Animal cytomegaloviruses.

Cytomegaloviruses are agents that infect a variety of animals. Human cytomegalovirus is associated with infections that may be inapparent or may result in severe body malformation. More recently, human cytomegalovirus infections have been recognized as causing severe complications in immunosuppressed individuals. In other animals, cytomegaloviruses are often associated with infections having relatively mild sequelae. Many of these sequelae parallel symptoms associated with human cytomegalovirus infections. Recent advances in biotechnology have permitted the study of many of the animal cytomegaloviruses in vitro. Consequently, animal cytomegaloviruses can be used as model systems for studying the pathogenesis, immunobiology, and molecular biology of cytomegalovirus-host and cytomegalovirus-cell interactions.     

The murine cytomegalovirus cell death suppressor m38.5 binds Bax and blocks Bax-mediated mitochondrial outer membrane permeabilization

Apoptosis is increasingly implicated as an early line of defense against viral infections. Viruses have devised numerous strategies to delay apoptosis of infected cells. Many viruses encode cell death suppressors that target mitochondrial apoptotic signaling pathway, indicating the importance of this pathway in the anti-viral response. Human and primate cytomegaloviruses encode the viral mitochondria-localized inhibitor of apoptosis vMIA, but no overt homologue of vMIA was identified in any non-primate cytomegalovirus. Here we report that m38.5 protein encoded by murine cytomegalovirus, which is unrelated to vMIA in its amino acid sequence, delays death receptor ligation-induced cell death, and that m38.5 associates with Bax, recruits it to mitochondria, and blocks Bax-mediated but not Bak-mediated mitochondrial outer membrane permeabilization. Thus, primate and murine cytomegaloviruses have evolved non-homologous but functionally similar cell death suppressors selectively targeting the Bax-mediated branch of the mitochondrial apoptotic signaling pathway, indicating the importance of this branch in the response of diverse host organisms against cytomegalovirus infections.     

Chronic congenital infections of man

This discussion focuses on the dynamic nature of three chronic congenital infections of man, namely those caused by cytomegaloviruses, rubella virus, and Toxoplasma gondii. The spectra of the fetal infection are described and the risks associated with the acute and chronic phases of the fetal infections are contrasted. Because of their frequency and subtlety, emphasis is placed on the late-appearing sequelae which are associated with the persistent and/or recurring aspects of these infections.     

Analysis and characterization of the complete genome of tupaia (tree shrew) herpesvirus

The tupaia herpesvirus (THV) was isolated from spontaneously degenerating tissue cultures of malignant lymphoma, lung, and spleen cell cultures of tree shrews (Tupaia spp.). The determination of the complete nucleotide sequence of the THV strain 2 genome resulted in a 195,857-bp-long, linear DNA molecule with a G+C content of 66.5%. The terminal regions of the THV genome and the loci of conserved viral genes were found to be G+C richer. Furthermore, no large repetitive DNA sequences could be identified. This is in agreement with the previous classification of THV as the prototype species of herpesvirus genome group F. The search for potential coding regions resulted in the identification of 158 open reading frames (ORFs) regularly distributed on both DNA strands. Seventy-six out of the 158 ORFs code for proteins that are significantly homologous to known herpesvirus proteins. The highest homologies found were to primate and rodent cytomegaloviruses. Biological properties, protein homologies, the arrangement of conserved viral genes, and phylogenetic analysis revealed that THV is a member of the subfamily Betaherpesvirinae. The evolutionary lineages of THV and the cytomegaloviruses seem to have branched off from a common ancestor. In addition, it was found that the arrangements of conserved genes of THV and murine cytomegalovirus strain Smith, both of which are not able to form genomic isomers, are colinear with two different human cytomegalovirus (HCMV) strain AD169 genomic isomers that differ from each other in the orientation of the long unique region. The biological properties and the high degree of relatedness of THV to the mammalian cytomegaloviruses allow the consideration of THV as a model system for investigation of HCMV pathogenicity.     

Tick-borne infections of animals and humans: a common ground

A wide variety of pathogens is transmitted from ticks to vertebrates including viruses, bacteria, protozoa and helminths, of which most have a life cycle that requires passage through the vertebrate host. Tick-borne infections of humans, farm and companion animals are essentially associated with wildlife animal reservoirs. While some flying insect-borne diseases of humans such as malaria, filariasis and Kala Azar caused by Leishmania donovani target people as their main host, major tick-borne infections of humans, although potentially causing disease in large numbers of individuals, are typically an infringement of a circulation between wildlife animal reservoirs and tick vectors. While new tick-borne infectious agents are frequently recognised, emerging agents of human tick-borne infections were probably circulating among wildlife animal and tick populations long before being recognised as clinical causes of human disease as has been shown for Borrelia burgdorferi sensu lato. Co-infection with more than one tick-borne infection is common and can enhance pathogenic processes and augment disease severity as found in B. burgdorferi and Anaplasma phagocytophilum co-infection. The role of wild animal reservoirs in co-infection of human hosts appears to be central, further linking human and animal tick-borne infections. Although transmission of most tick-borne infections is through the tick saliva, additional routes of transmission, shown mostly in animals, include infection by oral uptake of infected ticks, by carnivorism, animal bites and transplacentally. Additionally, artificial infection via blood transfusion is a growing threat in both human and veterinary medicine. Due to the close association between human and animal tick-borne infections, control programs for these diseases require integration of data from veterinary and human reporting systems, surveillance in wildlife and tick populations, and combined teams of experts from several scientific disciplines such as entomology, epidemiology, medicine, public health and veterinary medicine.     

Ocular herpes:the pathophysiology,management and treatment of herpetic eye diseases

Herpesviruses are a prominent cause of human viral disease, second only to the cold and influenza viruses. Most herpesvirus infections are mild or asymptomatic. However, when the virus invades the eye, a number of pathologies can develop and its associated sequelae have become a considerable source of ocular morbidity. The most common culprits of herpetic eye disease are the herpes simplex virus(HSV), varicella zoster virus(VZV), and cytomegalovirus(CMV). While primary infection can produce ocular disease, the most destructive manifestations tend to arise from recurrent infection. These recurrent infections can wreck devastating effects and lead to irreversible vision loss accompanied by a decreased quality of life, increased healthcare usage, and significant cost burden. Unfortunately, no method currently exists to eradicate herpesviruses from the body after infection. Treatment and management of herpes-related eye conditions continue to revolve around antiviral drugs, although corticosteroids, interferons, and other newer therapies may also be appropriate depending on the disease presentation. Ultimately, the advent of effective vaccines will be crucial to preventing herpesvirus diseases altogether and cutting the incidence of ocular complications.     

Ocular herpes: the pathophysiology,management and treatment of herpetic eye diseases

Herpesviruses are a prominent cause of human viral disease, second only to the cold and influenza viruses. Most herpesvirus infections are mild or asymptomatic. However, when the virus invades the eye, a number of pathologies can develop and its associated sequelae have become a considerable source of ocular morbidity. The most common culprits of herpetic eye disease are the herpes simplex virus (HSV), varicella zoster virus (VZV), and cytomegalovirus (CMV). While primary infection can produce ocular disease, the most destructive manifestations tend to arise from recurrent infection. These recurrent infections can wreck devastating effects and lead to irreversible vision loss accompanied by a decreased quality of life, increased healthcare usage, and significant cost burden. Unfortunately, no method currently exists to eradicate herpesviruses from the body after infection. Treatment and management of herpes-related eye conditions continue to revolve around antiviral drugs, although corticosteroids, interferons, and other newer therapies may also be appropriate depending on the disease presentation. Ultimately, the advent of effective vaccines will be crucial to preventing herpesvirus diseases altogether and cutting the incidence of ocular complications.     

Methicillin-resistant Staphylococcus aureus in animals

Methicillin-resistant Staphylococcus aureus (MRSA) is a critically important human pathogen that is also an emerging concern in veterinary medicine and animal agriculture. It is present in a wide range of animal species, including dogs, cats, rabbits, horses, cattle, pigs, poultry, and exotic species, both as a cause of infection and in healthy carriers. Identification of MRSA in various species and in food has led to concerns about the roles of animals, both pets and livestock, in the epidemiology of MRSA infection and colonization in humans. There is evidence of the role of food animals in human MRSA infections in some countries and of pets as a possible source of human infection. Some groups of individuals who work closely with animals, such as veterinarians, have high MRSA colonization rates. This article includes discussions of MRSA in human medicine, animals, and food, as well as its interspecies transmission, colonization, infection, strains, and affected populations. However, clear answers are lacking in many of these areas and limited studies may lead to premature conclusions. It is certain that animals are a source of human MRSA infection in some circumstances--but humans may also serve as sources of infection in animals. Changes in the epidemiology of MRSA in one species may be reflected in changes in other species. The true scope of MRSA in animals and its impact on human health are still only superficially understood, but it is clear that MRSA is a potentially important veterinary and public health concern that requires a great deal more study to enhance understanding and effective response.     

The use of transfer factors in chronic fatigue syndrome: prospects and problems

Chronic fatigue syndrome (CFS) is a heterogeneous disorder characterized by severe prolonged unexplained fatigue and a variety of associated symptoms such as arthralgias, myalgias, cognitive dysfunction, and severe sleep disturbances. Many patients initially present with an acute onset of apparent infectious origin with either an upper respiratory or gastrointestinal illness, fever, chills, tender lymphadenopathy, and malaise suggestive of a flu-like illness. In some cases, specific viral infections can be identified at the outset, particularly herpes viruses such as Epstein-Barr virus (EBV), human herpes virus-6 (HHV-6), and cytomegalovirus (CMV). Transfer factors (TF) with specific activity against these herpes viruses has been documented. With some studies suggesting that persistent viral activity may play a role in perpetuation of CFS symptoms, there appears to be a rationale for the use of TF in patients with CFS and recent reports have suggested that transfer factor may play a beneficial role in this disorder. This report focuses on the heterogeneity of CFS, the necessity for randomized coded studies, the importance of patient selection and sub-classification in clinical trials, and the need to utilize specific end-points for determining efficacy of treatment.     

Nonhuman primate infections after organ transplantation

Nonhuman primates, primarily rhesus macaques (Macaca mulatta), cynomolgus macaques (Macaca fascicularis), and baboons (Papio spp.), have been used extensively in research models of solid organ transplantation, mainly because the nonhuman primate (NHP) immune system closely resembles that of the human. Nonhuman primates are also frequently the model of choice for preclinical testing of new immunosuppressive strategies. But the management of post-transplant nonhuman primates is complex, because it often involves multiple immunosuppressive agents, many of which are new and have unknown effects. Additionally, the resulting immunosuppression carries a risk of infectious complications, which are challenging to diagnose. Last, because of the natural tendency of animals to hide signs of weakness, infectious complications may not be obvious until the animal becomes severely ill. For these reasons the diagnosis of infectious complications is difficult among post-transplant NHPs. Because most nonhuman primate studies in organ transplantation are quite small, there are only a few published reports concerning infections after transplantation in nonhuman primates. Based on our survey of these reports, the incidence of infection in NHP transplant models is 14%. The majority of reports suggest that many of these infections are due to reactivation of viruses endemic to the primate species, such as cytomegalovirus (CMV), polyomavirus, and Epstein-Barr virus (EBV)-related infections. In this review, we address the epidemiology, pathogenesis, role of prophylaxis, clinical presentation, and treatment of infectious complications after solid organ transplantation in nonhuman primates.     

Shell disease: abnormal conchiolin deposit in the abalone Haliotis tuberculata

Shell disease in the abalone Haliotis tuberculata L. is characterized by a conchiolin deposit on the inner surface of the shell. The gross clinical signs appear similar to the Brown Ring Disease (BRD) of clams. BRD has been extensively described in clams and is known to be responsible for severe mortalities and the collapse of the clam aquaculture industry in western France. In the clam, it was found to be caused by the infection of the mantle by Vibrio tapetis. Brown protein deposits have been observed in various abalone species around the world; some of these have been associated with a fungal infection in New Zealand, but the ones described here are similar to bacterial infections observed in clams. Larger animals appeared to be more affected by the disease, and a positive correlation of the number of successive infections found in the shells with the level of infestation of the shell by borers suggests that boring polychaetes and sponges may be vectors of the disease, or that the parasite infestation may increase the susceptibility of the animal to this infection. There is no evidence, however, that this infection causes mortality in abalone.     

Hemorrhagic fever of bunyavirus etiology: disease models and progress towards new therapies

A growing number of bunyaviruses are known to cause viral hemorrhagic fever (VHF), a severe febrile illness which can progress to hypovolemic shock and multi-organ failure and is characterized by hematologic abnormalities and vascular leak. At present, there are no approved vaccines or antiviral therapies to effectively prevent or treat VHF caused by pathogenic bunyaviruses. Advances in the modeling of bunyaviral infections have facilitated efforts towards the development of novel post-exposure prophylactic and therapeutic countermeasures, several of which may some day be approved for human use. Here, we review recent progress in animal models of severe bunyaviral infections essential to this mission, as well as promising antivirals and biologicals that are at various stages of the development process.     

The Relationship between Types of Human–Animal Interaction and Attitudes about Animals: An Exploratory Study

Existing theory and research suggests that understanding the nuances of particular instantiations of human–animal relationships is important in promoting positive, mutually beneficial relationships between people and animals. One such aspect of human–animal interaction (HAI) involves species of animal involved in the relationship, and how various types of HAI may impact individuals' attitudes about animals. Therefore, the purpose of this study was to explore if species and/or types of animal ownership were associated with feelings of emotional attachment, commitment, and moral orientation toward animals. A sample of young adults (n = 567) from the 4-H Study of Positive Youth Development completed a survey which included questions about animal ownership and attitudes about animals. Regression analyses demonstrated that the species of animal(s) a person owned significantly predicted all three dimensions of attitudes about animals. In addition, latent class analyses identified three prevalent types of animal interaction (no/few animals, small animals only, large and small animals), and multinomial logistic regression within the mixture model indicated that individuals in these subgroups significantly differed in moral orientation scores. Overall, the analyses strengthen support for the notion that species of animal involved in the interaction matters, and that relationships with various species of animals may differ qualitatively. These findings have implications for understanding the role of the relationship between types of animal ownership and attitudes about animals. Exploring the multifaceted nature of human–animal relationships is important in understanding how to optimize the person and animal characteristics that are associated with adaptive, mutually beneficial human–animal relationships.     

Genotype Distribution,Viral Load and Clinical Characteristics of Infants with Postnatal or Congenital Cytomegalovirus Infection

Background

Congenital cytomegalovirus infection is a leading cause of long-term sequelae. Cytomegalovirus is also frequently transmitted to preterm infants postnatally, but these infections are mostly asymptomatic. A correlation between cytomegalovirus genotypes and clinical manifestations has been reported previously in infants with congenital infection, but not in preterm infants with postnatal infection.

Objectives

The main objective of this study was to investigate cytomegalovirus genotype distribution in postnatal and congenital cytomegalovirus infection and its association with disease severity.

Methods

Infants admitted to the neonatal intensive care unit of the University Medical Center Utrecht, The Netherlands between 2003–2010 and diagnosed with postnatal or congenital cytomegalovirus infection were included. Classification of cytomegalovirus isolates in genotypes was performed upon amplification and sequencing of the cytomegalovirus UL55 (gB) and UL144 genes. Clinical data, cerebral abnormalities, neurodevelopmental outcome and viral load were studied in relation to genotype distribution.

Results

Genotyping results were obtained from 58 preterm infants with postnatal cytomegalovirus infection and 13 infants with congenital cytomegalovirus infection. Postnatal disease was mild in all preterm infants and all had favourable outcome. Infants with congenital infection were significantly more severely affected than infants with postnatal infection. Seventy-seven percent of these infants were symptomatic at birth, 2/13 died and 3/13 developed long-term sequelae (median follow-up 6 (range 2–8) years). The distribution of cytomegalovirus genotypes was comparable for postnatal and congenital infection. UL55 genotype 1 and UL144 genotype 3 were predominant genotypes in both groups.

Conclusions

Distribution of UL55 and UL144 genotypes was similar in asymptomatic postnatal and severe congenital CMV infection suggesting that other factors rather than cytomegalovirus UL55 and UL144 genotype are responsible for the development of severe disease.     

Immunogenicity of xenopeptide hormone therapies

Peptides are a growing class of agents whose therapeutic use originated with non-human treatments such as animal insulins. Xenopeptides continue to be explored for biotherapeutic development using genetic engineering, and through the rich resource of animal and plant polypeptides. One of the major concerns of therapeutic administration of xenopeptides is the potential for untoward immune responses that may lead to loss of drug efficacy or adverse events in recipients. An increased risk of immunogenicity is perceived with xenopeptides, however, human-derived therapies also induce antibody formation that in some cases has been associated with severe clinical sequelae. In this review, antibody responses to xenopeptides are highlighted looking at current hormone therapies used to treat endocrine disorders. Similar to clinical experiences with peptide-based agents in general, antibody responses against xenopeptide hormone therapies in majority of cases have been benign in nature with minimal clinical impact.     

Experimental congenital disease with simian cytomegalovirus in rhesus monkeys

Cytomegalovirus (CMV) infections occur worldwide and are responsible for severe damage to the child in from one to five newborns per 20,000 births. Animal models of congenital CMV infection resulting in disease have been developed in mice and guinea pigs. We report here the development of ventricular dilatation and leptomeningitis in rhesus monkeys, Macaca mulatta, following intrauterine infection with rhesus cytomegalovirus (RCMV). Central nervous system (CNS) lesions were associated with low cytomegalovirus fluorescent antibody titers in affected fetuses. In several infected animals, RCMV was isolated at necropsy from neural and nonneural tissues taken shortly after birth. This model allows investigators to study the pathogenesis and prevention of CNS changes following RCMV infection.     

Protective Efficacy of VP1-Specific Neutralizing Antibody Associated with a Reduction of Viral Load and Pro-Inflammatory Cytokines in Human SCARB2-Transgenic Mice

Hand-foot-mouth diseases (HFMD) caused by enterovirus 71 (EV71) and coxsackievirus 16 (CVA16) in children have now become a severe public health issue in the Asian-Pacific region. Recently we have successfully developed transgenic mice expressing human scavenger receptor class B member 2 (hSCARB2, a receptor of EV71 and CVA16) as an animal model for evaluating the pathogenesis of enterovirus infections. In this study, hSCARB2-transgenic mice were used to investigate the efficacy conferred by a previously described EV71 neutralizing antibody, N3. A single injection of N3 effectively inhibited the HFMD-like skin scurfs in mice pre-infected with clinical isolate of EV71 E59 (B4 genotype) or prevented severe limb paralysis and death in mice pre-inoculated with 5746 (C2 genotype). This protection was correlated with remarkable reduction of viral loads in the brain, spinal cord and limb muscles. Accumulated viral loads and the associated pro-inflammatory cytokines were all reduced. The protective efficacy of N3 was not observed in animals challenged with CVA16. This could be due to dissimilarity sequences of the neutralizing epitope found in CVA16. These results indicate N3 could be useful in treating severe EV71 infections and the hSCARB2-transgenic mouse could be used to evaluate the protective efficacy of potential anti-enterovirus agent candidates.     

Nonhuman primate models of intrauterine cytomegalovirus infection

Congenital human cytomegalovirus (HCMV) infection has long been recognized as a threat to the developing fetus, even though studies have shown that only a subset of congenital infections results in clinical signs of disease. Among the estimated 8000 children who develop sequelae from congenital CMV infection each year in the United States alone, most suffer permanent developmental defects within the central nervous system. Because there is currently no approved vaccine for HCMV, and anti-HCMV drugs are not administered to gravid women with congenital infection because of potential toxicity to the fetus, there is a clear clinical need for effective strategies that minimize infection in the mother, transplacental transmission of the virus, and/or fetal disease. Animal models provide a method to understand the mechanisms of HCMV persistence and pathogenesis, and allow for testing of novel strategies that limit prenatal infection and disease. The rhesus macaque model is especially well suited for these tasks because monkeys and humans share strong developmental, immunological, anatomical, and biochemical similarities due to their close phylogenetic relationship. This nonhuman primate model provides an invaluable system to accelerate the clinical development of promising new therapies for the treatment of human disease. This review addresses salient findings with the macaque model as they relate to HCMV infection and potential avenues of discovery, including studies of intrauterine CMV infection. The complexity of the natural history of HCMV is discussed, along with the ethical and logistical issues associated with studies during pregnancy, the recent contributions of animal research in this field of study, and future prospects for increasing our understanding of immunity against HCMV disease.