Mycobacterium tuberculosis

Tuberculosis is a disease resulting from infection with the intracellular bacterium, Mycobacterium tuberculosis. Infection occurs primarily via the respiratory route and is transmitted from person to person. More than 1.5 billion people are infected world-wide with this organism. Many remain healthy if the cellular immune system keeps the infection in check. However, bacteria frequently persist in the lungs and are reactivated when the individual becomes immunocompromised, as occurs for instance in an aged and/or chronically debilitated population. Because most infected individuals do not develop overt symptomatology, a skin test is used to confirm exposure. This consists of an intradermal challenge with purified protein derivative (PPD) from Mycobacterium tuberculosis. Previously infected individuals develop a cutaneous reaction, a consequence of reactivation of memory CD4+ T cells at the site of challenge. This cutaneous reaction (redness, edematous, cellular infiltration) is referred to in general as a delayed-type-hypersensi-tivity (DTH) reaction, and in this particular case as a Mantoux reaction. Ten million new cases of tuberculosis arise yearly, and more than two million people die each year from infection. In many third world countries, where tuberculosis is rampant, immunization with Baccillus Calmette-Guerin (BCG), an attenuated strain of Mycobacteria bovis, provides some protection from Mycobacterium tuberculosis. There is a pressing need to develop more effective and safer vaccines for this disease.

Host defense

Key cells in immunity to Mycobacterium tuberculosis are cytokine (IFNy, TNF) activated macrophages. IL-12 produced by activated macrophages is a potent activator of IFNy production by NK cells. Macrophages also secrete TNF. The significance of TNF in Mycobacterium tuberculosis infections was shown during studies with mice in which the gene for TNF was disabled. These animals showed significant impairment in their ability to resist challenge with the organism. IFNy has a dual role in host defense to this intracellular organism. First, IFNy enhances the production of reactive oxygen intermediates, nitric oxide, and reactive nitrogen intermediates. Secondly, ongoing production of IFNy by CD4+ Th1 cells in host defense to infection with Mycobacterium tuberculosis is contingent on the pres ence of this cytokine (NK cell derived initially) during the differentiation of naive CD4+ T cells (Fig. 9.4).

Some Mycobacterium tuberculosis organisms may survive in alveolar macrophages because components of their cell wall prevent the fusion of lysosomes with the phagosomes. As a result lysosomal enzymes cannot destroy the microbe. The enhanced virulence of Mycobacterium tuberculosis, in comparison with other organisms that also prevent phagolysosome fusion, may reflect the additional effect of scavenging reactive oxygen species, as has been shown for Mycobacterium leprae.

A notable feature of the immune response to Mycobacterium tuberculosis is the formation of granulomas. A granuloma is an aggregation of macrophages surrounded by CD4+ T lymphocytes secreting Type 1 cytokines, particularly IFNy. When the cells are arranged in this formation, cytokines secreted by activated T cells are available to large numbers of infected macrophages. In healthy individuals, the intracellular organisms are destroyed, or contained, with a residue of bacteria surviving in a quiescent state, and no observable clinical symptoms. Disruption of this homeostasis in previously infected individuals results in disease. Individuals at risk for overt disease are those with CD4+ T-cell defects, or those in whom differentiation of naive CD4+ Thp cells results in a polarization to Th2 cells secreting Type 2 cytokines rather than Type-1 cytokines.

Shigella dysenteriae

Shigelle dysenteriae, the causative agent of Shigella dysentery, infects epithelial cells in the intestinal lumen. Shigella dysenteriae produces a toxin, Shiga toxin, believed to be associated with damage to the colonic vasculature thus causing bloody diarrhea. Shigella dysenteriae variants that do not produce the toxins remain pathogenic but are less virulent. Shigella organisms that escape expulsion from the gastrointestinal tract by peristalsis, bind to M cells and are endocytosed within these cells. However, unlike most organisms Shigella dysenteriae lyses the endosomal wall and escapes into the M cell cytoplasm where they replicate (Fig. 11.7). From there, many of these organisms spread laterally to infect adjacent epithelial cells. Shigella dysenteriae that do not infect the adjacent epithelial cells pass through the M cell, into the lamina propria, where they are phagocy-tosed by macrophages, which are induced to undergo apoptosis.

Host Defenses to Fungi

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