While affecting all age groups, respiratory syncytial virus (RSV) infections can be particularly severe in infants, who develop functionally distinct immune responses, as well as in immunocompromised individuals. The extent to which environmental, viral and host factors contribute to the pathogenesis of RSV varies considerably between infected individuals. A correlation between the level of virus replication and pathogenesis has been established, and several viral proteins, in particular NS1 and NS2, modulate the immune response. Host immunity clearly contributes to RSV pathogenesis, and a number of specific cell populations may be involved. Ultimately, whether the response induced by RSV is protective or pathogenic depends on a combination of host factors, young age being one of the most important ones.
Dermatophyte research is poised to take off. The sequencing of seven dermatophyte genomes was recently completed, and the sequence information is now publically available. Analysis of the genome sequences demonstrates that a group of proteinases necessary for degradation of keratin is increased in number in the dermatophytes compared to closely related fungal species. These genome sequences, combined with better genetic tools and a promising model in which to study virulence, provide an optimistic outlook. Sequence information can be used to make informed hypotheses about which gene products, such as the proteinases, are important to virulence, and these genes can be deleted and tested in virulence models. These experiments will contribute to our understanding of how dermatophytes interact with human cells and cause disease. Knowing the fungal factors involved will allow development of better therapeutics and will inform preventative treatments.
The finding that prions can acquire resistance to drugs has significant implications for drug design. Drugs targeted to PrPSc may have to be administered in combination, as in the case of viruses, in particular HIV. Alternatively, drugs could be targeted to bind and stabilize PrPC or, in view of the finding that ablation of PrPC, at least in animals, is not detrimental to health, to suppress its synthesis. At present no therapeutically useful drugs are available, but deepening insight into the molecular biology of prions may pave the way to novel approaches.
Currently, no vaccine exists for hepatitis C virus (HCV), a major pathogen thought to infect 170 million people globally. Many studies suggest that host T cell responses are critical for spontaneous resolution of disease, and preclinical studies have indicated a requirement for T cells in protection against challenge. Recent research aimed to elicit HCV-specific T cells with the potential for protection using a recombinant adenoviral vector strategy in a phase 1 study of healthy human volunteers.
Two adenovirus vectors expressing NS proteins from HCV genotype 1B were constructed based on rare serotypes [human adenovirus 6 (Ad6) and chimpanzee adenovirus 3 (ChAd3)]. Both vectors primed T cell responses against HCV proteins; these T cell responses targeted multiple proteins and were capable of recognizing heterologous strains (genotypes 1A and 3A). HCV-specific T cells consisted of both CD4+ and CD8+ T cell subsets; secreted interleukin-2, interferon-γ, and tumor necrosis factor–α; and could be sustained for at least a year after boosting with the heterologous adenoviral vector. Studies using major histocompatibility complex peptide tetramers revealed long-lived central and effector memory pools that retained polyfunctionality and proliferative capacity. These data indicate that an adenoviral vector strategy can induce sustained T cell responses of a magnitude and quality associated with protective immunity and open the way for studies of prophylactic and therapeutic vaccines for HCV.
HIV-1 has been analysed by structural biology techniques more than any other virus, with partial or complete structures known for all 15 of its protein components and additional structures determined for substrate- and host factor-bound complexes. Three-dimensional molecular structures can provide detailed information on biological mechanisms and, for cases in which the molecular function affects human health, can significantly aid in the development of therapeutic interventions.
For almost 25 years, key components of the lentivirus HIV-1, including the envelope glycoproteins, the capsid and the replication enzymes reverse transcriptase, integrase and protease, have been scrutinized to near atomic-scale resolution. Moreover, structural analyses of the interactions between viral and host cell components have yielded key insights into the mechanisms of viral entry, chromosomal integration, transcription and egress from cells. This review article discusses recent advances in HIV-1 structural biology, focusing on the molecular mechanisms of viral replication and on the development of new therapeutics:
Haemoglobin, which gives blood its red color, is perhaps the most recognized and well studied protein in nature. It is also a critical molecule during infection, as many microbes rely on hemoglobin to grow within their hosts. This paper reviews the importance of hemoglobin to vertebrate physiology and how humans attempt to conceal hemoglobin from invading pathogens. It gives examples of the elaborate mechanisms employed by microbes to acquire hemoglobin during infection, and discusses how genetic variations within hemoglobin affect susceptibility to infectious diseases.
Prion diseases are fatal neurodegenerative disorders that are also infectious. Prions are composed of a misfolded, aggregated form of a normal cellular protein that is highly expressed in neurons. Prion-infected individuals show variability in the clinical signs and brain regions that selectively accumulate prions, even within the same species expressing the same prion protein sequence. The basis of these divergent disease phenotypes is unclear, but is thought to be due to different conformations of the misfolded prion protein, known as strains.
Researchers have characterized the neuropathology and biochemical properties of prion strains that efficiently or poorly invade the CNS from their peripheral entry site. Prion strains that efficiently invade the CNS also cause a rapidly terminal disease after an intracerebral exposure. These rapidly lethal strains were unstable when exposed to denaturants or high temperatures, and efficiently accumulated misfolded prion protein over a short incubation period in vivo. These findings indicate that the most invasive, rapidly spreading strains are also the least conformationally stable.
Biochemical Properties of Highly Neuroinvasive Prion Strains. (2012) PLoS Pathog 8(2): e1002522. doi:10.1371/journal.ppat.1002522
Infectious prions propagate from peripheral entry sites into the central nervous system (CNS), where they cause progressive neurodegeneration that ultimately leads to death. Yet the pathogenesis of prion disease can vary dramatically depending on the strain, or conformational variant of the aberrantly folded and aggregated protein, PrPSc. Although most prion strains invade the CNS, some prion strains cannot gain entry and do not cause clinical signs of disease. The conformational basis for this remarkable variation in the pathogenesis among strains is unclear. Using mouse-adapted prion strains, here we show that highly neuroinvasive prion strains primarily form diffuse aggregates in brain and are noncongophilic, conformationally unstable in denaturing conditions, and lead to rapidly lethal disease. These neuroinvasive strains efficiently generate PrPSc over short incubation periods. In contrast, the weakly neuroinvasive prion strains form large fibrillary plaques and are stable, congophilic, and inefficiently generate PrPSc over long incubation periods. Overall, these results indicate that the most neuroinvasive prion strains are also the least stable, and support the concept that the efficient replication and unstable nature of the most rapidly converting prions may be a feature linked to their efficient spread into the CNS.
Before they spread to the brain, prions often multiply in the lymphatic system –the group of organs that includes the spleen, lymph nodes, appendix and tonsils. Prions can hide in these tissues, turning individuals into silent carriers even if they never actually develop disease. Worse still, the spleen provides an easy entry-point for prions, allowing them to jump more easily from one species to another.
Facilitated cross-species transmission of prions in extraneural tissue. Science (2012) 335(6067): 472-475
Prions are infectious pathogens essentially composed of PrP(Sc), an abnormally folded form of the host-encoded prion protein PrP(C). Constrained steric interactions between PrP(Sc) and PrP(C) are thought to provide prions with species specificity and to control cross-species transmission into other host populations, including humans. We compared the ability of brain and lymphoid tissues from ovine and human PrP transgenic mice to replicate foreign, inefficiently transmitted prions. Lymphoid tissue was consistently more permissive than the brain to prions such as those causing chronic wasting disease and bovine spongiform encephalopathy. Furthermore, when the transmission barrier was overcome through strain shifting in the brain, a distinct agent propagated in the spleen, which retained the ability to infect the original host. Thus, prion cross-species transmission efficacy can exhibit a marked tissue dependence.
Rabies is an preventable virus disease transmitted from infected animals to other warm blooded animals (zoonotic), especially human. Rabies occurs in more than 150 countries and territories. According to an estimation by WHO, almost 55,000 people die because of rabies every year. Dogs are the major reason behind this, approximately 99% human deaths caused by dog’s bites. Developing and under developing countries, both are the victims of rabies. With the post-exposure preventive regimes, 327,000 people can prevent this disease annually. This article is a short overview of the rabies virus genome, virology, symptoms, epidemiology, diagnostic methods, and the high risk countries around the globe.
While affecting all age groups, respiratory syncytial virus (RSV) infections can be particularly severe in infants, who develop functionally distinct immune responses, as well as in immunocompromised individuals. The extent to which environmental, viral and host factors contribute to the pathogenesis of RSV varies considerably between infected individuals. A correlation between the level of virus replication and pathogenesis has been established, and several viral proteins, in particular NS1 and NS2, modulate the immune response. Host immunity clearly contributes to RSV pathogenesis, and a number of specific cell populations may be involved. Ultimately, whether the response induced by RSV is protective or pathogenic depends on a combination of host factors, young age being one of the most important ones.
