There is one form of survival, by convention linked to the so-called delayed type hypersensitivity (type IV) reaction, which provides a unique setting for organisms to persist despite immune attack. This is the microenvironment of the granuloma. Leprosy is regarded as the paradigm, as it illustrates
Figure 3.1. Mechanisms of immune evasion. Pathogens utilise a range of mechanisms to subvert detection by the immune system across the spectra of innate and adaptive responses. Upper panel: Residing in immune privilege sites and low antigen production (e.g., herpes simplex virus latency in central nervous system) result in lack of detection by immune recognition mechanisms. Lower panel - left to right: (1) Prevent phagocytosis (e.g., Streptococcus pneumoniae polysaccharide). (2) Inhibit pathogen processing and destruction (e.g., Mycobacterium tuberculosis inhibition of phagolysosome fusion. (3) Prevent clearance (e.g., Mycobacterium tuberculosis granuloma induction). (4) Modulate cytokine effects (e.g., Vaccinia virus induced secretion of antagonistic cytokine homologue). (5) Vary antigen expression (e.g., Trypansoma Cruzi antigen switching). (6) Inhibit antigen processing and presentation (e.g., cytomegalovirus inhibition of MHC expression).
that both paucibacillary ("tuberculoid," because this is the more conventional appearance in Mycobacterium tuberculosis infection) and multibacillary ("lep-romatous") symbiosis between macrophage and mycobacterium can occur (130). In parasitic diseases, too, the granuloma is important: even if by morphology the lesions are less well formed, as is seen in leishmaniasis, there is a similarity in the unusual relationship between cell and predator (113,131, 143). The schistosome that survives is in fact the hallmark of the typical liver granulomatous lesion that is seen in bilharzia (137). The antigens that the remaining parasites themselves generate will in turn determine the pattern of host immune responsiveness, and hence their own further survival (133).
What are the general factors that control the granuloma and contribute to survival of an initiating factor, such as a bacterium or a parasite? The relative role of cell turnover must be important - these immune granulomas « are sometimes described as "high turnover" where all stages of epithelioid g differentiation are seen, there are growth factors and receptors present, and a there is some local cell division (4, 145). There are several features of the
< infective agent that have been identified as being predisposing to both gran-
5 uloma formation and survival of the initiating factor despite the ongoing response. The nature of the antigens exposed on the surface of the organism may have a selective role in determining the pattern of the response (53). The organism may be resistant to host enzymes (11). Uptake via complement receptors rather than by scavenger or Fc receptors will avoid the respiratory burst and thus lead to unexpected survival despite an innate immune reaction that is otherwise adequate (30). The organism may enter the cytoplasm directly rather than via a typical phagosome and thus avoid the potential trap of lysosome-phagosome fusion and processing (142). There maybe interference in this phagosome-lysosome fusion stage (52). The requisite activation pathway necessary to limit survival and pathology may be inhibited (99). The capsule of the organism may mimic a foreign body and hence elicit a response resembling that seen to inert material (40). Once within the phagocyte the organism may shut down its own protein synthesis mechanism and thus remain dormant (66), and it also may interfere with the cytokine synthesis by the host cell (91, 127). As in other infections, there is a possibility that non-professional phagocytes - including epithelial cells and endothelial cells - may harbour the agent that promotes granuloma formation (20). Finally, the molecular mimicry theory has also been invoked and this too may be dependent upon sequestration and survival of an exogenous organism (33, 64).
Considerable interest in the pathogenesis of the granuloma in which mycobacteria can survive has been precipitated by the strong association of the diseases caused by these organisms with HIV-1 infection. In people with this condition there may be reactivation; and tuberculosis can take a "lepromatous" form with high organism counts. A T-cell role in determining this pattern has been suggested, and the possibility that there is activation of a specific "suppressor" form, which inhibits (or secretes a mediator inhibitor of) processing has been advocated (58). The proportional absence of CD4+ T cells in the HIV infection microenvironment may be a contributory factor (140, 162).
However, the question "What happens inside the macrophage to regulate mycobacterial survival?" has attracted most attention. This question is important not only in terms of mycobacterial diseases per se but also in conditions such as sarcoidosis and Crohn's disease, where an association has been suspected but no organisms and their remnants have been documented unequivocally (reviewed in (60) and (67)). Several studies have shown U that the "mycobacterial vacuole" is part of the classic endosomal pathway, but V it appears to be arrested at an early stage, in which cathepsin D is present g and acidification is inefficient (13, 36, 149). A molecular approach has also g recently been adopted to document how the type of infecting mycobacterium M may contribute to the question of survival (158). There appear to be partic- U ular strains that cause infection but survive without causing "disease," and E others that cause disease but are less readily transmissible. Furthermore, it S has been suggested that the more virulent strains are in fact those that are o more resistant to growth inhibition by the macrophages themselves (115). E
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