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Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002.

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Molecular Biology of the Cell. 4th edition.

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Cell Biology of Infection

We have just seen that pathogens constitute a diverse set of agents. There are correspondingly diverse ranges of mechanisms by which pathogens cause disease. But the survival and success of all pathogens require that they colonize the host, reach an appropriate niche, avoid host defenses, replicate, and exit the infected host to spread to an uninfected one. In this section, we examine the common strategies that are used by many pathogens to accomplish these tasks.

Pathogens Cross Protective Barriers to Colonize the Host

The first step in infection is for the pathogen to colonize the host. Most parts of the human body are well-protected from the environment by a thick and fairly tough covering of skin. The protective boundaries in some other human tissues (eyes, nasal passages and respiratory tract, mouth and digestive tract, urinary tract, and female genital tract) are less robust. For example, in the lungs and small intestine where oxygen and nutrients, respectively, are absorbed from the environment, the barrier is just a single monolayer of epithelial cells.

Skin and many other barrier epithelial surfaces are usually densely populated by normal flora. Some bacterial and fungal pathogens also colonize these surfaces and attempt to outcompete the normal flora, but most of them (as well as all viruses) avoid such competition by crossing these barriers to gain access to unoccupied niches within the host.

Wounds in barrier epithelia, including the skin, allow pathogens direct access to the interior of the host. This avenue of entry requires little in the way of specialization on the part of the pathogen. Indeed, many members of the normal flora can cause serious illness if they enter through such wounds. Anaerobic bacteria of the genus Bacteroides, for example, are carried as harmless flora at very high density in the large intestine, but they can cause life-threatening peritonitis if they enter the peritoneal cavity through a perforation in the intestine caused by trauma, surgery, or infection in the intestinal wall. Staphylococcus from the skin and nose, or Streptococcus from the throat and mouth, are also responsible for many serious infections resulting from breaches in epithelial barriers.

Dedicated pathogens, however, need not wait for a well-timed wound to allow them access to their host. A particularly efficient way for a pathogen to cross the skin is to catch a ride in the saliva of a biting insect. Many arthropods nourish themselves by sucking blood, and a diverse group of bacteria, viruses, and protozoa have developed the ability to survive in the arthropod so that they can use these biting animals as vectors to spread from one mammalian host to another. As discussed earlier, the Plasmodium protozoan that causes malaria develops through several forms in its life cycle, including some that are specialized for survival in a human and some that are specialized for survival in a mosquito (see Figure 25-10). Viruses that are spread by insect bites include the causative agents for several types of hemorrhagic fever, including yellow fever and Dengue fever, as well as the causative agents for many kinds of viral encephalitis (inflammation of the brain). All these viruses have acquired the ability to replicate in both insect cells and mammalian cells, as is required for a virus to be transmitted by an insect vector. Bloodborne viruses such as HIV that are not capable of replicating in insect cells are rarely, if ever, spread from insect to human.

The efficient spread of a pathogen via an insect vector requires that individual insects consume blood meals from numerous mammalian hosts. In a few striking cases, the pathogen appears to alter the behavior of the insect so that its transmission is more likely. Like most animals, the tsetse fly (whose bite spreads the protozoan parasite Trypanosoma brucei which causes sleeping sickness in Africa) stops eating when it is satiated. But tsetse flies carrying trypanosomes bite much more frequently and ingest more blood than do uninfected flies. The presence of trypanosomes impairs the function of the insect mechanoreceptors that measure blood flow through the gullet to assess the fullness of the stomach, effectively fooling the tsetse fly into thinking that it is still hungry. The bacterium Yersinia pestis, which causes bubonic plague, uses a different mechanism to ensure that a flea carrying it bites repeatedly: it multiplies in the flea's foregut to form aggregated masses that eventually enlarge and physically block the digestive tract. The insect is then unable to feed normally and begins to starve. During repeated attempts to satisfy its appetite, some of the bacteria in the foregut are flushed into the bite site, thus transmitting plague to a new host (Figure 25-18).

Figure 25-18. The spread of plague.

Figure 25-18

The spread of plague. This micrograph shows the digestive tract dissected from a flea that had dined about two weeks previously on the blood of an animal infected with the plague bacterium, Yersinia pestis. The bacteria multiplied in the flea gut to produce (more...)

Pathogens That Colonize Epithelia Must Avoid Clearance by the Host

Hitching a ride through the skin on an insect proboscis is just one strategy that pathogens use to pass through the initial barriers of host defense. Whereas many barrier zones such as the skin, mouth, and large intestine, are densely populated by normal flora, others including the lower lung, the small intestine, and the bladder, are normally kept nearly sterile, despite relatively direct access to the environment. The epithelium in these zones actively resists bacterial colonization. As discussed in Chapter 22, the respiratory epithelium is covered with a layer of protective mucus, and the coordinated beating of cilia sweeps the mucus and trapped bacteria and debris up and out of the lung. The epithelia lining the bladder and the upper gastrointestinal tract also have a thick layer of mucus, and these organs are periodically flushed by micturition and peristalsis, respectively, to wash away undesirable microbes. The pathogenic bacteria and parasites that infect these epithelial surfaces have specific mechanisms for overcoming these host cleaning mechanisms. Those that infect the urinary tract, for example, resist the washing action of urine by adhering tightly to the bladder epithelium via specific adhesins, proteins or protein complexes that recognize and bind to host cell-surface molecules. An important group of adhesins in uropathogenic E. coli strains are components of the P pili (see Figure 25-4E) that help the bacteria infect the kidney. These surface projections can be several micrometers long and are thus able to span the thickness of the protective mucus layer. At the tip of each pilus is a protein that binds tightly to a particular disaccharide linked to a glycolipid that is found on the surface of cells in the bladder and kidney (Figure 25-19)

Figure 25-19. Uropathogenic E. coli and P pili.

Figure 25-19

Uropathogenic E. coli and P pili. (A) Scanning electron micrograph of uropathogenic E. coli, a common cause of bladder and kidney infections, attached to the surface of epithelial cells in the bladder of an infected mouse. (B) A close-up view of the bacteria (more...)

One of the hardest organs for a microbe to colonize is the stomach. Besides peristaltic washing and protection by a thick layer of mucus, the stomach is filled with acid (average pH ~2). This extreme environment is lethal to almost all bacteria ingested in food. Nonetheless, it is colonized by the hardy and enterprising bacterium Helicobacter pylori, which was recognized only recently as a major causative agent of stomach ulcers and possibly stomach cancer. Although the older treatments for ulcers (acid-reducing drugs and bland diets) are still used to reduce inflammation, a short and relatively cheap course of antibiotics can now effectively cure a patient of recurrent stomach ulcers. The hypothesis that stomach ulcers could be caused by a persistent bacterial infection of the stomach lining initially met with considerable skepticism. The point was finally proven by the young Australian doctor who made the initial discovery: he drank a flask of a pure culture of H. pylori and developed a typical ulcer. One way that H. pylori survives in the stomach is by producing the enzyme urease, which converts urea to ammonia and carbon dioxide; in this way, the bacterium surrounds itself with a layer of ammonia, which neutralizes stomach acid in its immediate vicinity. The bacteria also express at least five types of adhesins, which enable them to adhere to the stomach epithelium, and they produce several cytotoxins that destroy the stomach epithelial cells, creating painful ulcers. The resulting chronic inflammation promotes cell proliferation and thus predisposes the infected individual to stomach cancer.

A more extreme example of active colonization is provided by Bordetella pertussis, the bacterium that causes whooping cough. The first step in a B. pertussis infection is colonization of the respiratory epithelium. The bacteria circumvent the normal clearance mechanism (the mucociliary escalator described in Chapter 22) by binding tightly to the surface of ciliated cells and multiplying on them. B. pertussis expresses at least four types of adhesins that bind tightly to particular glycolipids on the ciliated cells. The adherent bacteria produce various toxins which eventually kill the ciliated cells, compromising the host's ability to clear the infection. The most familiar of these is pertussis toxin, which—like cholera toxin—is an ADP-ribosylating enzyme. It ADP-ribosylates the α subunit of the G protein Gi, causing deregulation of the host cell adenylyl cyclase and overproduction of cyclic AMP (discussed in Chapter 15). Not content with this, B. pertussis also produces an adenylyl cyclase of its own, which is inactive unless bound to the eucaryotic Ca2+-binding protein calmodulin. The bacterially-produced enzyme is therefore active only in the cytoplasm of a eucaryotic cell. Although both B. pertussis and V. cholerae have the similar effect of drastically raising cAMP levels in the host cells to which they adhere, the symptoms of the diseases are very different because the two bacteria colonize different sites in the host: B. pertussis colonizes the respiratory tract and causes paroxysmal coughing, whereas V. cholerae colonizes the gut and causes watery diarrhea.

Not all examples of specific colonization require that the bacterium express adhesins that bind to host cell glycolipids or proteins. Enteropathogenic E. coli, which causes diarrhea in young children, instead uses a type III secretion system (see Figure 25-7) to deliver its own bacterially-expressed receptor protein (called Tir) into its host cell (Figure 25-20A). After Tir is inserted into the host cell membrane, a bacterial surface protein binds to the extracellular domain of Tir, triggering a remarkable series of events inside the host cell. First, the Tir receptor protein is phosphorylated on tyrosine residues by a host protein tyrosine kinase. Unlike eucaryotic cells, bacteria generally do not phosphorylate tyrosine residues, yet Tir contains a peptide domain that is a specific recognition motif for a eucaryotic tyrosine kinase. The phosphorylated Tir then is thought to recruit a member of the Rho family of small GTPases, which promotes actin polymerization through a series of intermediate steps (discussed in Chapter 16). The polymerized actin forms a unique cell surface protrusion, called a pedestal, that pushes the tightly adherent bacteria up about 10 μm from the host cell surface (Figure 25-20B, C).

Figure 25-20. Interaction of enteropathogenic E. coli (EPEC) with host cells.

Figure 25-20

Interaction of enteropathogenic E. coli (EPEC) with host cells. (A) When EPEC contacts an epithelial cell in the lining of the human gut, it delivers a bacterial protein, Tir, into the host cell through a type III secretion system. Tir then inserts into (more...)

These examples of host colonization illustrate the importance of host-pathogen communication in the infection process. Pathogenic organisms have acquired genes that encode proteins that interact specifically with particular molecules of the host cells. In some cases, such as the B. pertussis adenylyl cyclase, an ancestor of the pathogen may have acquired the gene from its host, whereas in others, such as Tir, random mutation may have given rise to protein motifs that are recognized by a eucaryotic protein partner.

Intracellular Pathogens Have Mechanisms for Both Entering and Leaving Host Cells

Many pathogens, including V. cholerae and B. pertussis, infect their host without entering host cells. Others, however, including all viruses and many bacteria and protozoa, are intracellular pathogens. Their preferred niche for replication and survival is within the cytoplasm or intracellular compartments of particular host cells. This strategy has several advantages. The pathogens are not accessible to antibodies (discussed in Chapter 24), and they are not easy targets for phagocytic cells (discussed below). This lifestyle, however, does require that the pathogen develop mechanisms for entering host cells, for finding a suitable subcellular niche where it can replicate, and for exiting the infected cell to spread the infection. In the remainder of this section, we consider some of the myriad ways that individual intracellular pathogens exploit and modify host cell biology to satisfy these requirements.

Viruses Bind to Molecules Displayed on the Host Cell Surface

The first step for any intracellular pathogen is to bind to the surface of the host target cell. For viruses, binding is accomplished through the association of a viral surface protein with a specific receptor on the host cell surface. Of course, no host cell receptor evolved for the sole purpose of allowing a pathogen to bind to it; these receptors all have other functions. The first such “virus receptor” identified was the E. coli surface protein that allows the bacteriophage lambda to bind to the bacterium. Its normal function is as a transport protein responsible for the uptake of maltose.

Viruses that infect animal cells generally use cell-surface receptor molecules that are either very abundant (such as sialic-acid-containing oligosaccharides, which are used by the influenza virus) or uniquely found on those cell types in which the virus can replicate (such as the nerve growth factor receptor, the nicotinic acetylcholine receptor, or the cell-cell adhesion protein N-CAM, all of which are used by the rabies virus to specifically infect neurons). Often, a single type of receptor is used by many types of virus, and some viruses can use several different receptors. Moreover, different viruses that infect the same cell type may each use a different receptor. Hepatitis, for example, is caused by at least six viruses, all of which preferentially replicate in liver cells. Receptors for four of the hepatitis viruses have been identified, and they are all different. Receptors need not be proteins; herpes simplex virus, for example, binds to heparan sulfate proteoglycans through specific viral membrane proteins.

Frequently, viruses require both a primary receptor and a secondary co-receptor for efficient attachment and entry into host cells. An important example is HIV. Its primary receptor is CD4, a protein involved in immune recognition which is found on the surface of many T cells and macrophages (discussed in Chapter 24). Viral entry also requires the presence of a co-receptor, either CCR5 (a receptor for β-chemokines) or CXCR4 (a receptor for α-chemokines), depending on the particular variant of the virus (Figure 25-21). Macrophages are susceptible only to HIV variants that use CCR5 for entry, whereas T cells are most efficiently infected by variants that use CXCR4. The viruses that are found within the first few months after HIV infection almost invariably require CCR5, which presumably explains why individuals who carry a defective ccr5 gene are not susceptible to HIV infection. In the later stages of infection, viruses may either switch to use the CXCR4 co-receptor or adapt to use both co-receptors; in this way, the virus can change the cell types it infects as the disease progresses.

Figure 25-21. Receptor and co-receptors for HIV.

Figure 25-21

Receptor and co-receptors for HIV. All strains of HIV require CD4 as a primary receptor. Early in an infection, most of the viruses use CCR5 as a co-receptor, allowing them to infect macrophages and their precursors, monocytes. As the infection progresses, (more...)

Viruses Enter Host Cells by Membrane Fusion, Pore Formation, or Membrane Disruption

After recognition and attachment to the host cell surface, the virus must next enter the host cell and release its nucleic acid genome from its protective protein coat or lipid envelope. In most cases, the liberated nucleic acid remains complexed with some viral proteins. Enveloped viruses enter the host cell by fusing either with the plasma membrane or with the endosomal membrane following endocytosis (Figure 25-22A,B). Fusion is thought to proceed via a mechanism similar to SNARE-mediated fusion of vesicles during normal intracellular vesicular traffic (discussed in Chapter 13).

Figure 25-22. Four virus uncoating strategies.

Figure 25-22

Four virus uncoating strategies. (A) Some enveloped viruses, such as HIV, fuse directly with the host cell plasma membrane to release their capsid (green) into the cytosol. (B) Other enveloped viruses, such as influenza virus, first bind to cell-surface (more...)

Fusion is regulated both to ensure that virus particles fuse only with the appropriate host cell membrane and to prevent virus particles from fusing with one another. For viruses such as HIV that fuse at neutral pH at the plasma membrane, binding to receptors or co-receptors usually triggers a conformational change in the viral envelope protein to expose a normally buried fusion peptide (see Figure 13-16). Other enveloped viruses, such as influenza, postpone fusion until after endocytosis; in this case, it is frequently the acid environment in the early endosome that triggers the conformational change in a viral surface protein that exposes the fusion peptide (Figure 25-23). The H+ pumped into the early endosome enters the influenza particle through an ion channel and triggers the uncoating of the viral nucleic acid, which is directly released into the cytosol as the virus fuses with the endosomal membrane. For some viruses, uncoating occurs after release into the cytosol. In the case of Semliki forest virus, for example, the binding of host ribosomes to the capsid causes the capsid proteins to separate from the viral genome.

Figure 25-23. The entry strategy used by the influenza virus.

Figure 25-23

The entry strategy used by the influenza virus. The globular heads of the viral hemagglutinin (HA) mediate binding of the virus to sialic-acid-containing cell-surface receptors. The virus-receptor complexes are endocytosed and, in the acidic environment (more...)

It is more difficult to envision how nonenveloped viruses enter host cells, as it is not obvious how large assemblies of protein and nucleic acid can cross the plasma or endosomal membrane. Where the entry mechanism is understood, nonenveloped viruses generally either form a pore in the cell membrane to deliver the viral genome into the cytoplasm or they disrupt the endosomal membrane after endocytosis.

Poliovirus uses the first strategy. Binding of poliovirus to its receptor triggers both receptor-mediated endocytosis and a conformational change in the viral particle. The conformational change exposes a hydrophobic projection on one of the capsid proteins, which apparently inserts into the endosomal membrane to form a pore. The viral genome then enters the cytoplasm through the pore, leaving the capsid either in the endosome or on the cell surface, or in both places (see Figure 25-22C).

Adenovirus uses the second strategy. It is initially taken up by receptor-mediated endocytosis. As the endosome matures and becomes more acidic, the virus undergoes multiple uncoating steps in which structural proteins are sequentially removed from the capsid. Some of these steps require the action of a viral protease, which is inactive in the extracellular virus particle (probably because of intrachain disulfide bonds) but which is activated in the reducing environment of the endosome. One of the proteins released from the capsid lyses the endosomal membrane, releasing the remainder of the virus into the cytosol. This trimmed-down virus then docks onto the nuclear pore complex, and the viral DNA genome is released through the pore into the nucleus, where it is transcribed (see Figure 25-22D).

In these various entry strategies, viruses exploit a variety of host cell molecules and processes, including cell-surface components, receptor-mediated endocytosis, and endosomal maturation steps. These strategies again illustrate the sophisticated ways that pathogens have evolved to utilize the basic cell biology of their hosts.

Bacteria Enter Host Cells by Phagocytosis

Bacteria are much larger than viruses, and they are too large to be taken up by receptor-mediated endocytosis. Instead, they enter host cells through phagocytosis. Phagocytosis of bacteria is a normal function of macrophages. They patrol the tissues of the body and ingest and destroy unwanted microbes. Some pathogens, however, have acquired the ability to survive and replicate within macrophages after they have been phagocytosed.

Tuberculosis, a serious lung infection that is widespread in some urban populations, is caused by one such pathogen, Mycobacterium tuberculosis. This bacterium is usually acquired by inhalation into the lungs, where it is phagocytosed by alveolar macrophages. Although the microbe can survive and replicate within macrophages, the macrophages of most healthy individuals, with the help of the adaptive immune system, contain the infection within a lesion called a tubercle. In most cases, the lesion becomes walled off within a fibrous capsule that undergoes calcification, after which it can easily be seen on an X-ray of the lungs of an infected person. An unusual feature of M. tuberculosis is its ability to survive for decades within macrophages contained in such lesions. Later in life, especially if the immune system becomes weakened by disease or drugs, the infection may be reactivated, spreading in the lung and even to other organs.

Tuberculosis has been an obvious presence in human populations for thousands of years, but another bacterium that lives within alveolar macrophages was first recognized as a human pathogen only in 1976. Legionella pneumophila is normally a parasite of freshwater amoebae, which take it up by phagocytosis. When droplets of water containing L. pneumophila or infected amoebae are inhaled into the lung, the bacteria can invade and live inside alveolar macrophages (Figure 25-24), which, to the bacteria, must seem just like large amoebae. This infection leads to the type of pneumonia known as Legionnaire's disease. The pathogen can be efficiently spread by central air conditioning systems, as the amoebae that are the bacterium's normal host are particularly adept at growing in air-conditioning cooling towers; moreover, these cooling systems produce microdroplets of water that are easily inhaled. The incidence of Legionnaire's disease has increased dramatically in recent decades, and outbreaks are frequently traced to the air conditioning systems in office buildings, hospitals, and hotels. Other forms of modern aerosolization, including decorative fountains and produce sprayers in supermarkets, have also been implicated in outbreaks of this disease.

Figure 25-24. Uptake of Legionella pneumophila by a human mononuclear phagocyte.

Figure 25-24

Uptake of Legionella pneumophila by a human mononuclear phagocyte. This electron micrograph shows the unusual coil structure induced on the surface of the phagocyte by the bacterium. (From M.A. Horwitz, Cell 36:27–33, 1984. © Elsevier.) (more...)

Some bacteria invade cells that are normally nonphagocytic. One way that bacteria can induce such a cell to phagocytose them is by expressing an adhesin that binds with high affinity to a cell adhesion protein that the cell normally uses to adhere to another cell or to the extracellular matrix (discussed in Chapter 19). For example, a bacterium that causes diarrhea, Yersinia pseudotuberculosis (a close relative of the plague bacterium Yersinia pestis), expresses a protein called invasin that binds to β1 integrins, and Listeria monocytogenes, which causes a rare but serious form of food poisoning, expresses a protein that binds to E-cadherin. Binding to these transmembrane adhesion proteins fools the host cell into attempting to form a cell junction, and it begins moving actin and other cytoskeletal components to the site of bacterial attachment. Since the bacterium is small relative to the host cell, the host cell's attempt to spread over the adhesive surface of the bacterium results in the phagocytic uptake of the bacterium—a process known as the zipper mechanism of invasion (Figure 25-25A). The similarity of this form of invasion to the natural process of cell adhesion was underscored by the determination of the three-dimensional structure of invasin. This bacterial protein has an RGD motif, the structure of which is almost identical to that of the normal β1-integrin-binding site in laminin (discussed in Chapter 19).

Figure 25-25. Mechanisms used by bacteria to induce phagocytosis by nonphagocytic host cells.

Figure 25-25

Mechanisms used by bacteria to induce phagocytosis by nonphagocytic host cells. (A) The zipper and (B) trigger mechanisms for pathogen-induced phagocytosis both require polymerization of actin at the site of bacterial entry. (C) Frames from a time-lapse (more...)

A second pathway by which bacteria can invade nonphagocytic cells is known as the trigger mechanism (Figure 25-25B). It is used by various pathogens, including Salmonella enterica, which causes food poisoning. This dramatic form of invasion is initiated when the bacterium injects a set of effector molecules into the host cell cytoplasm through a type III secretion system. Some of these effector molecules activate Rho-family GTPases, which stimulate actin polymerization (discussed in Chapter 16). Others interact with cytoskeletal elements more directly, severing actin filaments and causing the rearrangement of cross-linking proteins. The net effect is to cause dramatic localized ruffling on the surface of the host cell (Figure 25-25C), which throws up large actin-rich protrusions that fold over and trap the bacterium within large endocytic vesicles called macropinosomes. The overall appearance of cells being invaded by the trigger mechanism is similar to the dramatic ruffling induced by some growth factors, suggesting that similar intracellular signaling cascades are activated in both cases.

Intracellular Parasites Actively Invade Host Cells

The uptake of viruses by receptor-mediated endocytosis and bacteria by phagocytosis requires energy provided by the host cell. The pathogen is a relatively passive participant, usually providing a trigger to initiate the invasion process, but not contributing any metabolic energy. In contrast, the invasion of intracellular eucaryotic parasites, which are typically much larger than bacteria, proceeds through a variety of complex pathways that usually require significant energy expenditure on the part of the parasite.

Toxoplasma gondii, the cat parasite that also causes occasional serious human infections, is an instructive example. When this protozoan contacts a host cell, it protrudes a microtubule-ribbed structure called a conoid and then reorients so that the conoid is touching the host cell surface. The parasite then slowly pushes its way into the host cell. The energy for invasion seems to come entirely from the parasite, and the process can be disrupted by depolymerizing the parasite's—but not the host's—actin cytoskeleton. As the parasite moves into the host cell, it secretes lipids from a pair of specialized organelles, generating a vacuolar membrane that is made primarily of parasite lipids and proteins. In this way, the organism protects itself in a membrane-enclosed compartment within the host cell that does not participate in host cell membrane trafficking pathways and does not fuse with lysosomes (Figure 25-26). The specialized vacuolar membrane allows the parasite to take up metabolic intermediates and nutrients from the host cell cytosol but excludes larger molecules.

Figure 25-26. The life cycle of the intracellular parasite Toxoplasma gondii.

Figure 25-26

The life cycle of the intracellular parasite Toxoplasma gondii. (A) After attachment to a host cell, T. gondii secretes lipids (red) from internal organelles. After invasion, the parasite replicates in the special vacuole formed from parasite lipids. (more...)

An entirely different, but no less peculiar, invasion strategy is used by the protozoan Trypanosoma cruzi, which causes a multiorgan disease (Chagas disease) mainly in Mexico and Central and South America. After attachment to β1 integrins on the host cell surface, this parasite induces a local elevation of Ca2+ in the host cell cytoplasm. The Ca2+ signal recruits lysosomes to the site of parasite attachment, which then fuse with the plasma membrane, allowing the parasite to enter a vacuole derived almost entirely from lysosomal membrane (Figure 25-27). As we discuss below, most intracellar pathogens go to great lengths to avoid exposure to the hostile, proteolytic environment of the lysosome, but this trypanosome uses the lysosome as its means of entry. In the vacuole, the parasite secretes a transsialidase enzyme that removes sialic acid from lysosomal glycoproteins and transfers it to its own surface molecules, thereby coating itself with host cell sugars. Next, the parasite secretes a pore-forming toxin that lyses the vacuolar membrane, releasing the parasite into the host cell cytosol, where it replicates.

Figure 25-27. Invasion of Trypansoma cruzi.

Figure 25-27

Invasion of Trypansoma cruzi. .This parasite recruits host cell lysosomes to its site of attachment. The lysosomes fuse with the plasma membrane to create a vacuole constructed almost entirely of lysosomal membrane. After a brief stay in the vacuole, (more...)

Many Pathogens Alter Membrane Traffic in the Host Cell

The two examples of intracellular parasites discussed in the preceding section raise a general problem that faces all pathogens with an intracellular lifestyle, including viruses, bacteria, and parasites. They must deal in some way with membrane traffic in the host cell. After endocytosis by a host cell, they usually find themselves in an endosomal compartment that normally would fuse with lysosomes. They therefore must either modify the compartment to prevent its fusion, escape from the compartment before getting digested, or find ways to survive in the hostile environment of the phagolysosome (Figure 25-28).

Figure 25-28. The choices faced by an intracellular pathogen.

Figure 25-28

The choices faced by an intracellular pathogen. After entry, generally through endocytosis or phagocytosis into a membrane-enclosed compartment, intracellular pathogens may use one of three strategies to survive and replicate. Pathogens that follow strategy (more...)

Most pathogens use either the first or second strategy. It is much less common to find pathogens that can survive in the phagolysosome. As we have seen, Trypanosoma cruzi uses the escape route, as do essentially all viruses (see Figure 25-22). The bacterium Listeria monocytogenes also uses this strategy. It is taken up into cells via the zipper mechanism discussed earlier and secretes a protein called hemolysin that forms large pores in the phagosomal membrane, eventually disrupting the membrane and releasing the bacteria into the cytosol. Once in the cytosol, the bacteria continue to secrete hemolysin, but it does not destroy the plasma membrane. The hemolysin selectively destroys only the phagosomal membrane for two reasons: first, it is ten times more active at the acidic pH found in the phagosome than at neutral pH found in the cytosol, and second, the hemolysin contains a PEST sequence (a peptide motif rich in proline, glutamate, serine, and threonine), which is recognized by the protein degradation machinery of the host cell, leading to the rapid degradation of the bacterial hemolysin in the proteasome (see Figure 6-86). The hemolysin is stable in the phagosome, as the degradation machinery does not have access to it there (Figure 25-29). The hemolysin secreted by L. monocytogenes is closely related to hemolysins secreted by other bacteria that are not intracellular pathogens. These related hemolysins, however, all lack PEST sequences. It seems that the L. monocytogenes hemolysin has acquired an essentially eucaryotic protein domain expressly to allow its activity to be regulated in the host cell.

Figure 25-29. Selective destruction of the phagosomal membrane by Listeria monocytogenes.

Figure 25-29

Selective destruction of the phagosomal membrane by Listeria monocytogenes. L. monocytogenes attaches to E-cadherin on the surface of epithelial cells and induces its own uptake by the zipper mechanism (see Figure 25-25A). Within the phagosome, the bacterium (more...)

By far the most common strategy used by intracellular bacteria and parasites is to modify the endosomal compartment so that they can remain there and replicate. They must modify the compartment in at least two ways: first, they must prevent lysosomal fusion, and second, they must provide a pathway for importing nutrients from the host cytosol. Different pathogens have distinct strategies for doing this. As we have seen, Toxoplasma gondii creates its own membrane-enclosed compartment that does not participate in normal host cell membrane traffic and allows nutrient transport. This option is not open to bacteria, which are too small to carry in their own supply of membrane. Mycobacterium tuberculosis somehow prevents the very early endosome that contains it from maturing, so that it never acidifies or acquires the characteristics of a late endosome. Endosomes containing Salmonella enterica, in contrast, do acidify and acquire markers of late endosomes, but they arrest their maturation at a stage prior to lysosomal fusion. Other bacteria seem to find shelter in intracellular compartments that are completely distinct from the usual endocytic pathway. Legionella pneumophila, for example, replicates in compartments that are wrapped in layers of rough endoplasmic reticulum. Chlamydia trachomatis, a sexually transmitted bacterial pathogen that can cause sterility and blindness, replicates in a compartment that seems to be most similar to part of the exocytic pathway (Figure 25-30). The mechanisms used by these organisms to alter their membrane compartments are not yet understood.

Figure 25-30. Modifications of intracellular membrane trafficking by bacterial pathogens.

Figure 25-30

Modifications of intracellular membrane trafficking by bacterial pathogens. Four intracellular bacterial pathogens, Mycobacterium tuberculosis, Salmonella enterica, Legionella pneumophila, and Chlamydia trachomatis, all replicate in membrane-enclosed (more...)

Viruses also often alter membrane traffic in the host cell. Enveloped viruses must acquire their membrane from host cell phospholipids. In the simplest cases, virally encoded proteins are inserted into the ER membrane and follow the usual path through the Golgi apparatus to the plasma membrane, undergoing various posttranslational modifications en route. The viral capsid then assembles at the plasma membrane and buds off from the cell surface. This is the mechanism used by HIV. Other enveloped viruses interact in complex ways with membrane trafficking pathways in the host cell (Figure 25-31). Even some nonenveloped viruses alter membrane traffic in the host cell to suit their own purposes. The replication of poliovirus, for example, is carried out by a membrane-associated, virus-encoded RNA polymerase. Replication can proceed more quickly if the surface area of the host cell membranes is increased. To accomplish this, the virus induces increased lipid synthesis in the host cell and blocks secretion from the ER. Intracellular membranes thereby accumulate, expanding the surface area on which RNA replication can occur (Figure 25-32).

Figure 25-31. Complicated strategies for viral envelope acquisition.

Figure 25-31

Complicated strategies for viral envelope acquisition. (A) Herpes virus capsids are assembled in the nucleus and then bud through the inner nuclear membrane, acquiring a membrane coat. They then apparently lose this coat when they fuse with the outer (more...)

Figure 25-32. Intracellular membrane alterations induced by a poliovirus protein.

Figure 25-32

Intracellular membrane alterations induced by a poliovirus protein. Poliovirus, like other positive-stranded RNA viruses, replicates its RNA genome using a polymerase that associates with intracellular membranes. Several of the proteins encoded in its (more...)

Viruses and Bacteria Exploit the Host Cell Cytoskeleton for Intracellular Movement

The cytoplasm of mammalian cells is extremely viscous. It is crowded with organelles and supported by networks of cytoskeletal filaments, all of which inhibit the diffusion of particles the size of a bacterium or a viral capsid. If a pathogen must reach a particular part of the cell to carry out part of its replication cycle, it must move there actively. As with transport of intracellular organelles, pathogens generally use the cytoskeleton for active movement.

Several bacteria that replicate in the host cell cytosol (rather than in membrane-enclosed compartments) have adopted a remarkable mechanism for moving, which depends on actin polymerization. These bacteria, including Listeria monocytogenes, Shigella flexneri, and Rickettsia rickettsii (which causes Rocky Mountain spotted fever) induce the nucleation and assembly of host cell actin filaments at one pole of the bacterium. The growing filaments generate substantial force and push the bacteria through the cytoplasm at rates up to 1 μm/sec. New filaments form at the rear of each bacterium and are left behind like a rocket trail as the bacterium advances, depolymerizing again within a minute or so as they encounter depolymerizing factors in the cytosol. When a moving bacterium reaches the plasma membrane, it continues to move outward, inducing the formation of a long, thin protrusion with the bacterium at its tip. This projection is often engulfed by a neighboring cell, allowing the bacterium to enter the neighbor's cytoplasm without exposure to the extracellular environment, thereby avoiding recognition by antibodies produced by the host's adaptive immune system (Figure 25-33).

Figure 25-33. The actin-based movement of Listeria monocytogenes within and between host cells.

Figure 25-33

The actin-based movement of Listeria monocytogenes within and between host cells. (A) These bacteria induce the assembly of actin-rich tails in the host cell cytoplasm, which enable them to move rapidly. Motile bacteria spread from cell to cell by forming (more...)

The molecular mechanism of pathogen-induced actin assembly has been determined for two of these bacteria. The mechanisms are different, suggesting that they evolved independently. Although both make use of the same host cell regulatory pathway that normally controls the nucleation of actin filaments, they exploit different points in the pathway. As discussed in Chapter 16, activation of the small GTPase Cdc42 by growth factors or other external signals causes the activation of a protein called N-WASp, which in turn activates the ARP complex that can nucleate the growth of a new actin filament. An L. monocytogenes surface protein directly binds to and activates the ARP complex to initiate the formation of an actin tail, while an unrelated surface protein on S. flexneri binds to and activates N-WASp, which then activates the ARP complex. Remarkably, vaccinia virus uses yet another mechanism to move intracellularly by inducing actin polymerization, again exploiting this same regulatory pathway (Figure 25-34).

Figure 25-34. Molecular mechanisms for actin nucleation by various pathogens.

Figure 25-34

Molecular mechanisms for actin nucleation by various pathogens. The bacteria Listeria monocytogenes and Shigella flexneri and the virus vaccinia all move intracellularly using actin polymerization. To induce actin nucleation, all of these pathogens recruit (more...)

Other pathogens rely primarily on microtubule-based transport to move within the host cell. This movement is particularly well-illustrated by viruses that infect neurons. An important example is provided by the neurotropic alpha herpes viruses, a group that includes the virus that causes chicken pox. Upon infection of sensory neurons, the virus particles are transported to the nucleus by microtubule-based transport, probably mediated by attachment of the capsids to the motor protein dynein. After replication and assembly in the nucleus, the enveloped virus is transported along microtubules away from the neuronal cell body down the axon, presumably by attachment to a kinesin motor protein (Figure 25-35).

Figure 25-35. Trafficking of herpes virus in an axon.

Figure 25-35

Trafficking of herpes virus in an axon. This nerve cell has been infected with an alpha herpes virus that has been genetically engineered to express green fluorescent protein (GFP) fused to one of its capsid proteins. In this segment of the axon, several (more...)

One bacterium that is known to associate with microtubules is Wolbachia. This fascinating genus includes many species that are parasites or symbionts of insects and other invertebrates, living in the cytosol of each cell in the animal. The infection is spread vertically from mother to offspring, as Wolbachia are also present in eggs. The bacteria ensure their transmission into every cell by binding to microtubules, and they are therefore segregated by the mitotic spindle simultaneously with chromosome segregation when an infected cell divides (Figure 25-36). As we discuss later, Wolbachia infection can significantly alter the reproductive behavior of its insect hosts.

Figure 25-36. Fluorescence micrograph of Wolbachia (red) associated with the microtubules (green) of mitotic spindles in a Drosophila embryo.

Figure 25-36

Fluorescence micrograph of Wolbachia (red) associated with the microtubules (green) of mitotic spindles in a Drosophila embryo. The clumps of bacteria at the spindle poles will be segregated into the two daughter cells when each infected cell divides. (more...)

Viruses Take Over the Metabolism of the Host Cell

Most intracellular bacteria and parasites carry the basic genetic information required for their own metabolism and replication, and they rely on their host cells only for nutrients. Viruses, in contrast, use the basic host cell machinery for most aspects of their reproduction: they all depend on host cell ribosomes to produce their proteins, and some also use host cell DNA and RNA polymerases for replication and transcription, respectively.

Many viruses encode proteins that modify the host transcription or translation apparatus to favor the synthesis of viral proteins over those of the host cell. As a result, the synthetic capability of the host cell is directed principally to the production of new virus particles. Poliovirus, for example, encodes a protease that specifically cleaves the TATA-binding factor component of TFIID (see Figure 6-16), effectively shutting off all host cell transcription via RNA polymerase II. Influenza virus produces a protein that blocks both the splicing and the polyadenylation of mRNA transcripts, which therefore fail to be exported from the nucleus (see Figure 6-40).

Translation initiation of most host cell mRNAs depends on recognition of their 5′ cap by a group of translation initiation factors (see Figure 6-71). Translation initiation of host mRNAs is often inhibited during viral infection, so that the host cell ribosomes can be used more efficiently for synthesis of viral proteins. Some viruses encode endonucleases that cleave the 5′ cap from host cell mRNAs. Some even then use the liberated 5′ caps as primers to synthesize viral mRNAs, a process called cap snatching. Several other viral RNA genomes encode proteases that cleave certain translation initiation factors. These viruses rely on 5′ cap-independent translation of the viral RNA, using internal ribosome entry sites (IRESs) (see Figure 7-102).

A few DNA viruses use host cell DNA polymerase to replicate their genome. These viruses need to solve a problem: DNA polymerase is expressed at high levels only during S phase of the cell cycle, whereas most cells that the viruses infect spend most of their time in G1 phase. Adenovirus solves this problem by inducing the host cell to enter S phase. Its genome encodes proteins that inactivate both Rb and p53, two key suppressors of cell-cycle progression (discussed in Chapter 17). As might be expected for any mechanism that induces unregulated DNA replication, these viruses are frequently oncogenic.

Pathogens Can Alter the Behavior of the Host Organism to Facilitate the Spread of the Pathogen

As we have seen, pathogens often alter the behavior of the host cell in ways that benefit the survival and replication of the pathogen. Similarly, pathogens often alter the behavior of the whole host organism to facilitate pathogen spread, as we saw earlier for Trypanosoma brucei and Yersinia pestis. In some cases, it is difficult to tell whether a particular host response is more for the benefit of the host or for the pathogen. Pathogens like Salmonella enterica that cause diarrhea, for example, usually produce self-limiting infections because the diarrhea efficiently washes out the pathogen. The bacteria-laden diarrhea, however, can spread the infection to a new host. Similarly, coughing and sneezing help to clear patho-gens from the respiratory tract, but they also spread the infection to new individuals. A person with a common cold may produce 20,000 droplets in a single sneeze, all carrying rhinovirus or corona virus.

A frightening example of a pathogen modifying host behavior is seen in rabies, as first described in Egyptian writings over 3000 years ago. This virus replicates in neurons and causes infected people or animals to become “rabid”: they are unusually aggressive and develop a strong desire to bite. The virus is shed in the saliva and transmitted through the bite wound into the bloodstream of the victim, spreading the infection to a new host.

Toxoplasma gondii, a eucaryotic parasite that forms lesions in muscle and brain tissue, provides an equally remarkable example. It can complete its life cycle only in its normal host—cats. If it infects an intermediate host, such as a rodent or human, the infection is a dead end for the parasite, unless the intermediate host is eaten by a cat. Behavioral studies show that rats infected with T. gondii lose their innate fear of cats and instead preferentially seek out locations perfumed with cat urine over locations perfumed with rabbit urine, exactly the opposite of normal rat behavior.

But the most dramatic example of pathogens modifying host behavior belongs to Wolbachia. These bacteria manipulate the sexual behavior of their host to maximize their dissemination. As described earlier, Wolbachia are passed vertically into offspring through eggs. If they live in a male, however, they hit a dead end, as they are excluded from sperm. In some species of Drosophila, Wolbachia modify the sperm of their host so that they can fertilize the eggs only of infected females. This modification creates a reproductive advantage for infected females over uninfected females, so that the overall proportion of Wolbachia carriers increases. In other host species, a Wolbachia infection kills males but spares females, increasing the number of females in the population and thus the number of individuals that can produce eggs to pass on the infection. In a few types of wasp, Wolbachia infections enable the females to produce eggs that develop parthenogenetically without the need for fertilization by sperm; in this species, males have been completely eliminated. For some of its hosts, Wolbachia has become an indispensable symbiont, and curing the infection causes death of the host. In one case, humans are making use of this dependence: the filarial nematode that causes African river blindness is difficult to kill with antiparasite medications, but when people with river blindness are treated with antibiotics that cure the nematode's Wolbachia infection, the nematode infection is also arrested.

Pathogens Evolve Rapidly

The complexity and specificity of the molecular interactions between pathogens and their host cells might suggest that virulence would be difficult to acquire by random mutation. Yet, new pathogens are constantly emerging, and old pathogens are constantly changing in ways that make familiar infections difficult to treat. Pathogens have two great advantages that enable them to evolve rapidly. First, they replicate very quickly, providing a great deal of material for the engine of natural selection. Whereas humans and chimpanzees have acquired a 2% difference in genome sequences over about 8 million years of divergent evolution, poliovirus manages a 2% change in its genome in 5 days, about the time it takes the virus to pass from the human mouth to the gut. Second, this rapid genetic variation is acted on by powerful selective pressures provided by the host's adaptive immune system and by modern medicine, which destroy pathogens that fail to change.

A small-scale example of the constant battle between infection and immunity is the phenomenon of antigenic variation. An important adaptive immune response against many pathogens is the production of antibodies that recognize specific antigens on the pathogen surface (discussed in Chapter 24). Many pathogens evade complete elimination by antibodies by changing these antigens during the course of an infection. Some parasites, for example, undergo programmed rearrangements of the genes encoding their surface antigens. The most striking example occurs in African trypanosomes such as Trypanosoma brucei, a parasite that causes sleeping sickness and is spread by an insect vector (T. brucei is a close relative of T. cruzi (see Figure 25-27), but it replicates extracellularly rather than inside cells). T. brucei is covered with a single type of glycoprotein, called variant-specific glycoprotein (VSG), which elicits a protective antibody response that rapidly clears most of the parasites. The trypanosome genome, however, contains about 1000 VSG genes, each encoding a VSG with distinct antigenic properties. Only one of these genes is expressed at any one time, by being copied into an active expression site in the genome. The VSG gene expressed can be changed repeatedly by gene rearrangements that copy new alleles into the expression site. In this way, a few trypanosomes with an altered VSG escape the antibody-mediated clearance, replicate, and cause a recurrence of disease, leading to a chronic cyclic infectionFigure 25-37).

Figure 25-37. Antigenic variation in trypanosomes.

Figure 25-37

Antigenic variation in trypanosomes. (A) There are about 1000 distinct VSG genes in Trypanosoma brucei but only one site for VSG gene expression. An inactive gene is copied into the expression site by gene conversion, where it is now expressed. Rare switching (more...)

A different type of antigenic variation occurs during the course of infection by viruses that have error-prone replication mechanisms. Retroviruses, for example, acquire on average one point mutation every replication cycle, because the viral reverse transcriptase that produces DNA from the viral RNA genome cannot correct nucleotide misincorporation errors. A typical, untreated HIV infection may eventually involve HIV genomes with every possible point mutation. In some ways, the high mutation rate is beneficial for the pathogen. By a microevolutionary process of mutation and selection within each host, the virus can switch from infecting macrophages to infecting T-cells (as described earlier), and, once treatment is begun, it can quickly acquire resistance to drugs. If the reverse transcriptase error rate were too high, however, deleterious mutations might accumulate too rapidly to allow the virus to survive. Furthermore, rapid viral diversification in one host does not necessarily lead to rapid evolution of the virus in the population, as a mutated virus may not be able to infect a new host. For HIV-1, the extent of this constraint can be estimated by examining the sequence diversity among different individuals infected with the virus. Remarkably, only about one-third of the nucleotide positions in the coding sequence of the virus are invariant, and nucleotide sequences in some parts of the genome, such as the env gene, can differ by as much as 30%. This extraordinary genomic plasticity greatly complicates attempts to develop vaccines against HIV, and it can also lead to rapid drug resistance (see below). A further consequence has been rapid diversification and emergence of new HIV strains. Sequence comparisons between various strains of HIV and the very similar simian immunodeficiency virus (SIV) from a variety of different monkey species seem to indicate that the most virulent type of HIV, HIV-1, may have jumped from chimpanzees to humans as recently as 1930Figure 25-38).

Figure 25-38. Diversification of HIV-1, HIV-2, and related strains of SIV.

Figure 25-38

Diversification of HIV-1, HIV-2, and related strains of SIV. The genetic distance between any two viral isolates is found by following the shortest path joining them in the tree. HIV-1 is divided into two groups, major (M) and outlier (O). The HIV-1 M (more...)

Rapid evolution in bacteria frequently takes place by horizontal gene transfer rather than by point mutation. Most of this horizontal gene transfer is mediated by the acquisition of plasmids and bacteriophages. Bacteria readily pick up pathogenicity islands and virulence plasmids (see Figure 25-5) from other bacteria. Once a bacterium has acquired a new set of virulence-related genes, it may quickly establish itself as a new cause of human epidemics. Yersinia pestis, for example, is an infection endemic to rats and other rodents that first appeared in human history in 542 A.D., when the city of Constantinople was devastated by plague. Sequence comparisons of Y. pestis to its close relative Y. pseudotuberculosis, which causes a severe diarrheal disease, suggest that Y. pestis may have emerged as a distinct strain only a few thousand years ago, not long before its debut in the field of urban devastation.

The emergence and evolution of new infectious disease is in many cases exacerbated by changes in human behavior. For example, crowded and filthy living conditions in medieval cities contributed to the spread of plague to humans from the natural rodent host. The tendency of modern humans to live at high population densities in large cities has also created the opportunity for infectious organisms to initiate epidemics, such as influenza, tuberculosis, and AIDS, which could not have spread so rapidly or so far among sparser human populations. Air travel can, in principle, allow an asymptomatic, newly infected host to carry an epidemic to any previously unexposed population within a few hours or days. Modern agricultural practices also foster the emergence of certain types of infectious agents that could not have easily developed in the hunter-gatherer societies of early humans. Influenza viruses, for example, are unusual in that their genome consists of several (usually eight) strands of RNA. When two strains of influenza infect the same host, the strands of the two strains can reshuffle to form a new and distinct type of influenza virus. Prior to 1900, the influenza strain that infected humans caused a very mild disease; a separate influenza strain infected fowl such as ducks and chickens but could not infect humans. Both the avian and the human strains, however, are capable of infecting pigs, and can recombine in a pig host to form new strains that can cause serious human disease. In communities where pigs are farmed together with chickens or turkeys, newly recombined influenza strains periodically emerge and cause worldwide epidemics. The first and most serious of these epidemics was the “Spanish flu” epidemic of 1918, which killed more people than did World War I.

Drug Resistant Pathogens Are a Growing Problem

While some human activities have promoted the spread of certain infectious diseases, advances in public sanitation and in medicine have prevented or alleviated the suffering caused by many others. Effective vaccines and worldwide vaccination programs have eliminated smallpox and severely reduced poliomyelitis, and many deadly childhood infections such as mumps and measles are now rarities in wealthy industrialized nations. However, there are still many widespread and devastating infectious diseases, such as malaria, for which no effective vaccines are available. Of equal importance is the development of drugs that cure rather than prevent infections. The most successful class are the antibiotics, which kill bacteria. Penicillin was one of the first antibiotics used to treat infections in humans, introduced into clinical use just in time to prevent tens of thousands of deaths from infected battlefield wounds in World War II. The rapid evolution of pathogens, however, has enabled targeted bacteria to develop resistance to antibiotics very quickly; the typical lag between introduction of an antibiotic into clinical use and the appearance of resistant strains is only a few years. Similar drug resistance arises rapidly among viruses when infections are treated with antiviral agents. The virus population in an HIV-infected person treated with the reverse transcriptase inhibitor AZT, for example, will acquire complete resistance to the drug within a few months. The current protocol for treatment of HIV infections involves the simultaneous use of three drugs, which helps to minimize the acquisition of resistance.

There are three general strategies by which pathogens develop drug resistance. Pathogens can (1) produce an enzyme that destroys the drug, (2) alter the molecular target of the drug so that it is no longer sensitive to the drug, or (3) prevent access to the target by, for example, actively pumping the drug out of the pathogen. Once a pathogen has chanced upon an effective strategy, the newly acquired or mutated genes that confer that resistance are frequently spread throughout the pathogen population and may even be transferred to pathogens of different species that are treated with the same drug. The highly effective and very expensive antibiotic vancomycin, for example, has been used as a treatment of last resort for many severe hospital-acquired bacterial infections that are already resistant to most other known antibiotics. Vancomycin prevents one step in bacterial cell wall biosynthesis, by binding to part of the growing peptidoglycan chain and preventing it from being cross-linked to other chains. Resistance can arise if the bacterium synthesizes a different type of cell wall, using different subunits that do not bind vancomycin. The most effective type of vancomycin resistance depends on a transposon that encodes seven genes. The products of these genes work together to sense the presence of vancomycin, shut down the normal pathway for bacterial cell wall synthesis, and generate a different type of cell wall. Although the joining of these genes into a single transposon must have been a difficult evolutionary task (it took 15 years for vancomycin resistance to develop, rather than the typical lag of a year or two), the transposon can now be readily transmitted to many other pathogenic bacterial species.

Like most other aspects of infectious disease, the problem of drug resistance has been exacerbated by human behavior. Many patients take antibiotics for viral diseases that are not helped by the drugs, including influenza, colds, and earaches. Persistent and chronic misuse of antibiotics in this way can eventually result in the antibiotic resistance of the normal flora, which can then transfer the resistance to pathogens. Several antibiotic-resistant outbreaks of infectious diarrhea caused by Shigella flexneri, for example, originated in this way. The problem is particularly severe in countries where antibiotics are available without a physician's prescription, as in Brazil, where more than 80% of the strains of S. flexneri found in infected patients are resistant to four or more antibiotics.

Antibiotics are also misused in agriculture, where they are commonly employed as food additives to promote the growth of healthy animals. An antibiotic closely related to vancomycin was commonly added to cattle feed in Europe. Resistance arising in the normal flora of these animals is widely believed to be one of the original sources for the vancomycin resistance that is now seen in life-threatening human infections.


All pathogens share the ability to interact with host cells in ways that promote replication and spread of the pathogen, but these host-pathogen interactions are diverse. Pathogens often colonize the host by adhering to or invading through the epithelial surfaces that line the lungs, gut, bladder, and other surfaces in direct contact with the environment. Intracellular pathogens, including all viruses and many bacteria and protozoa, replicate inside a host cell, which they invade by one of a variety of mechanisms. Viruses rely largely on receptor-mediated endocytosis for host cell entry, while bacteria exploit cell adhesion and phagocytic pathways. Protozoa employ unique invasion strategies that usually require significant metabolic expense. Once inside, intracellular pathogens seek out a niche that is favorable for their replication, frequently altering host cell membrane traffic and exploiting the cytoskeleton for intracellular movement. Besides altering the behavior of individual host cells, pathogens frequently alter the behavior of the host organism in ways that favor spread to a new host. Pathogens evolve rapidly, so new infectious diseases frequently emerge, and old diseases acquire new ways to evade human attempts at treatment, prevention, and eradication.

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Copyright © 2002, Bruce Alberts, Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, and Peter Walter; Copyright © 1983, 1989, 1994, Bruce Alberts, Dennis Bray, Julian Lewis, Martin Raff, Keith Roberts, and James D. Watson .
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