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Chapter: Medical Microbiology: An Introduction to Infectious Diseases: Host-Parasite Relationships

Strategy for Survival: Avoid, Circumvent, Subvert, or Manipulate Normal Host Cell Defenses

Once a pathogenic species reaches its unique niche, it may face formidable host defense mechanisms including dangerous phagocytic cells.

Strategy for Survival: Avoid, Circumvent, Subvert, or Manipulate Normal Host Cell Defenses

Once a pathogenic species reaches its unique niche, it may face formidable host defense mechanisms including dangerous phagocytic cells. Such a site may be devoid of a normal heavy commensal bacterial burden precisely because it contains added defense measures not found at the usual mucosal sites. The ways by which microbes avoid, circumvent, or even subvert or manipulate such host barriers are relatively unique for each species, al-though certain common pathogenic tactics have begun to be appreciated. We now know that bacterial pathogenicity is a multifaceted process that can be likened to a symphony in which each part contributes to a common theme. Yet, even though pathogenic species sometimes use genetic homologs and exhibit similar tactics to outwit host defenses, each pathogen has evolved a unique style of survival — a pathogenic signature.

Getting into Cells

Many pathogenic bacteria are content to fight their way to the mucosal surface, adhere, nullify local host defense factors, and multiply. However, adherence to a cellular surface may only be the first step in other infections. Some pathogenic microbes are capable of entering into and surviving within eukaryotic cells. Some organisms direct their uptake into host cells that are not normally phagocytic, including epithelial cells lining mucosal surfaces and endothelial cells lining blood vessels. Invasion may provide a means for a microorganism to breach host epithelial barriers. Presumably, this invasion tactic ensures a protected cellular niche for the microbe to replicate or persist. Alternatively, phagocytic cells, such as macrophages, may internalize organisms actively by several mechanisms. Pathogens that survive and replicate within phagocytic cells possess additional mecha-nisms that enhance their survival. Even quite different organisms can employ mechanisti-cally similar invasion strategies.

Intracellular growth and replication is an essential step for all viruses. Bacterial entry into host cells is usually divided into two broad groups. Bacteria that, like viruses, are ob-ligate intracellular pathogens, include the typhus group (Rickettsia) and the trachoma group (Chlamydia). Other microbes such as the typhoid – paratyphoid group (Salmo-nella), the dysentery group (Shigella), the Legionnaires’ disease bacillus (Legionella), andthe tubercle bacillus (Mycobacterium) are classified as facultative intracellular pathogens and can grow as free-living cells in the environment as well as within host cells. Whereas some pathogens do whatever they can to avoid phagocytosis, these virulent facultative intracellular organisms establish themselves and replicate within the intracellular environ-ment of phagocytes. All of these bacteria are taken up by host cells through a specific re-ceptor-mediated, often bacterial-directed, phagocytic event. The entering bacteria initially are seen within a membrane-bound, host-vesicular structure. Yet, both the facultative and obligate bacterial pathogens can be further classified with respect to the mechanism by which they replicate intracellularly. Thus, Shigella and some Rickettsia lyse the phago-some and multiply in the nutrient-rich safe haven of the host cell cytosol. In contrast, Salmonella, Chlamydia, Legionella, and Mycobacterium remain enclosed in a host cell –derived membrane for their entire intracellular life and modulate their environment to suit their own purposes. They survive and replicate intracellularly within a host cell vacuole by thwarting the normal host cell trafficking pattern to avoid becoming fused to the hydrolytically active components of lysosomes.

Generally, invasive organisms adhere to host cells by one or more adhesins but em-ploy a class of molecules, called invasins, that either direct bacterial entry into cells or provide an intimate direct contact between the bacterial surface and the host cell plasma membrane. In both cases, invasins are the first step in mediating direct interaction be-tween one or more bacterial products and host cell molecules. Invasins are adhesins in their own right, but obviously not all adhesins (such as the pili mentioned earlier) medi-ate entry into host cells. Invasins usually trigger or activate signals in the host cell that directly or indirectly mediate and facilitate specific membrane – membrane interaction and, in some cases, bacterial entry. For example, enteropathogenic E. coli and Heli-cobacter pylori, the causative agent of peptic ulcer, use contact-dependent secretory sys-tems to actually insert bacterial proteins into the host cell membrane. This is the first step in a cascade of events that triggers a massive redeployment of host cell cytoskeletal elements. The bacteria in question do not enter the host cell but remain tightly affixed to the host cell. The molecular manipulation by the bacteria leads to a microenvironment that is essential for bacterial persistence and proliferation. The host suffers from diarrhea in one case or an inflamed gastric mucosa in the other, an unfortunate consequence for many infected hosts. Likewise, some other bacteria do not enter host cells. The typhoid bacillus and the etiologic agent of dysentery adhere intimately to the host cell surface, and, in a contact-dependent manner, directly “inject” bacterial proteins into the host cell cytoplasm, which induces a cataclysmic rearrangement of host cell actin that envelops the bacteria by a process that resembles normal macropinocytosis. Thus, ultimately, host cell cytoskeletal components and normal cellular mechanisms are exploited by bacteria to their own end. The specific tactics used by different microbes are discussed in subse-quent.

Following cell entry, the invading bacterium immediately is localized within a mem-brane-bound vacuole inside the host cell. As noted, the invading pathogen organism may or may not escape this vacuole, depending on the pathogen and its strategy for survival. A small number of bacterial species appear to forcibly enter directly into host cells by a lo-cal enzymatic digestion of the host cell membrane following adherence to the cell surface. One such pathogen, Rickettsia prowazekii, produces phospholipases that appear to degrade the host wall localized beneath the adherent organisms, thereby enabling the pathogen to enter directly into the cytoplasm. How the bacterium controls the enzymatic degradation to prevent host cell lysis and how the host cell reseals its membrane after in-vasion remain uncharacterized.

Invasin binding sites can be members of the integrin family, a family of integral mem-brane glycoproteins mediating cell – cell and cell – extracellular matrix interactions. Integrins include the receptors for fibronectin, collagen, laminin, vitronectin, and the complement binding receptor of phagocytes. Integrins are linked to the actin microfilament system through a variety of molecules, including talin, vinculin, and -actinin. Thus, the binding of a microbe to an integrin or integrin-like molecule on the host surface may trigger a host cell signal that causes actin filaments to link to the membrane-bound receptor, which then gener-ates the force necessary for parasite uptake. Understanding the cell biology of microbial inva-sion is still in its early stages, but once again it is important to emphasize that pathogenic microbes most often gain entry into the host cell by altering or exploiting normal host cell mechanisms.

Some viruses are internalized in much the same way. For example, rhinoviruses of the common cold use membrane-bound glycoprotein intercellular adhesion molecule 1 (ICAM-1) as a receptor. ICAM-1 is also a ligand of certain integrins. More often, as al-ready discussed, virus particles are taken up by the receptor-mediated endocytosis mecha-nism , which is normally responsible for internalizing hormones, growth factors, and some important nutrients.

Avoiding Intracellular Pitfalls

Intracellular pathogens enjoy a number of advantages. Besides avoiding the host immune system, intracellular localization places pathogens in an environment potentially rich in nutrients and devoid of competing microorganisms. Intracellular life is not free of diffi-culty. Viruses that enter by fusion are “dumped” directly into the cytoplasm where they may begin the replicative cycle. Bacteria or viruses internalized through the reorganiza-tion of the cytoskeleton find themselves in a membrane-bound vesicle in an acidic envi-ronment and may be destined for fusion with potentially degradative lysosomes. Some viruses  respond  to  the  acidic  environment  by  changing  conformation,  binding  to  the endosomal membrane, and releasing their nucleic acid into the cytoplasm. Bacteria suchas Shigella, the cause of bacillary dysentery, and Listeria monocytogenes, a causative agent of meningitis and sepsis in the very young or very old, elaborate an enzyme that dissolves away the surrounding membrane and permits the bacterium to replicate withinthe relative safety of the cytoplasm. Other organisms, such as the typhoid bacillus and the tubercle bacillus, apparently tolerate the initial endosome – lysosome fusion event; how-ever, most recent evidence suggests that they then modify this intracellular compartment into a privileged niche in which they can replicate optimally. Mycobacterium somehow inhibit the acidification of the phagosome. Still other organisms, for example, the proto-zoan Toxoplasma gondii, inhibit the acidification of the endosomal vesicle and this, in turn, inhibits lysosomal fusion. The common theme again is that the microorganism has found a way to circumvent or to exploit host cell factors to suit its own purpose.

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