Rita A Trammell

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.

Effects of a Physical Activity Behavior Change Intervention on Inflammation and Related Health Outcomes in Breast Cancer Survivors Pilot Randomized Trial

Background. The goal of this pilot study was to determine the magnitude and direction of intervention effect sizes for inflammatory-related serum markers and relevant health outcomes among breast cancer survivors (BCSs) receiving a physical activity behavior change intervention compared with usual care. Methods. This randomized controlled trial enrolled 28 stage I, II, or IIIA BCSs who were post–primary treatment and not regular exercisers. Participants were assigned to either a 3-month physical activity behavior change intervention group (ING) or usual care group (UCG). Intervention included supervised aerobic (150 weekly minutes, moderate-intensity) and resistance (2 sessions per week) exercise that gradually shifted to home-based exercise. Outcomes were assessed at baseline and 3 months. Results. Cardiorespiratory fitness significantly improved in the ING versus the UCG (between-group difference = 3.8 mL/kg/min; d = 1.1; P = .015). Self-reported sleep latency was significantly reduced in the ING versus the UCG (between group difference = −0.5; d = −1.2; P = .02) as was serum leptin (between-group difference = −9.0 ng/mL; d = −1.0; P = .031). Small to medium nonsignificant negative effect sizes were noted for interleukin (IL)-10 and tumor necrosis factor (TNF)-α and ratios of IL-6 to IL-10, IL-8 to IL-10, and TNF-α to IL-10, whereas nonsignificant positive effect sizes were noted for IL-6 and high-molecular-weight adiponectin. Conclusions. Physical activity behavior change interventions in BCSs can achieve large effect size changes for several health outcomes. Although effect sizes for inflammatory markers were often small and not significant, changes were in the hypothesized direction for all except IL-6 and IL-10.

Biobehavioral Factors Mediate Exercise Effects on Fatigue in Breast Cancer Survivors

PURPOSE This study aimed to examine mediators of fatigue response to an exercise intervention for breast cancer survivors in a pilot randomized controlled trial. METHODS Postmenopausal breast cancer survivors (n = 46; ≤stage 2), off primary treatment, and reporting fatigue and/or sleep dysfunction were randomized to a 3-month exercise intervention (160 min·wk of moderate-intensity aerobic walking, twice weekly resistance training with resistance bands) or control group. Six discussion group sessions provided behavioral support to improve adherence. Fatigue, serum cytokines, accelerometer physical activity, cardiorespiratory fitness, sleep dysfunction, and psychosocial factors were assessed at baseline and 3 months. RESULTS The exercise intervention effect sizes for fatigue were as follows: fatigue intensity d = 0.30 (P = 0.34), interference d = -0.38 (P = 0.22), and general fatigue d = -0.49 (P = 0.13). Using the Freedman-Schatzkin difference-in-coefficients tests, increase in fatigue intensity was significantly mediated by interleukin 6 (IL-6) (82%), IL-10 (94%), IL-6/IL-10 (49%), and tumor necrosis factor-α (TNF-α):IL-10 (78%) with reduced sleep dysfunction increasing the relationship between intervention and fatigue intensity rather than mediating intervention effects (-88%). Decrease in fatigue interference was mediated by sleep dysfunction (35%), whereas IL-10 and pro-anti-inflammatory cytokine ratios increased the relationship between intervention and interference (-25% to -40%). The reduction in general fatigue was significantly mediated by minutes of physical activity (76%), sleep dysfunction (45%), and physical activity enjoyment (40%), with IL-10 (-40%) and IL-6/IL-10 (-11%) increasing the intervention-fatigue relationship. In the intervention group, higher baseline fatigue, anxiety, depression, and perceived exercise barrier interference predicted a greater decline in fatigue interference and/or general fatigue during the intervention. CONCLUSIONS Biobehavioral factors mediated and enhanced intervention effects on fatigue, whereas psychosocial factors predicted fatigue response. Further study is warranted to confirm our results and to improve understanding of relationships that mediate and strengthen the intervention-fatigue association.

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.

Inflammation and psychosocial factors mediate exercise effects on sleep quality in breast cancer survivors: Pilot randomized controlled trial

To improve mechanistic understanding, this pilot randomized controlled trial examined mediators of an exercise intervention effects on sleep in breast cancer survivors (BCS).

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.

Adenosine receptor antagonists and behavioral activation in NF-κB 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.

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.

Inflammation and psychosocial factors mediate exercise effects on sleep quality in breast cancer survivors: pilot randomized controlled trial: Mediators of exercise effects on sleep in breast cancer survivors

To improve mechanistic understanding, this pilot randomized controlled trial examined mediators of an exercise intervention effects on sleep in breast cancer survivors (BCS).

Inflammation and psychosocial factors mediate exercise effects on sleep quality in breast cancer survivors

To improve mechanistic understanding, this pilot randomized controlled trial examined mediators of an exercise intervention effects on sleep in breast cancer survivors (BCS).