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Biomedical subjects

G Berry

Publications and source records attributed to G Berry.

At least 19 recordsLinked to original sources

Respiratory infection with influenza A virus interferes with the induction of tolerance to aeroallergens.

Viral respiratory infections have been implicated in influencing allergen sensitization and the development of asthma, but their exact role remains controversial. Because respiratory exposure to Ag normally engenders T cell tolerance and prevents the development of airway hyperreactivity (AHR) and inflammation, we examined the effects of influenza A virus infection on tolerance induced by exposure to intranasal (i.n.) OVA and the subsequent development of AHR. We found that concurrent infection with influenza A abrogated tolerance induced by exposure to i.n. OVA, and instead led to the development of AHR accompanied by the production of OVA-specific IgE, IL-4, IL-5, IL-13, and IFN-gamma. When both IL-4 and IL-5 were neutralized in this system, AHR was still induced, suggesting that influenza-induced cytokines such as IL-13, or mechanisms unrelated to cytokines, might be responsible for the development of AHR. The length of time between influenza A infection and i.n. exposure to OVA was crucial, because mice exposed to i.n. OVA 15-30 days after viral inoculation developed neither AHR nor OVA-specific tolerance. These mice instead acquired Th1-biased OVA-specific immune responses associated with vigorous OVA-induced T cell proliferation, and reduced production of OVA-specific IgE. The protective effect of influenza A on AHR was dependent on IFN-gamma, because protection was abrogated with a neutralizing anti-IFN-gamma mAb. These results suggest that viral respiratory infection interferes with the development of respiratory allergen-induced tolerance, and that the time interval between viral infection and allergen exposure is critical in determining whether viral infection will enhance, or protect against, the development of respiratory allergen sensitization and AHR.

Administration, Intranasal↗

Vaccination with heat-killed Listeria as adjuvant reverses established allergen-induced airway hyperreactivity and inflammation: role of CD8+ T cells and IL-18.

Asthma is a respiratory disorder characterized by airway hyperreactivity (AHR) and inflammation and is associated with high serum IgE and overproduction of IL-4, IL-5, and IL-13 by allergen-specific Th2 cells. Our previous studies demonstrated that heat-killed Listeria monocytogenes (HKL) as an adjuvant in immunotherapy successfully reversed ongoing Ag-specific Th2-dominated responses toward Th1-dominated responses, but it was unclear if such immune modulation could reverse ongoing, established disease in target organs such as the lung. In this paper we show that a single dose of Ag plus HKL as adjuvant significantly reduced AHR in a murine model for asthma and reversed established AHR when given late after allergen sensitization. HKL as adjuvant also dramatically inhibited airway inflammation, eosinophilia, and mucus production, significantly reduced Ag-specific IgE and IL-4 production, and dramatically increased Ag-specific IFN-gamma synthesis. The inhibitory effect of HKL on AHR depended on the presence of IL-12 and CD8+ T cells and was associated with an increase of IL-18 mRNA expression. Thus, our results demonstrate that HKL as an adjuvant for immunotherapy mediates immune deviation from a pathological Th2-dominated response toward a protective immune response in peripheral lymphoid tissues and in the lungs and may be clinically effective in the treatment of patients with established asthma and allergic disease.

Adjuvants, Immunologic↗

Particulate emboli capture by an intra-aortic filter device during cardiac surgery.

OBJECTIVE: Particulate embolization is associated with neurologic morbidity after cardiac surgery. Crossclamp manipulation has been identified as the single most significant cause of particulate emboli release during cardiac surgery. A new intra-aortic filtration method has been assessed with regard to its safety and its ability to capture particulate emboli before they enter the central circulation. METHODS: Patients undergoing cardiac surgery with cardiopulmonary bypass through standard median sternotomy were selected for emboli management by means of intra-aortic filtration. A novel intra-aortic filter device was inserted through a modified 24F arterial cannula immediately before releasing the crossclamp in 77 patients. Filters remained in the aorta until cardiopulmonary bypass was discontinued and the heart was fully ejecting. The procedure was assessed for facility, safety, and effect on routine cardiopulmonary bypass operation and function. RESULTS: The insertion and removal of the intra-aortic filter were safe, easy, and uneventful in most patients. Patient hemodynamics and bypass flow rates remained normal throughout the filter dwell period. No strokes or gross neurologic defects were noted. Electron microscopic analysis of 12 filters revealed an insignificant degree of platelet adhesion on filter surfaces. Histology samples (n = 44) were examined, and 66% (n = 29) showed evidence of atheromatous material, 36% (n = 16) with platelet-fibrin, 25% (n = 11) with true thrombus and/or blood clot, 7% (n = 3) with normal vessel wall, and 2% (n = 1) with aggregates of cholesterol or grumous portion of atheromatous plaque. CONCLUSION: The intra-aortic filter can be safely deployed and captures particulate emboli, the predominant origin of which is atheromatous. The beneficial effects of this device on neurologic outcomes have yet to be determined.

Adult↗

Mechanisms preventing allergen-induced airways hyperreactivity: role of tolerance and immune deviation.

BACKGROUND: Aeroallergens continuously enter the respiratory tract of atopic individuals and provoke the development of asthma characterized by airway hyperreactivity (AHR) and inflammation. By contrast, nonatopic individuals are exposed to the same aeroallergens, but airway inflammation does not develop. However, the mechanisms that prevent allergen-induced respiratory diseases in nonatopic subjects are poorly characterized. OBJECTIVE: In this study we compared the role of allergen-specific T-cell tolerance and immune deviation in conferring protection against the development of allergen-induced AHR. METHODS: We exposed mice to intranasal ovalbumin (OVA) to induce T-cell tolerance and examined its effects on the subsequent development of AHR and inflammation. RESULTS: We demonstrated that exposure of mice to intranasal OVA resulted in peripheral CD4(+) T-cell unresponsiveness that very efficiently prevented not only the development of AHR but also greatly inhibited airway inflammation and OVA-specific IgE production. The induction of peripheral T-cell tolerance and protection against AHR were not dependent on the presence of IFN-gamma or IL-4. The development of AHR was also prevented by an OVA-specific T(H)1-biased immune response induced by inhalation of OVA in the presence of IL-12. However, the OVA-specific T(H)1 response was associated with a significant degree of pulmonary inflammation. CONCLUSION: These results indicate that both allergen-specific T-cell tolerance and T(H)1-biased immune deviation prevent the development of AHR, but T(H)1 responses are associated with significantly greater inflammation in the lung than is associated with T-cell unresponsiveness. Therefore CD4(+) T-cell unresponsiveness critically regulates immune responses to aeroallergens and protects against the development of allergic disease and asthma.

Allergens↗

Suspected acute pulmonary emboli: cost-effectiveness of chest helical computed tomography versus a standard diagnostic algorithm incorporating ventilation-perfusion scintigraphy.

BACKGROUND: There is a controversy regarding the investigation of patients with suspected acute pulmonary embolism (PE). AIMS: To compare the cost-effectiveness of alternative methods of diagnosing acute PE. Chest helical computed tomography (CT) alone and in combination with venous ultrasound (US) of legs and pulmonary angiography (PA) were compared to a conventional algorithm using ventilation-perfusion (V/Q) scintigraphy supplemented in selected cases by US and PA. METHODS: A decision-analytical model was constructed to model the costs and effects of the three diagnostic strategies in a hypothetical cohort of 1000 patients each. Transition probabilities were based on published data. Life years gained by each strategy were estimated from published mortality rates. Schedule fees were used to estimate costs. RESULTS: The V/Q protocol is both more expensive and more effective than CT alone resulting in 20.1 additional lives saved at a (discounted) cost of $940 per life year gained. An additional 2.5 lives can be saved if CT replaces V/Q scintigraphy in the diagnostic algorithm but at a cost of $23,905 per life year saved. CONCLUSIONS: The more effective diagnostic strategies are also more expensive. In patients with suspected PE, the incremental cost-effectiveness of the V/Q based strategy over CT alone is reasonable in comparison with other health interventions. The cost-effectiveness of the supplemented CT strategy is more questionable.

Algorithms↗

Lung function growth and its relation to airway hyperresponsiveness and recent wheeze. Results from a longitudinal population study.

To evaluate the association between growth in height and growth in lung function, and to identify the potential temporal relationships between airway hyperresponsiveness (AHR), respiratory symptoms, and lung function growth during adolescence and young adulthood, we analyzed data collected from the Belmont cohort. Among the 718 schoolchildren initially studied at 1982 (aged 8-10 yr), 557 were studied between two times and six times at 2-yr intervals until 1992. Baseline lung function, AHR by histamine inhalation test, and recent wheeze by questionnaires, were measured at each visit. We found that between 17 and 19 yr of age, when growth in height had stopped, growth in FEV(1) was approximately 200 ml/yr in boys and 100 ml/yr in girls. Peak growth velocity of height occurred at age 13 both in boys and in girls, whereas peak growth velocity of FEV(1) occurred at the same age only in girls and 1 yr later in boys. Having AHR and recent wheeze at the previous study time were both associated with lower subsequent growth in FEV(1), but not with subsequent growth in FVC. We conclude that lung function continues to grow after the cessation of height growth and that growth in FEV(1) is reduced in subjects with AHR and/or recent wheeze.

Body Height↗

CD4(+) T helper cells engineered to produce latent TGF-beta1 reverse allergen-induced airway hyperreactivity and inflammation.

T helper 2 (Th2) cells play a critical role in the pathogenesis of asthma, but the precise immunological mechanisms that inhibit Th2 cell function in vivo are not well understood. Using gene therapy, we demonstrated that ovalbumin-specific (OVA-specific) Th cells engineered to express latent TGF-beta abolished airway hyperreactivity and airway inflammation induced by OVA-specific Th2 effector cells in SCID and BALB/c mice. These effects correlated with increased concentrations of active TGF-beta in the bronchoalveolar lavage (BAL) fluid, demonstrating that latent TGF-beta was activated in the inflammatory environment. In contrast, OVA-specific Th1 cells failed to inhibit airway hyperreactivity and inflammation in this system. The inhibitory effect of TGF-beta-secreting Th cells was antigen-specific and was reversed by neutralization of TGF-beta. Our results demonstrate that T cells secreting TGF-beta in the respiratory mucosa can indeed regulate Th2-induced airway hyperreactivity and inflammation and suggest that TGF-beta-producing T cells play an important regulatory role in asthma.

Allergens↗

Meta-analysis on the association between environmental tobacco smoke (ETS) exposure and the prevalence of lower respiratory tract infection in early childhood.

The aim of this study was to obtain quantitative information from published data on the association between environmental tobacco smoke (ETS) exposure and the prevalence of serious lower respiratory tract infections (LRTI) in infancy and early childhood. We identified 21 relevant publications on the relation between ETS and the prevalence of serious LRTI by reviewing reference lists in relevant reports and by conducting manual and computer searches (Medline database; Dissertation abstracts index of Xerox University Microfilms) of published reports between 1966 and 1995. Thirteen studies were included in a quantitative overview using random effects modeling to derive pooled odds ratios. Sensitivity analyses were conducted to test the decision rules used in extracting odds ratio data. The results of community and hospital studies are broadly consistent and show that the child of a parent who smokes is at approximately twice the risk of having a serious respiratory tract infection in early life that requires hospitalization. This association was pronounced in children younger than age two and diminished after the age of two. The combined odds ratio for hospitalization for lower respiratory tract infections in infancy or early childhood is 1.93 (95% CI 1.66-2.25); the combined odds ratio of prevalence of serious LRTI at age less than 2 years, between 0 and 6 years, and between 3 and 6 years were 1.71 (95% CI 1.33-2.20); 1.57 (1.28-1.91), and 1.25 (0.88-1.78), respectively. There was no evidence of heterogeneity across the studies in these combined odds ratios. We conclude that this meta-analysis provides strong evidence that exposure to ETS causes adverse respiratory health outcomes such as either a serious LRTI or hospitalization for LRTI. New public health campaigns are urgently needed to discourage smoking in the presence of young children.

Age Distribution↗

Underground coal miners' foot and boot problems.

The New South Wales (NSW) Joint Coal Board Health and Safety Trust funded an investigation into foot problems reported by 400 randomly selected underground coal miners from 15 mines in NSW. Miners were interviewed and their responses were entered directly into laptop computers. Digital cameras were also used to take pictures of skin conditions and miners' posture. Observations of the skin results indicate that miners find gumboots to be hot, sweaty and uncomfortable. Skin breakdown and tinea, is frequent and disabling and responsible for absences from the workforce that are costly for both miner and employer. A more comfortable and better designed boot is needed, fabricated in waterproof leather together with socks that 'wick' the moisture away from the foot. Socks worn were of varying components and washed at irregular intervals, indicating a need for regular changes of socks and improved hygiene.

Coal↗

Models for mesothelioma incidence following exposure to fibers in terms of timing and duration of exposure and the biopersistence of the fibers.

The health effects of inhaled fibers are related to the intensity and duration of exposure and occur many years after the exposure. In particular, the incidence of mesothelioma after exposure to asbestos is proportional to the intensity of exposure (fibers per milliliter of air) and the duration of exposure, and to the time that has elapsed since the exposure. The incidence increases with time since exposure to a power of between 3 and 4. The disease process resulting from exposure to fibers in the air is presumably related to the dose of fibers in the lungs, which depends on the exposure level and duration, and also on the size characteristics of the fibers influencing their inhalation and retention in the lungs. Models incorporating these characteristics have been found to be satisfactory in explaining the incidence of mesothelioma over time after exposure to asbestos. Most of the epidemiological modeling has been for occupational exposure to one of the amphibole asbestos types (crocidolite or amosite), for which heavy exposure produces a high incidence of mesothelioma. Occupational exposure to chrysotile asbestos has resulted in a much lower incidence of mesothelioma. Crocidolite asbestos is much more biopersistent than chrysotile asbestos in the sense that after retention in the lungs it is eliminated only slowly (half-time of several years). If fibers are eliminated then the dose in the lungs declines following exposure, and this may influence the disease process. This concept is more important for synthetic mineral fibers, such as glass wool, which are used as a substitute for asbestos. These fibers are much less biopersistent than asbestos, with half-times of weeks or even days. Biopersistence is related to the dissolution of fibers. This is a physical-chemical process that may be expected to proceed at about the same rate in rats and humans. The predicted effect of biopersistence of fibers has been explored using the basic mesothelioma incidence model generalized to include a term representing exponential elimination over time. The influence of solubility of fibers on the mesothelioma rate is 17 times higher in humans than in rats. This is because rats are aging and developing cancer at a much quicker rate than humans, and hence the influence of dissolution is less. Thus, the predicted mesothelioma incidence in humans is highly dependent on the rate of elimination across the range covering asbestos and the more durable synthetic fibers, but in rats a similar dependence occurs at a 17 times higher rate of elimination corresponding to the less durable synthetic fibers. The possible carcinogenic effects of fibers are often determined from animal experiments, but these results suggest that the extrapolation from rats to humans is highly dependent on the biopersistence of fibers, in the situation where the elimination is through dissolution of fibers at a rate independent of species and the speed of the cancer process is species dependent. This implies that relatively soluble fibers that do not produce disease in rat experiments are even less likely to produce disease in humans.

Algorithms↗

Allergen-specific Th1 cells fail to counterbalance Th2 cell-induced airway hyperreactivity but cause severe airway inflammation.

Allergic asthma, which is present in as many as 10% of individuals in industrialized nations, is characterized by chronic airway inflammation and hyperreactivity induced by allergen-specific Th2 cells secreting interleukin-4 (IL-4) and IL-5. Because Th1 cells antagonize Th2 cell functions, it has been proposed that immune deviation toward Th1 can protect against asthma and allergies. Using an adoptive transfer system, we assessed the roles of Th1, Th2, and Th0 cells in a mouse model of asthma and examined the capacity of Th1 cells to counterbalance the proasthmatic effects of Th2 cells. Th1, Th2, and Th0 lines were generated from ovalbumin (OVA)-specific T-cell receptor (TCR) transgenic mice and transferred into lymphocyte-deficient, OVA-treated severe combined immunodeficiency (SCID) mice. OVA-specific Th2 and Th0 cells induced significant airway hyperreactivity and inflammation. Surprisingly, Th1 cells did not attenuate Th2 cell-induced airway hyperreactivity and inflammation in either SCID mice or in OVA-immunized immunocompetent BALB/c mice, but rather caused severe airway inflammation. These results indicate that antigen-specific Th1 cells may not protect or prevent Th2-mediated allergic disease, but rather may cause acute lung pathology. These findings have significant implications with regard to current therapeutic goals in asthma and allergy and suggest that conversion of Th2-dominated allergic inflammatory responses into Th1-dominated responses may lead to further problems.

Allergens↗

Retinopathy in older persons without diabetes and its relationship to hypertension.

OBJECTIVE: To assess the prevalence and relationship of retinopathy lesions in older subjects without diabetes to systemic hypertension. METHODS: Three thousand six hundred fifty-four people aged 49 years or older attending the Blue Mountains Eye Study underwent a detailed eye examination, including medical history, blood pressure measurement, and fasting blood collection. Retinopathy lesions (hemorrhages and microaneurysms) were assessed from masked grading of stereoretinal photographs. Subjects with a history of diabetes or an elevated blood glucose level were excluded. Hypertension was defined as the current use of antihypertensive medications or an elevated blood pressure measurement on examination. RESULTS: Retinopathy was present in 325 subjects without diabetes, a prevalence of 9.8% (95% confidence interval [CI], 8.9%-10.9%), which increased with age. An increased age-adjusted relative risk (RR) for retinopathy was found for women (RR, 1.67; 95% CI, 1.26-2.21) and men (RR, 1.47; 95% CI, 1.07-2.00) with hypertension. In people using antihypertensive medications, retinopathy prevalence was higher for uncontrolled compared with controlled blood pressure but was not related to hypertension duration. Significant (P=.02 to P=.001) trends were found between increasing blood pressure quartiles and age-adjusted retinopathy prevalence, a relationship that was maintained after adjusting for fasting plasma glucose level at 3 diagnostic cut points for diabetes. CONCLUSIONS: This study supports the Beaver Dam Eye Study findings that retinal hemorrhages and microaneurysms are relatively frequent lesions in older people without diabetes and are significantly related to the presence and severity of hypertension.

Aged↗

Quantitative fluorescence resonance energy transfer measurements using fluorescence microscopy.

Fluorescence resonance energy transfer (FRET) is a technique used for quantifying the distance between two molecules conjugated to different fluorophores. By combining optical microscopy with FRET it is possible to obtain quantitative temporal and spatial information about the binding and interaction of proteins, lipids, enzymes, DNA, and RNA in vivo. In conjunction with the recent development of a variety of mutant green fluorescent proteins (mtGFPs), FRET microscopy provides the potential to measure the interaction of intracellular molecular species in intact living cells where the donor and acceptor fluorophores are actually part of the molecules themselves. However, steady-state FRET microscopy measurements can suffer from several sources of distortion, which need to be corrected. These include direct excitation of the acceptor at the donor excitation wavelengths and the dependence of FRET on the concentration of acceptor. We present a simple method for the analysis of FRET data obtained with standard filter sets in a fluorescence microscope. This method is corrected for cross talk (any detection of donor fluorescence with the acceptor emission filter and any detection of acceptor fluorescence with the donor emission filter), and for the dependence of FRET on the concentrations of the donor and acceptor. Measurements of the interaction of the proteins Bcl-2 and Beclin (a recently identified Bcl-2 interacting protein located on chromosome 17q21), are shown to document the accuracy of this approach for correction of donor and acceptor concentrations, and cross talk between the different filter units.

Animals↗

Agreement between medical record data and patients' accounts of their medical history and treatment for dyspepsia.

We examined agreement between data abstracted from medical records and interview data for patients with dyspepsia admitted to hospital for endoscopy, to determine the extent to which health records could be used to validate self-reports of dyspepsia and the management of this condition. Results from the sample of 220 patients showed that there was poor agreement between data sources for information about duration of dyspepsia (k=0.34) and previous barium meal examination (k=0.34). Patients reported significantly longer dyspepsia histories (Wilcoxon sign test Z=4.13, p<0.0001) and significantly more barium meals (sign test Z=8.43, p<0.0001) than were documented in their records. There was also disagreement between data sources regarding the number of drugs taken before and after endoscopy (k=0.28 and k=0.31, respectively). Where there was disagreement for number of drugs there was no significant difference in the direction of the disagreement. There was moderate agreement regarding the name of pre-endoscopy medication (k=0.55) and substantial agreement for the name of medication used post-endoscopy (k=0.62). There was very poor agreement regarding diagnosis. The medical record was the gold standard for this information. Choice of data source, medical records or self-reports, will in many instances provide significantly different results and it is likely that this may also be true for other variables of interest to researchers. Thus in the case where no gold standards are available researchers need to consider carefully the implication of choice of data source on their results.

Dyspepsia↗

The use of cardiac biopsy to demonstrate reduced cardiotoxicity in AIDS Kaposi's sarcoma patients treated with pegylated liposomal doxorubicin.

BACKGROUND: Pegylated liposomal doxorubicin (PL-DOX) has been shown in preclinical models to induce less cardiotoxicity than non-liposomal doxorubicin. Endomyocardial biopsy is a highly sensitive and specific method for detecting anthracycline-induced cardiac damage. PATIENTS AND METHODS: Myocardial tissue from ten KS patients who had received cumulative PL-DOX (20 mg/m2/biweekly) of 440-840 mg/m2 was evaluated for evidence of anthracycline-induced cardiac damage. Controls were assembled from patients who had received cumulative doxorubicin doses of 174-671 mg/m2 in two earlier cardiac biopsy protocols. Two control groups were selected on the basis of both cumulative (+/- 10 mg/m2) and peak doxorubicin dose (60 or 20 mg/m2, control group 1), or peak dose alone (20 mg/m2, control group 2). RESULTS: PL-DOX patients had significantly lower biopsy scores compared with those of doxorubicin controls despite higher cumulative doses of anthracycline. The median biopsy scores for the PL-DOX and doxorubicin groups, respectively, were 0.3 vs. 3.0 (P = 0.002, Cochran-Mantel-Haenszel row mean difference test) for group 1 and 1.25 for group 2 (P < 0.001, Wilcoxon rank-sum test). CONCLUSIONS: Less severe cardiac changes were seen in patients given PL-DOX relative to historical control patients given comparable cumulative doses of doxorubicin.

Acquired Immunodeficiency Syndrome↗

Bcl-2 and Bax interactions in mitochondria probed with green fluorescent protein and fluorescence resonance energy transfer.

It has been hypothesized that interaction of Bcl-2 and Bax may regulate apoptosis. The spatial and temporal interaction of Bcl-2 and Bax at the single cell level has not, however, been demonstrated. To achieve this goal, we have developed two-fusion FRET (fluorescence resonance energy transfer). Using green fluorescent protein (GFP)-Bax and blue fluorescent protein (BFP)-Bcl-2 fusion proteins coexpressed in the same cell, we demonstrate a direct interaction between Bcl-2 and Bax in individual mitochondria. Mitochondrially localized cytochrome c-GFP and BFP-Bcl-2 showed little or no FRET, while nuclear-localized GFP-human papillomavirus E6 and BFP-Bcl-2 did not interact when coexpressed in the same cell. These findings indicate that two-fusion FRET provides an opportunity to examine the interaction between two different proteins coexpressed in single intact mammalian cells.

3T3 Cells↗

Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein.

bcl-2, the prototypic cellular antiapoptotic gene, decreases Sindbis virus replication and Sindbis virus-induced apoptosis in mouse brains, resulting in protection against lethal encephalitis. To investigate potential mechanisms by which Bcl-2 protects against central nervous system Sindbis virus infection, we performed a yeast two-hybrid screen to identify Bcl-2-interacting gene products in an adult mouse brain library. We identified a novel 60-kDa coiled-coil protein, Beclin, which we confirmed interacts with Bcl-2 in mammalian cells, using fluorescence resonance energy transfer microscopy. To examine the role of Beclin in Sindbis virus pathogenesis, we constructed recombinant Sindbis virus chimeras that express full-length human Beclin (SIN/beclin), Beclin lacking the putative Bcl-2-binding domain (SIN/beclinDeltaBcl-2BD), or Beclin containing a premature stop codon near the 5' terminus (SIN/beclinstop). The survival of mice infected with SIN/beclin was significantly higher (71%) than the survival of mice infected with SIN/beclinDeltaBcl-2BD (9%) or SIN/beclinstop (7%) (P < 0.001). The brains of mice infected with SIN/beclin had fewer Sindbis virus RNA-positive cells, fewer apoptotic cells, and lower viral titers than the brains of mice infected with SIN/beclinDeltaBcl-2BD or SIN/beclinstop. These findings demonstrate that Beclin is a novel Bcl-2-interacting cellular protein that may play a role in antiviral host defense.

Alphavirus Infections↗