Congenital Cytomegalovirus Infection: New Prospects for Prevention and Therapy.
ABSTRACT Cytomegalovirus is the commonest congenital viral infection in the developed world, with an overall prevalence of approximately 0.6%. Approximately 10% of congenitally infected infants have signs and symptoms of disease at birth, and these symptomatic infants have a substantial risk of subsequent neurologic sequelae. These include sensorineural hearing loss, mental retardation, microcephaly, development delay, seizure disorders, and cerebral palsy. Antiviral therapy for children with symptomatic congenital cytomegalovirus infection is effective at reducing the risk of long-term disabilities and should be offered to families with affected newborns. An effective preconceptual vaccine against CMV could protect against long-term neurologic sequelae and other disabilities.
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ABSTRACT: Development of a vaccine against congenital cytomegalovirus (CMV) infection is a public health priority, but CMVs encode immune evasion genes that complicate live virus vaccine design. To resolve this problem, this study employed guanosyl phosphoribosyl transferase (gpt) mutagenesis to generate a recombinant guinea pig CMV (GPCMV) with a knockout of a viral chemokine gene, GPCMV MIP (gp1). MIP deletion virus replicated with wild-type kinetics in cell culture but was attenuated in nonpregnant guinea pigs, demonstrating reduced viremia and reduced inflammation and histopathology (compared to a control virus with an intact GPCMV MIP gene) following footpad inoculation. In spite of attenuation, the vaccine was immunogenic, eliciting antibody responses comparable to those observed in natural infection. To assess its protective potential as a vaccine, either recombinant virus or placebo was used to immunize seronegative female guinea pigs. Dams were challenged in the early 3rd trimester with salivary gland-adapted GPCMV. Immunization protected against DNAemia (1/15 in vaccine group versus 12/13 in the control group, P < 0.01). Mean birth weights were significantly higher in pups born to vaccinated dams compared to controls (98.7 g versus 71.2 g, P < 0.01). Vaccination reduced pup mortality, from 35/50 (70%) in controls to 8/52 (15%) in the immunization group. Congenital GPCMV infection was also reduced, from 35/50 (70%) in controls to 9/52 (17%) in the vaccine group (P < 0.0001). We conclude that deletion of an immune modulation gene can attenuate the pathogenicity of GPCMV while resulting in a viral vaccine that retains immunogenicity and demonstrates efficacy against congenital infection and disease.Clinical and Developmental Immunology 08/2013; 2013:906948. DOI:10.1155/2013/906948 · 2.93 Impact Factor
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ABSTRACT: Fetal and neonatal infections caused by human cytomegalovirus (CMV) are important causes of morbidity and occasional mortality. Development of a vaccine against congenital CMV infection is a major public health priority. Vaccine design is currently focused on strategies that aim to elicit neutralizing antibody and T-cell responses, toward the goal of preventing primary or recurrent infection in women of child-bearing age. However, there has been relatively little attention given to understanding the mechanisms of immune protection against acquisition of CMV infection in the fetus and newborn and how this information might be exploited for vaccine design. There has similarly been an insufficient study of what deficits in the immune response to CMV, both for mother and fetus, may increase susceptibility to congenital infection and disease. Protection of the fetus against vertical transmission can likely be achieved by protection of the placenta, which has its own unique immunological milieu, further complicating the analysis of the correlates of protective immunity. In this review, the current state of knowledge about immune effectors of protection against CMV in the maternal, placental, and fetal compartments is reviewed. A better understanding of immune responses that prevent and/or predispose to infection will help in the development of novel vaccine strategies.Clinical and Developmental Immunology 08/2013; 2013:501801. DOI:10.1155/2013/501801 · 2.93 Impact Factor
Article: Syndromic Hearing Loss: an update[Show abstract] [Hide abstract]
ABSTRACT: Hearing impairment is one of the commonest clinical conditions. It has been estimated that approximately 1 in 10 persons has hearing concerns. Further epidemiological studies have found that the percentage of the general population with hearing loss greater than 45 dB HL and 65 dB HL is 1.3% and 0.3%, respectively, between 30 and 50 years of age; and 2.3% and 7.4% between 60 and 70 years of age. The prevalence of childhood and adolescent hearing loss is around 3%. At birth, between one and two out of 1000 newborns are affected by hearing loss of such a degree as to require treatment (auditory training and rehabilitation, hearing aids or cochlear implantation). To summarize, hearing impairment affects up to 30% of the international community and estimates indicate that 70 million persons are deaf. The causes of hearing loss differ and they can vary in severity and physiopathology. In many cases it is not possible to define a definite aetiology. Nevertheless, it is known that most are due to a genetic cause and among these the majority appear in a non-syndromic form. The aetiology of hearing loss in children is unknown in 40% of cases, genetic non-syndromic in 30%, and genetic syndromic in 3–5%. The two most common genes involved in hearing loss are GJB2 and SLC26A4. Mutations in these genes can be responsible for syndromic hearing loss, as keratitis ichthyosis deafness (KID) and Pendred syndromes, respectively, or non-syndromic hearing loss (as DFNB1 and DFNB4, respectively). DFNB1 with GJB2 mutations is the most common non-syndromic form and Pendred syndrome is the most common syndromic form. Neither of these last two is usually characterized by congenital macroscopic dysmorphic features, and affected children can be generally considered as well babies. Nonetheless, 2–4% of live births have congenital malformations, most commonly caused by multifactorial defects, followed by chromosomal disorders, single gene mutations and teratogens (alcohol, drugs). Some of these conditions could directly affect the auditory system and be responsible for sensorineural, conductive or mixed hearing loss. The London Dysmorphology Database lists approximately 400 syndromes that include hearing loss among the clinical features. Other conditions such as cystic fibrosis are not usually responsible for hearing loss but they can indirectly affect the auditory system as a consequence of the management of the disease. Other systemic disorders can lead to hearing impairment when the disease involves a part of the auditory system from the external ear to the auditory cortex. From this standpoint there are a huge number of syndromes or conditions that can directly or indirectly cause hearing impairment. They can be responsible for congenital or prelingual, progressive and post-lingual hearing loss, with sensorineural, mixed or conductive deficits. In this updating research we have focused on syndromic forms that are known to be associated with hearing loss or that directly affect the auditory system. Some conditions of particular interest, or with high incidence, are also included.08/2013; DOI:10.3109/21695717.2013.820514