Molecular features of infective disease

 
OVERVIEW OF PROKARYOTES

Infectious agents demonstrate a vast repertoire of successful molecular strategies profoundly different from the mam malian (or to be precise, human) regulation which has been discussed so far. Prokaryotic cells do not possess a nucleus, and generally have smaller genomes than humans.For example, bacterial genomes are around 1/1000 to 1/10000 the size of the human genome, and viral genomes a further two to three orders of magnitude smaller. However, the organisation of their genes is more elaborate than in humans, with the same stretch of bases coding for several genes reading in different directions, or in different frames Instead of organisation into linear chromosomes, the DNA in many bacteria such as Escherichia coli is organised in a circular form. Different viral species use either DNA or RNA as their nucleic acid, and these may be linear or circular.

Although prokaryotes will be discussed in detail in Chapter 2, this section will be used to introduce two of the different mechanisms.

HIV-A RETROVIRUS WITH AN RNA GENOME

HIV, a member of the Lentivirinae subgroup of retroviruses, has an RNA genome, with each mature spherical HIV-1 particle containing two positive strands of viral RNA. These linear strands encode critical viral genes. In addition to RNA, the viral core contains reverse transcriptase, structural proteins derived from the gag gene, and additional regulatory proteins. The core surrounded by a matrix and the entire structure enveloped by an outer lipid-bilayer membrane. Embedded in the membrane are proteins derived from the viral env gene (gp120 and gp41), on and various immune molecules, especially MHC class II in molecules derived on budding from a human cell. In part due to the high replication error rate of the reverse transcriptase, HIV-1 displays marked genetic variability, especially in the gp120 region, rendering vaccine development more difficult.

The virus recognises susceptible host cells via its highaffinity receptor, the CD4+ antigen, but fusion of viral and host cell membranes requires a co-receptor, such as CCR5 in initial infections. The virus then injects its RNA, gag and pol proteins, and DNA reverse-transcribed from the RNA template. The resultant double-stranded proviral DNA migrates to the nucleus where it uses the long terminal repeat sequences to integrate into the host chromosomes, particularly of replicating cells. According to the state of the cell and supply of factors activating the HIV promoter, the viral sequences may remain latent or be transcribed to produce viral proteins which assemble into new virions and bud from the cell surface. The consequences of such infection are discussed in Chapter 2.

The susceptibility of a particular individual to infection by HIV is in part determined by sequence variations in co-receptors such as CCR5. Some accelerate and o delay disease progression. For example, some indi (= 1% in Western Europe) who appear relatively res HIV infection are homozygous for a 32 bp deletion (CCR5A32) and do not express a functioning CCR5 receptor .There appear to be no ill effects for European homozygotes, probably reflecting the fact that other receptors may compensate or that functioning CCR5 is only required for immunity against infections that are not endemic temperate zones. In contrast to previous examples, mutation' would therefore appear to be beneficial.

PRION DISEASES-THE RESULT OF AN INFECTIOUS PROTEIN SPECIES?

A group of inexorably progressive neurodegenerative conditions affecting several species are transmissible from affected individuals, though a long incubation period (averaging over 10 years in humans) is characteristic. In humans, the best-known forms are Creutzfeldt-Jakob disease (CJD) and kuru, the clinical consequences of which are discussed on page 1016.

The predominant if not sole component of the infectious particle is a protein, termed PrP. This is expressed in all mammalian brains as the soluble cellular PrPC, which becomes infectious if it acquires a new conformation rendering it insoluble, as in the scrapie agent (PrpSc). Normally, PrPC only rarely adopts this conformation (accounting for the occasional sporadic cases of CJD), but inherited mutations in the PrP gene render this more likely and result in the familial forms of disease. Most importantly, once one PrpSc molecule is present within a cell, it acts as a template to enhance the conversion of the normal PrPC to PrPSc, resulting in pathogenesis.

The BSE story in the UK

Prior to 1980, the prion disease bovine spongiform encephalopathy (BSE) was virtually unknown in UK cattle populations, although scrapie, a similar disease affecting sheep, had been endemic for over 30 years and cattle were fed sheep derivatives. By 1987, there was a significant incidence of BSE, which was thought to be due to an alteration in feeding practices which were banned in 1988. Nevertheless, the incidence of BSE continued to rise, peaking in 1992.

Examples of prion diseases Species Disease
Species Disease Transmission Cases
Humans
  • Kuru
  • Creutzfeldt-Jakob (CJD)
  • Gerstmann-Straussler-Scheinker
  • Fatal familial insomnia
  • Infectious (ritual cannibalism, New Guinea 1957-82)
  • (a) Sporadic
  • (b) Familial (autosomal dominant)
  • (C) Infectious-from humans (e.g. pituitary growth hormone, dural grafts) -?from cows (atypical form, BSE association)
  • Familial (autosomal dominant)
  • Familial (autosomal dominant)
  • = 2500
  • 1 in 106
  • 1 in 107
  • =100
  • > 15
  • Rare
  • Rare
Sheep Scrapie
Cattle Bovine spongiform encephalopathy (BSE)