Establishment: Overcoming the Host’s Immune System

Establishment: Overcoming the Host’s Immune System

Once a microorganism has breached the surface epithelial barrier, it is subject to a series of nonspecific and specific processes designed to remove, inhibit, or destroy it. These de-fenses are complex, dynamic, and interactive. Microorganisms that reach the subepithelial tissues are immediately exposed to the intercellular tissue fluids, which have defined properties that inhibit multiplication of many bacteria. For example, most tissues contain lysozyme in sufficient concentrations to disrupt the cell wall of some Gram-positive bac-teria. Other less well-defined inhibitors from leukocytes and platelets have also been described. Tissue fluid itself is a suboptimal growth medium for most bacteria and defi-cient in free iron. Iron is essential for bacterial growth, but it is sequestered by the body’s iron-binding proteins such as transferrin and lactoferrin and is inaccessible to organisms that do not themselves produce siderophores . Virtually all pathogenic species come equipped with a means to extract the essential iron they need from the host’s iron-sequestering defenses.

If an organism proceeds beyond the initial physical and biochemical barriers, it may meet strategically placed phagocytic cells of the monocyte/macrophage lineage whose function is to engulf, internalize, and destroy large particulate matter, including infectious agents. Examples of such resident phagocytic cells include the alveolar macrophages, liver Kupffer cells, brain microglial cells, lymph node and splenic macrophages, kidney mesangial cells, and synovial A cells. As noted above, many pathogens are facultative in-tracellular parasites that actually seek out, enter, and replicate within these phagocytic defenders. One of the most common tactics of these pathogens is to induce programmed cell death (apoptosis). This clever microbial tactic not only inactivates the killing poten-tial of the phagocyte but also reduces the number of defenders available to inhibit other bacterial invaders. The invading bacteria that induce apoptosis obtain the added benefit that death by apoptosis nullifies the normal cellular signaling processes of cytokine and chemokine signaling of necrotic death. Hence, the myriads of microbes that infect humans and make up their normal flora are held at bay by our innate and adaptive im-mune mechanisms. Pathogenic bacteria, almost by definition, can overcome these bio-chemical and cellular shields after they breach the mucosal barrier.

Not all pathogens can deactivate the host’s early warning system, inflammation. In-flammation is a normal host response to a traumatic or infectious injury. When many microorganisms multiply in the tissues, the usual result is an inflammatory response, which has several immediate defensive effects. It increases tissue fluid flow from the bloodstream to the lymphatic circulation and brings phagocytes, complement, and any existing antibody to the site of infection. Macrophage-derived interleukin-1 (IL-1) and tumor necrosis factor (TNF) stimulates or enhances these processes. The increased lymphatic drainage serves to bring microbes or their antigens into contact with the cells in the local lymph nodes that mediate the development of specific immune responses. Microorganisms that escape from a local lesion into the lymphatic circulation or blood-stream are rapidly cleared by reticuloendothelial cells or arrested in the small pul-monary capillaries and then ingested by phagocytic cells. This process is so efficient that when a million organisms are injected into a vein of a rabbit, few, if any, are recov-erable in cultures of blood taken 15 minutes after injection, although the ultimate result of such clearance may not be a cure. The end results are the classic inflammatory mani-festations of swelling (tumor), vasodilatation of surface vessels with erythema (rubor), heat (calor) from increased skin temperature, pain (dolor) from increased pressure andtissue damage, and loss of function because of reflex nerve inhibition or the pain caused by movement.

Fever, a frequent concomitant of inflammation, is mediated primarily by IL-1 andTNF released by macrophages. The value of fever is not completely clear; however, it in-creases the effectiveness of several processes involved in phagocytosis and microbial killing and frequently reduces the multiplication or replication rate of bacteria or viruses. Taken together, these host cell factors serve to produce an environment that is highly hos-tile to most organisms and also is hostile to adjacent normal tissue. Lysosomal enzymes, including collagenase and elastase, when released from polymorphonuclear neutrophils (PMNs) damage tissues and contribute to the enhancement of the inflammatory process; however, failure of the phagocytes to clear bacteria results in continued release of toxic products from the inflammatory exudate, which can be as damaging to the host as re-leased bacterial virulence products. Ultimately, phagocytes kill almost all bacteria. When the invading microorganisms (or their surviving antigenic material) cannot be degraded or are resistant to removal or degradation, T cells accumulate and release lymphokines. This leads to the aggregation and proliferation of macrophages and the characteristic appear-ance of a nodular mass called a granuloma, which consists of multinucleate giant cells, epithelioid cells, and activated macrophages. Granulomas are characteristic of infections caused by the tubercle bacillus Mycobacterium tuberculosis and other facultative intracel-lular parasites.