The pig: a model for human infectious diseases

An animal model to study human infectious diseases should accurately reproduce the various aspects of disease. Domestic pigs (Sus scrofa domesticus) are closely related to humans in terms of anatomy, genetics and physiology, and represent an excellent animal model to study various microbial infectious diseases. Indeed, experiments in pigs are much more likely to be predictive of therapeutic treatments in humans than experiments in rodents. In this review, we highlight the numerous advantages of the pig model for infectious disease research and vaccine development and document a few examples of human microbial infectious diseases for which the use of pigs as animal models has contributed to the acquisition of new knowledge to improve both animal and human health.     

Leprosy as a genetic model for susceptibility to common infectious diseases

Leprosy (Hansen’s disease) is a human infectious disease that can be effectively treated with long-term administration of multi-drug therapy. In 2006, over 250,000 new cases were reported to the World Health Organization. In the nineteenth century, disagreement among leprologists regarding the hereditary or infectious nature of leprosy was resolved with the identification of the etiological agent, Mycobacterium leprae. However, epidemiological studies maintain the importance of host genetics in leprosy susceptibility. A model free genome-wide linkage scan in multi-case families from Vietnam led to the positional cloning of global genetic risk factors in the PARK2/PACRG and LTA genes. The process of identifying the susceptibility variants provided invaluable insight into the replication of genetic effects, particularly the importance of considering population-specific linkage-disequilibrium structure. As such, these studies serve to improve our understanding of leprosy pathogenesis by implicating novel biological pathways while simultaneously providing a genetic model for common infectious diseases.     

The guinea pig as an animal model for developmental and reproductive toxicology studies

BACKGROUND : Regulatory guidelines for developmental and reproductive toxicology (DART) studies require selection of “relevant” animal models as determined by kinetic, pharmacological, and toxicological data. Traditionally, rats, mice, and rabbits are the preferred animal models for these studies. However, for test articles that are pharmacologically inactive in the traditional animal models, the guinea pig may be a viable option. This choice should not be made lightly, as guinea pigs have many disadvantages compared to the traditional species, including limited historical control data, variability in pregnancy rates, small and variable litter size, long gestation, relative maturity at birth, and difficulty in dosing and breeding. METHODS : This report describes methods for using guinea pigs in DART studies and provides results of positive and negative controls. Standard study designs and animal husbandry methods were modified to allow mating on the postpartum estrus in fertility studies and were used for producing cohorts of pregnant females for developmental studies. RESULTS : A positive control study with the pregnancy-disrupting agent mifepristone resulted in the anticipated failure of embryo implantation and supported the use of the guinea pig model. Control data for reproductive endpoints collected from 5 studies are presented. CONCLUSION : In cases where the traditional animal models are not relevant, the guinea pig can be used successfully for DART studies. Birth Defects Res (Part B)86: 92-97, 2009. © 2009 Wiley-Liss, Inc.     

Pathogenesis of cytomegalovirus-associated labyrinthitis in a guinea pig model

Cytomegalovirus infects fetuses through the placenta, resulting in various congenital disorders in newborns, including hearing loss. We developed a monoclonal antibody to guinea pig cytomegalovirus (GPCMV) that was available for immunohistochemistry, and investigated the expression of the GPCMV antigen in animal models of direct and congenital infections. Injection of GPCMV, directly to the inner ear, increased the sound pressure level and resulted in labyrinthitis with severe inflammation. Immunohistochemistry detected GPCMV-infected cells mainly in the scala tympani, scala vestibule and spinal ganglion, but rarely in the cochlear duct. Injection of GPCMV to 5-week pregnant guinea pigs resulted in severe labyrinthitis in fetuses. Immunohistochemistry detected GPCMV-infected cells in the perilymph area and spinal ganglion, but not in the endolymph area, including hair cells. These data suggest that the virus spreads via the perilymph and neural routes in the inner ear of both models of direct and congenital infections.     

Oscillatory phenomena in a model of infectious diseases

Oscillations of the number of cases around an average endemic level are common in several infectious diseases. In this paper we study simple deterministic models, where the oscillations arise either solely from periodically varying contact rates or from the combined effect of large initial perturbation, small periodic variation of the contact rate, and the destabilizing nature of infectious and latent periods when described as time delays. The main results are: (a) For a model with a periodically varying contact rate and a recovery rate, a threshold amplitude of variation is found by numerical and analytic methods at which 2-year subharmonic resonance appears. (b) Approximate analytic relationships are derived for the amplitude and phase of the forced 1-year oscillations below this threshold and for the 2-year oscillations above it—in terms of the reproduction rate of the infection. (c) Similar calculations are performed when the recovery rate is replaced by a fixed infectious period represented by a pure time delay. The threshold amplitude of variation in the contact rate is found here to be smaller than in the recovery rate model. (d) A model with a fixed infectious period and a constant contact rate is considered. The nontrivial steady state is shown to be locally stable for the parameter range of interest. However, the ratio of the imaginary to real parts of the eigenvalues in the characteristic equation is increased as compared to the corresponding model with a recovery rate. (e) For the model with a fixed infectious period and a constant contact rate an approximation method indicates consistency in a certain range of contact rates with the existence of an unstable periodic solution about the locally stable steady state. The actual existence of such a solution is not verified. The interpretation is that the destabilizing effect of the introduction of a pure delay into the model becomes more significant as the distance in the variables space from the endemic steady state is increased. (f) For a fixed infectious period and very small subthreshold variation in the contact rate, two different types of solutions are found numerically: yearly small-amplitude oscillations about an endemic average and large-amplitude oscillations of a subharmonic period. The pattern seen depends on the initial conditions. For a sufficiently large initial deviation from the endemic level even very small seasonal variations lead to regular recurrent outbreaks of the disease. The effect of latent periods and of changing the form of the interaction are also considered.     

Open-thorax guinea pig model for defibrillation

BACKGROUND AND PURPOSE: Guinea pigs are used as models for study of ventricular tachyarrhythmias (VT); however, the tachyarrhythmia often is transient and does not persist. We developed an open-thorax guinea pig model of sustained ventricular fibrillation (VF). METHODS: Bilateral thoracotomy was performed on eight guinea pigs weighing 865 to 1,464 g, and two sutures were positioned in the right ventricular apex for the purpose of pacing. Two methods were used to induce VF: a 50-Hz burst (normal pacing), and an initial 15 beats at 70% of the R-R interval followed by a 100-Hz burst for 84 beats (rapid pacing). Fifteen attempts at inducing VF were performed by use of each method. Blood pressure was recorded before and after development of VF, which was defined as VT with mean blood pressure consistently <10 mm Hg. A final observation was obtained using the normal pacing method without defibrillation. RESULTS: Use of both methods successfully induced VF. A significant relationship between body weight >1,021 g and ability to sustain and survive VF was detected. CONCLUSION: The guinea pig is a useful rodent model for the study of VF and defibrillation.     

Emotions as infectious diseases in a large social network: the SISa model

Human populations are arranged in social networks that determine interactions and influence the spread of diseases, behaviours and ideas. We evaluate the spread of long-term emotional states across a social network. We introduce a novel form of the classical susceptible–infected–susceptible disease model which includes the possibility for ‘spontaneous’ (or ‘automatic’) infection, in addition to disease transmission (the SISa model). Using this framework and data from the Framingham Heart Study, we provide formal evidence that positive and negative emotional states behave like infectious diseases spreading across social networks over long periods of time. The probability of becoming content is increased by 0.02 per year for each content contact, and the probability of becoming discontent is increased by 0.04 per year per discontent contact. Our mathematical formalism allows us to derive various quantities from the data, such as the average lifetime of a contentment ‘infection’ (10 years) or discontentment ‘infection’ (5 years). Our results give insight into the transmissive nature of positive and negative emotional states. Determining to what extent particular emotions or behaviours are infectious is a promising direction for further research with important implications for social science, epidemiology and health policy. Our model provides a theoretical framework for studying the interpersonal spread of any state that may also arise spontaneously, such as emotions, behaviours, health states, ideas or diseases with reservoirs.     

Development and characterization of a guinea pig model for Marburg virus

The Angolan strain of Marburg virus(MARV/Ang) can cause lethal disease in humans with a case fatality rate of up to 90%, but infection of immunocompetent rodents do not result in any observable symptoms. Our previous work includes the development and characterization of a MARV/Ang variant that can cause lethal disease in mice(MARV/Ang-MA), with the aim of using this tool to screen for promising prophylactic and therapeutic candidates. An intermediate animal model is needed to confirm any findings from mice studies before testing in the gold-standard non-human primate(NHP) model. In this study, we serially passaged the clinical isolate of MARV/Ang in the livers and spleens of guinea pigs until a variant emerged that causes 100% lethality in guinea pigs(MARV/AngGA). Animals infected with MARV/Ang-GA showed signs of filovirus infection including lymphocytopenia, thrombocytopenia, and high viremia leading to spread to major organs, including the liver, spleen, lungs, and kidneys. The MARV/Ang-GA guinea pigs died between 7–9 days after infection, and the LD50 was calculated to be 1.1×10~(–1) TCID_(50)(median tissue culture infective dose). Mutations in MARV/Ang-GA were identified and compared to sequences of known rodent-adapted MARV/Ang variants, which may benefit future studies characterizing important host adaptation sites in the MARV/Ang viral genome.     

The pig as a model of tachycardia and dilated cardiomyopathy

Chronic Supraventricular Tachycardia (SVT) can produce a dilated cardiomyopathy which has a poorly understood association with ventricular dysfunction in humans and animals. The purpose of this study was to produce a model of chronic SVT and dilated cardiomyopathy using swine, which have a cardiac anatomy similar to man. Eight pigs were implanted with chronic atrial catheters and a pacemaker, with four additional sham-operated pigs serving as controls. We examined ventricular function and morphology at baseline (120 +/- 3 bpm), pacing baseline (240 bpm), and at 1, 2 and 3 weeks of rapid atrial pacing (240 bpm). Ventricular ejection fractions fell significantly from baseline following 1 week (left: 38 +/- 3% vs baseline 61 +/- 1%; right: 31 +/- 5% vs baseline 56 +/- 1%; p less than 0.05) and deteriorated further by 3 weeks of SVT (left: 26 +/- 4%, right: 19 +/- 3%; p less than 0.05). Significant biventricular chamber dilation developed by 2 weeks of SVT (left: 50 +/- 5 cc vs paced baseline 27 +/- 2 cc; right: 67 +/- 6 cc vs paced baseline 28 +/- 3 cc; p less than 0.05) and continued to increase by week 3 of SVT (left: 66 +/- 11 cc; right: 78 +/- 8 cc; p less than 0.05). Five additional paced pigs, without chronic atrial catheters, were followed using echocardiography.(ABSTRACT TRUNCATED AT 250 WORDS)     

The pig as a model for myocardial ischemia and exercise

The pig has been well characterized as an appropriate model for the study of coronary physiology, the coronary collateral circulation and exercise physiology. We compared both Yucatan miniature swine and young farm pigs in experiments involving myocardial ischemia, infarction and exercise. The Yucatan pig was vigorous, docile and proved to be an appropriate model of coronary physiology and exercise in man. The exercise capacity of the Yucatan pig was greater than that of the similar weight Hampshire pig, apparently because of the higher hematocrit and larger heart size. Both breeds were able to increase their maximal oxygen consumption (VO2 max) by approximately 25% after 10 weeks of training. Experiments measuring maximal coronary capacity suggest that the vascular capacity was similar to that of man, but less than that of the dog. Acute occlusion of the coronary artery in pigs infarcted most of the tissue of the vascular bed at risk. The collateral circulation of the pig is less than one fourth that of the dog and is similar to that of man. Slow occlusion of the left circumflex coronary artery produces an ischemic vascular bed which is collaterally dependent with only 5% infarction. Collateral flow is sufficient to meet resting conditions, but during exercise, severe ischemia is unmasked. This ischemia is present for up to 16 weeks following occlusion. The observation of limited infarction in conjunction with limited collateral vessel development suggests that this is a good model for investigating the growth and development of coronary collateral circulation in man.     

Dietary phytoestrogens have anti-inflammatory activity in a guinea pig model of asthma

Phytoestrogens are a normal constituent of soy protein and have been shown to have anti-inflammatory activity in various in vitro and in vivo models. The present study was designed to determine if a diet enriched in the phytoestrogen isoflavones, genistin and daidzin, would alter the antigen-induced cellular infiltration, particularly eosinophilia, characteristic of a guinea pig model of asthma. Throughout the duration of the study, guinea pigs were maintained on a control diet (standard guinea pig chow) or the same diet enriched in isoflavones. The animals were placed on the diet 2 weeks prior to active sensitization with ovalbumin (OA). Three weeks after sensitization, animals were challenged with OA aerosol. The cellular infiltration into the lung and protein and red blood cells (RBC) in the bronchoalveolar lavage fluid (BAL) were determined 17 hr later. In animals maintained on the control diet, OA aerosol challenge resulted in the expected increase in eosinophils in both the BAL and the lung tissue, an increase in neutrophils in the BAL, and an increase in protein and the number of RBC in the BAL. In contrast, in animals maintained on the isoflavone diet, the OA-induced eosinophilia in the lung tissue was significantly attenuated. In addition, OA challenge caused a greater increase in BAL protein in animals maintained on the isoflavone diet compared with animals on the control diet. Our results indicated that a diet enriched in isoflavones results in reduced antigen-induced eosinophilia in the lung in the guinea pig model of asthma. However, this beneficial anti-inflammatory effect of dietary phytoestrogens is accompanied by a potentially detrimental increase in antigen-induced leakage of protein into the airspace.     

An experimental model of ameboma in guinea pig.

Among the wide variety of clinicopathological manifestations of intestinal amebiasis, amebomas occur rarely and their pathogenesis is not well understood. When cholesterol-fed, 2- to 4-week-old guinea pigs were infected intracecally with a virulent, monoaxenic strain of Entamoeba histolytica, gross and histologically characteristic amebomas developed in 85% of the animals by the 3rd day, in 94% by the 9th day, and in 96% by the 12th day postinfection, by which time most of them had died. Amebomas were confirmed by histopathology. Thus, a model of consistent production of amebomas was documented.     

Global dynamics of a staged-progression model with amelioration for infectious diseases

We analyze the global dynamics of a mathematical model for infectious diseases that progress through distinct stages within infected hosts with possibility of amelioration. An example of such diseases is HIV/AIDS that progresses through several stages with varying degrees of infectivity; amelioration can result from a host's immune action or more commonly from antiretroviral therapies, such as highly active antiretroviral therapy. For a general n-stage model with constant recruitment and bilinear incidence that incorporates amelioration, we prove that the global dynamics are completely determined by the basic reproduction number R(0). If R(0)≤1, then the disease-free equilibrium P(0) is globally asymptotically stable, and the disease always dies out. If R(0)>1, P(0) is unstable, a unique endemic equilibrium P* is globally asymptotically stable, and the disease persists at the endemic equilibrium. Impacts of amelioration on the basic reproduction number are also investigated.     

The structure of immunoregulatory cells as a reflection of their interaction in infectious diseases

Analysis of the structure of immunoregulatory cells (IRC) as the reflection of cell interaction in healthy persons and in patients with typhoid fever, tick-borne encephalitis, or chronic opisthorchiasis has shown that the characteristics under study (information entropy, structural information, the coefficient of ecological-genetic correspondence) are highly sensitive and specific, which makes it possible to use them quite effectively for differentiating health from disease and for identifying this disease. The study of IRC structure as the reflection of cell interrelations helps evaluate the changes in the organization of IRC system as a whole in different infectious diseases.     

The Rhesus monkey as a model for the study of infectious disease

Models for bacterial and viral infections and intoxication were developed in rhesus macaques (Macaca mulatta). Manifestations of acute-phase illnesses, e.g., temperature, white blood cell (WBC) counts, blood cultures, etc., were monitored at regular intervals. Viral infection was established by inoculating subcutaneously 412 plaque-forming units of Trinidad strain, Venezuelan equine encephalomyelitis virus. A diphasic febrile response developed, with the first fever peak on days 1 to 2 and a second peak on days 3 to 5. Viremia occurred within 12 hours and persisted in some animals for as long as five days. WBC responses were typical of viral infection. Gram-positive infections were induced by intravenous (IV) inoculation of 10⁸ Type I Diplococcus pneumoniae. Peak febrile response and bacteremia (10² to 10⁶ pneumococci per milliliter) occurred within 48 hours. Gram-negative infections, obtained by IV inoculation with 10⁹ Salmonella typhimurium, induced maximal febrile responses within 24 to 48 hours. Leukopenia occurred in 75% of animals; all were bacteremic. Mortality was 40% at 72 hours. Manifestations of intoxication following IV administration of purified staphylococcal enterotoxin B (10 μg per kg body weight) consisted of vomiting, diarrhea, leukopenia, and fever within one to three hours and resembled nonlethal staphylococcal food poisoning of man. These studies indicate that the rhesus macaque has reproducible and characteristic responses to a variety of microbial stimuli and therefore is eminently suitable for studying pathophysiologic, metabolic, and immunologic parameters of infectious or toxic disease processes.