to surrogate viral and bacterial infections. The data indicate similarities and differences in early lung responses to in vivo compared with in vitro exposure to these inflammatory substances. Therefore, resident cells in the lung appear to respond to some challenges in a strain-independent manner, whereas some stimuli may elicit recruitment of peripheral inflammatory cells that generate the subsequent response in a genotype-related manner. These results add to the body of information pointing to host genotype as a crucial factor in mediating the severity of microbial infections and demonstrate that some of these effects may not be apparent in vitro.

Markers for heightened monitoring, imminent death, and euthanasia in aged inbred mice.

The goal of this study was to identify objective criteria that would reliably predict spontaneous death in aged inbred mice. We evaluated male and female AKR/J mice, which die at a relatively young age due to the development of lymphoma, as well as male C57BL/6J and BALB/cByJ mice. Mice were implanted subcutaneously with an identification chip that also allowed remote measurement of body temperature. Temperatures and body weights were measured weekly until spontaneous death occurred or until euthanasia was performed for humane reasons. In AKR/J mice, hypothermia and weight loss began about 4 wk prior to death and increased gradually during that antemortem interval. In C57BL/6J and BALB/cByJ mice, these declines began earlier and were more prolonged prior to death. However, C57BL/6J and BALB/cByJ mice developed a relatively precipitous hypothermia during the 2 wk prior to death. For all 3 strains, the derived composite score of temperature × weight, expressed as a percentage of stable values for each mouse, was similarly informative. These changes in individual and composite measures can signal the need for closer observation or euthanasia of individual mice. Validated markers of clinical decline or imminent death can allow the use of endpoints that reduce terminal distress, do not significantly affect longevity or survival data, and permit timely collection of biologic samples.

Host genetic background and the innate inflammatory response of lung to influenza virus.

Many studies of influenza severity have focused on viral properties that confer virulence, whereas the contributory role of the host genetic background on infection severity remains largely unexplored. In this study, we measure the impact of inoculation with influenza virus in four strains of inbred mice - BALB/cByJ, C57BL/6J, A/J, and DBA/2J. To evaluate the extent to which responses are inherent to lung per se, as opposed to effects of the systemic response to lung infection, we also measured cytokines and chemokines in lung slices exposed to the virus in vitro. Finally, we evaluate the in vivo responses of recombinant inbred (RI) and select consomic strains of mice to search for genomic loci that contribute to phenotypic variance in response to influenza infection. We found marked variation among mouse strains after challenge with virus strain A/HKX31(H3N2), consistent with previous reports using more virulent strains. Furthermore, response patterns differ after in vivo versus in vitro exposure of lung to virus, supporting a predominant role of the systemic host inflammatory response in generating the strain differences. These results add to the body of information pointing to host genotype as a crucial factor in mediating the severity of influenza infections.

Evaluation of an extract of North American ginseng (Panax quinquefolius L.) in Candida albicans-infected complement-deficient mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Ginseng is a widely consumed aromatic herb that is purported to have health benefits. Several studies report a beneficial impact of ginseng or its derivatives on Candida albicans infection in mice and suggest that its immune-modulatory properties contribute to this effect. However, these studies generally administered ginseng to experimental animals by injection, whereas people typically ingest ginseng. Furthermore, although disseminated candiasis is typically a disease of immune-impaired hosts, previous studies have generally used immune competent host species in the assessments. MATERIALS AND METHODS: We evaluated the efficacy of an ingested extract of ginseng against Candida albicans infection in DBA/2J mice, which are highly susceptible to Candida albicans infection. A ginseng extract was added to the drinking water for two days before and for the remainder of the study after intravenous inoculation of mice with Candida albicans. Mice were evaluated for morbidity, mortality, Candida albicans titers, and concentrations of inflammatory cytokines and chemokines. RESULTS: Ingestion of the ginseng extract did not significantly affect overall morbidity or mortality. However, ingestion of the extract was associated with significantly lower renal titers of Candida albicans and with significantly lower concentrations of some inflammatory cytokines in kidney and/or serum. CONCLUSIONS: Assessment of morbidity, mortality, inflammatory markers, and renal titers after spontaneous ingestion of ginseng by susceptible hosts represents a comprehensive approach to characterizations of therapeutic efficacy against infectious agents. Our findings extend previous reports of the efficacy of ginseng against Candida albicans by demonstrating significant reductions in infectious load and some markers of inflammation in susceptible mice. Our data therefore support further assessment of the immune-modulatory properties of this widely consumed herb and its components.

Development of a mouse model for assessing fatigue during chemotherapy.

Fatigue and disturbed sleep are common problems for cancer patients and affect both quality of life and compliance with treatment. Fatigue may be associated with cancer itself and with the treatment, particularly for therapies with neurotoxic side effects. To develop a model system for evaluation of chemotherapy-related fatigue, we studied mice treated with either a commonly used formulation of the chemotherapeutic agent paclitaxel (paclitaxel; Taxol), which is known to have neurotoxic properties, or a nano- particle formulation of paclitaxel (nab-paclitaxel; Abraxane) that is reported to have greater potency and efficacy yet fewer side effects than does paclitaxel. Mice were treated with 1 of these 2 agents (10 mg/kg IV daily for 5 consecutive days) and were monitored from 1 wk before through 4 wk after treatment. Dependent measures included running wheel activity, locomotor activity on the cage floor, core temperature, sleep patterns, CBC count, serum cytokine and chemokine concentrations, and neurologic assessment. For both drugs, mice showed the most severe perturbations of activity during the first recovery week after drug administration. Mice treated with paclitaxel showed greater neutropenia and motor deficits than did mice treated with nab-paclitaxel. However, deficits had largely resolved by 4 wk after administration of either drug. We conclude that these measures provide an assessment of chemotherapy-related fatigue that potentially can distinguish toxicity associated with different formulations of the same agent.

Markers for predicting death as an outcome for mice used in infectious disease research.

Our goal in this study was to identify objective criteria that could be used to predict an outcome of death in mice subjected to experimental inoculation with infectious organisms. We conducted a retrospective analysis of data collected from 4 independent studies that used several infectious agents (influenza virus strains A/HK/x31[H3N2] and A/Puerto Rico/8/34[H1N1], Streptococcus pneumoniae, and Candida albicans) and mouse strains (A/J, DBA/2J, C57BL/6J, BALB/cByJ). Postinoculation periods ranged from 5 to 21 d, with survival of 30% to 60% of the subjects. In all studies, mice were implanted with either a subcutaneous identification microchip or an intraabdominal radiofrequency transmitter to allow remote measurement of body temperature. After inoculation, mice were weighed and monitored regularly until death occurred or euthanasia was performed. Hypothermia was the most valuable characteristic for distinguishing mice that would survive or succumb to the infection. In addition, weight loss was useful in some of the models. In some cases, the derived measure of the product of temperature and body weight provided the best differentiation of mice in the 2 outcome categories. Therefore, the utility of these measures varied substantially depending on the specific model. This study demonstrates that specific endpoint markers are not uniformly applicable to different models. Rather, such markers should be developed and tested in the context of the model in which they will be used. The use of validated markers for eventual death can signal the need for preemptive euthanasia to alleviate terminal distress and permit timely collection of biologic samples.

Lack of association of a spontaneous mutation of the Chrm2 gene with behavioral and physiologic phenotypic differences in inbred mice.

The nucleotide substitution C797T in the Chrm2 gene causes substitution of leucine for proline at position 266 (P266L) of the CHRM2 protein. Because Chrm2 codes for the type 2 muscarinic receptor, this mutation could influence physiologic and behavioral phenotypes of mice. Chrm2 mRNA was not differentially expressed in 2 brain regions with high cholinergic innervation in a mouse strain that does (BALB/cByJ) or does not (C57BL/6J) have the mutation. In addition, strains of mice with and without the C797T point mutation in Chrm2 did not differ significantly in muscarinic binding properties. Variation across strains was detected in terms of acoustic startle, prepulse inhibition, and the physiologic effects of the muscarinic agonist oxotremorine. However, interstrain differences in these measures did not correlate with the presence of the mutation. Although we were unable to associate a measurable phenotype with the Chrm2 mutation, assessment of the mutation on other genetic backgrounds or in the context of other traits might reveal differential effects. Therefore, despite our negative findings, evaluation of characteristics that involve muscarinic function should be undertaken with caution when comparing mice with different alleles of the Chrm2 gene.

Identification of markers for imminent death in mice used in longevity and aging research.

The goal of this study was to identify objective criteria that would reliably predict imminent death in aged mice. Male and female ICR mice (age, 8 mo) were subcutaneously implanted with an identification chip for remote measurement of body temperature. Mice then were weighed and monitored regularly until spontaneous death occurred or until euthanasia was administered for humane reasons. Clinical signs that signaled implementation of euthanasia included inability to walk, lack of response to manipulation, large or ulcerated tumors, seizures, and palpable hypothermia. In mice that died spontaneously, gradual weight loss was the most frequent and earliest sign of imminent death. Hypothermia developed during the 2 wk prior to death. Slow or labored breathing were observed in about half of the mice before death. A composite score of temperature x weight can be used to provide an objective benchmark to signal increased observation or euthanasia of individual mice. Such assessment may allow the collection of terminal tissue samples without markedly altering longevity data, although application of this criterion may not be appropriate for all studies of longevity. Timely euthanasia of mice based on validated markers of imminent death can allow implementation of endpoints that alleviate terminal distress in aged mice, may not significantly affect longevity data, and can permit timely collection of biologic samples.

Assessment of immune activation in mice before and after eradication of mite infestation.

Mite infestation of mice remains a persistent problem for many institutions, leading to numerous health problems and creating unknown and unwanted variables for research. In this study, mice with mite infestation demonstrated significantly higher levels of inflammatory cytokines, both at draining lymph nodes (axillary) and systemically, as compared with mice without mites. In addition, histologic evaluation revealed significant inflammation in mite-infested mice. Inflammatory changes were still present in the skin of mice at 6 to 8 wk after treatment, despite absence of detectable infestation at that time. Because these significant and lasting local and systemic changes have the potential to alter research findings, eradication of mites infestations should be an important goal for all institutions.

Adenosine receptor antagonists and behavioral activation in NF-kappaB p50 subunit knockout mice.

AIMS: Our previous work revealed that mice lacking the p50 subunit of transcription factor nuclear factor kappa B (NF-kappaB) (p50 KO mice) and genetically intact F2 mice have similar locomotion under basal conditions, yet p50 KO mice show greater locomotor activation after caffeine ingestion. In this report, we test whether KO mice display altered caffeine pharmacokinetics or increased caffeine-induced DA turnover relative to F2 mice, and evaluate the impact of intraperitoneal administration of specific adenosine and DA receptor antagonists on locomotor activity. MAIN METHODS: Concentrations of DA and caffeine were measured using high performance liquid chromatography. DA turnover was measured after treatment of mice with an inhibitor of tyrosine hydroxylase. Locomotor activity was measured using telemetry. KEY FINDINGS: The data reveal that 1) caffeine concentrations in blood and brain are similar in KO and F2 mice after oral or intraperitoneal administration; 2) KO mice show greater DA turnover under basal conditions, but turnover is similar in both strains after caffeine administration; 3) the specific A2AAR antagonist SCH 58261 induces greater locomotion in KO versus F2 mice; and 4) the activating effect of SCH 58261 in KO mice is prevented by prior treatment with the D2R antagonist raclopride. SIGNIFICANCE: These findings support the conclusions that 1) A2AAR has a major impact on behavioral activation of p50 KO mice, and 2) D2R mediated neurotransmission is important to this effect.

Fatigue and sleep during cancer and chemotherapy: translational rodent models.

The frequent occurrence of fatigue and disturbed sleep in cancer survivors and the negative effect of these symptoms on quality of life and clinical outcome underscore the need to identify mechanisms that cause cancer-related fatigue, with a view toward developing more effective treatments for this problem. Human studies of fatigue and disturbed sleep are limited by high interindividual genetic and environmental variability, difficulties with behavioral or reporting compliance, and the subjective nature of the problems. Although animal models also must overcome the barrier of assessing fatigue and sleep disturbance in the absence of obvious objective clinical markers, animal studies are easier to control and standardize than are studies of people. Moreover, animal models are crucial to the identification and understanding of underlying disease mechanisms. This review describes the need for, the feasibility of, and several possible approaches to measuring fatigue in animal models of cancer and to relating such measures to disturbed sleep, immune function, and other potential mechanisms. Developing and using animal models to better understand fatigue and disturbed sleep related to cancer and its treatment has an enormous potential to expand the knowledge base and foster hypotheses necessary for the future development and testing of interventions.

Genetic susceptibility and resistance to influenza infection and disease in humans and mice.

Although genetic risk factors for influenza infection have not yet been defined in people, differences in genetic background and related variation in the response to infection, as well as viral virulence, are all likely to influence both the likelihood of infection and disease severity. However, apart from characterization of viral binding sites in avian and mammalian hosts, relatively little investigation has focused on host genetic determinants of susceptibility or resistance to infection, or the severity of the associated disease in humans or other species. Similarly, the role of genetic background in the generation of an efficacious immune response to either infection or vaccination has not been extensively evaluated. However, genetic influences on susceptibility and resistance to numerous infectious agents and on the resultant host inflammatory and immune responses are well established in both humans and other animals. Mouse-adapted strains of human influenza viruses and the use of inbred strains of laboratory mice have supported extensive characterization of the pathogenesis and immunology of influenza virus infections. Like individual humans, inbred strains of mice vary in their reactions to influenza infection, particularly with regard to the inflammatory response and disease severity, supporting the potential use of these mice as a valuable surrogate for human genetic variation. Relying heavily on what we have learned from mice, this overview summarizes existing animal, human and epidemiologic data suggestive of host genetic influences on influenza infection.