Germs are everywhere: in air, soil, rocks, and water; in plants and animals; and, of course, in our own bodies. Some thrive in intense heat, while others require extreme subzero temperatures. Many have a remarkable ability to replicate themselves rapidly—reproducing every few hours in some cases—an evolutionary trick that makes them highly adaptable to changing environments and to the medicines we use to ﬁght them.
By studying germs and how our body responds to them, scientists have unraveled many of the battle secrets—and vulnerabilities—of the immune defense system, revealing how it normally operates in its daily war on microbes and how its malfunction can contribute to disease.
Scientists now know that most biological bad guys fall into four basic categories: viruses, fungi, bacteria, and parasites. Each type of predator has its own invade-and-infect strategy.
|Bird ﬂu, or avian inﬂuenza, refers to a group of related viral diseases that attack birds. It infects primarily poultry, but human cases were discovered in Hong Kong beginning in 1997. New strains of these viruses, if they undergo genetic changes so that they can infect humans, have the potential to kill millions because humans lack immunity to them. Goldsmith, J. Katz, and S. Zaki|
Viruses are not whole cells but consist of one or more molecules of DNA or RNA. DNA, or deoxyribonucleic acid, carries a cell’s genetic information and synthesizes RNA, or ribonucleic acid, which carries information from the nucleus to the body of the cell to assemble proteins. The viruses may be shaped like rods or spheres or may be multisided. In some ways, viruses are like biological pirates: they invade cells, hijack the internal machinery, and start reproducing, unleashing thousands of duplicate viruses (known as clones) that invade and take over other cells. Viruses also change their appearance, or mutate, often, and they can jump from one species to another (from certain animals to people, for example). Examples of viral illnesses include:
- colds, ﬂu, and other common respiratory illnesses spread from one person to another;
- bird ﬂu, a new and particularly deadly type of ﬂu caused by a virus that jumped from birds to people;
- rabies, a deadly nervous system disease
transmitted through the bite of an infected animal;
- and West Nile virus, another nervous system disease, transmitted through the bite of an infected mosquito.
Take a walk in the woods or stroll along the aisles of a grocery store and you’ll see one type of fungus—a mushroom. Fungi are actually a primitive vegetable and are found in air, soil, plants, and water. Thousands of types of fungi have been identiﬁed, including yeast, mold, and mildew, and there are surely many more types, about half of which cause disease in humans. Disease-causing fungi tend to infect moist areas of the body.
| Athlete’s foot attacks between the toes, eroding the skin.SPL / Photo Researchers, Inc.|
|Pictured are the rounded, single-cell spores and threads characteristic of the athlete’s foot fungus. The fungus infects the foot by means of the spores and thrives in moist areas, including the ﬂoors of showers.Biophoto Associates /Photo Researchers, Inc. Courtesy of Rocky Mountain Labratories|
Athlete’s foot, for example, is a common rash that results from fungi that often lurk in a shared shower (as at the gym) and then thrive and reproduce when your feet sweat. But not all fungi cause disease; some actually help ﬁght it. Penicillin, the antibiotic that transformed the treatment of infectious diseases, was discovered when a laboratory scientist noticed that a petri dish with mold growing on it was free of bacteria.
Bacteria are single-celled organisms that may be shaped like balls, rods, or spirals. Larger and more complicated than viruses, bacteria don’t need to hijack your cells to wreak havoc—they can do it all on their own. Fortunately, most bacteria are helpful. Some live in the stomach and intestine and help digest food. But about one in eight bacteria can make you sick. Harmful bacteria can cause problems in three ways: some invade and attack a speciﬁc part of the body; others produce chemical poisons that cause illness; still others multiply so much that they obstruct blood vessels or prevent the heart from functioning normally. Some examples of bacterial infections and the way in which they occur:
- food poisoning, caused by eating contaminated food;
- anthrax poisoning, for which authorities carefully watch, caused by inhaling or swallowing contaminated powder;
- and Lyme disease, which is transmitted by infected ticks and causes muscle and joint pain and sometimes damages the nervous system.
|E. coli is a bacterium that exists naturally in the lower intestine of humans. It is also used as a research organism in labs. A toxin it produces can cause illness. One particularly dangerous strain, E. coli 0157, has been known to cause death. NIAID, NIH|
|A computer model shows the structure of the anthrax bacterial toxin, which is a bioterrorism concern. Cutaneous anthrax (anthrax infection on the skin) causes painful blisters and swelling, while inhalation anthrax (anthrax infection in the lungs) can cause a host of symptoms, including fever, chest pain, and shock. R. John Collier, Harvard Medical School|
Parasites comprise single-celled protozoa and multicellular animals, such as nematodes and helminths (worms), that require a moist environment to survive and usually cause disease in humans. A person can become infected after drinking contaminated water or eating infected food, or eating with unwashed hands. One example of a parasitic infection is malaria, which causes recurring bouts of fever and chills after someone is bitten by an infected mosquito. Although the immune system responds, parasites are capable of mounting follow-up attacks: they can go into hiding in the cells for a while and then, start replicating again when the immune defense has diminished.
| Mosquitoes can spread diseases, such as West Nile virus and malaria when they bite. James Gathany|
Considering this daily barrage from all directions, it’s a wonder that we aren’t sick all the time. Fortunately, the human immune system has evolved to handle this onslaught, operating like a highly efﬁcient killing machine to fend off germs wherever and whenever they appear. Although the immune system employs a variety of weapons and strategies based on the speciﬁc threat, in general your immune system mounts a three-step defensive process.
Step 1: Sounding the Alarm
The ﬁrst defenders on the scene of a germ attack are components of your innate immune system. The white blood cells that make up the innate immune system circulate throughout the body constantly, much like police on patrol, always on the lookout for biological suspects. These patrolling white blood cells belong to the phagocyte family, but they have many subtypes (just as a police force consists of detectives, sergeants, captains, and patrol ofﬁcers). Phagocytes consist of macrophages, dendritic cells, and granulocytes. In various ways, the different types of phagocytes identify, engulf, and ingest germs and other invaders. Phagocytes lead the way in many critical innate reactions.
Knowing that where one harmful virus or germ lurks more may be hiding, phagocytes sound chemical alarms to bring the more specialized immune cells to the scene. First, dendritic cells display an antigen—a chemical that identiﬁes the invader—so that the appropriate immune system specialist cells are able to recognize the culprit. The specialists, which consist of B and T cells, are known collectively as lymphocytes, and they make up the body’s adaptive immune system. As its name implies, the adaptive immune system adapts and adjusts to speciﬁc threats as the need arises, whereas the innate immune system is pre-existing and less speciﬁc. Although B cells can recognize and respond to antigens without much assistance, T cells require a second “danger” signal in the form of a biological ﬂag, known as an MHC molecule, which an antigen-presenting cell (such as a macrophage or dendritic cell) uses to clearly designate that an invader is foreign. The phagocytes also release chemical messengers known as cytokines.
Germ breaches the body’s natural barriers
Alert the immune system
Trigger the ﬁrst
line of defense
(innate immune system)
Recruit and trigger the second line of defense (adaptive immune system)
|This ﬂow chart describes the steps of the body’s immune response to a foreign organism or substance. A foreign substance triggers ﬁrst the innate and subsequently the adaptive immune systems. In a successful response the pathogens are killed and antibodies are produced to more efﬁciently respond to future attacks. |
|A scanning electron micrograph image shows a macrophage (right) and two lymphocytes (left). Lymphocytes and macrophages are types of white blood cells. Macrophages form in the bone marrow and can attack many types of foreign organisms. Lymphocytes are stored in lymph nodes. Macrophages are also found in lymph nodes and “ﬁlter” pathogens (such as bacteria) from the lymph that passes through them. SPL / Photo Researchers, Inc.|
These danger signals rouse the T cells, which quickly multiply and rush to the scene. The elapsed time before these defenses arrive may be days to weeks, but repeated exposure to an invader will teach T cells to respond quicker. Vaccines, which will be discussed later, take advantage of this immune system memory.
Step 2: The Battle Escalates
Lymphocytes mount a two-pronged attack, one directed at infected cells and the other at hostile microbes circulating in the blood. The cell-targeting attack is directed by T cells. Killer T cells directly kill infected cells that have been marked for destruction by the phagocytes, while helper T cells coordinate the attack and send for reinforcements as needed. Meanwhile, B cells produce antibodies that bind to free-ﬂoating microbes circulating in the blood so that they cannot infect other cells. Phagocytes then engulf and destroy the antibody-studded invaders. Antibodies also activate complement proteins, which destroy microbes by punching holes in them.
As the battle rages at the microscopic level, you may start to be aware that something is amiss. If you’ve been infected with a cold virus, for example, your throat will become sore, your eyes watery, and your sinuses congested. These are the physical signs of inﬂammation, the buildup of ﬂuid and cells that occurs as the immune system ﬁghts a hostile invader.
Step 3: Remember and Recover
Once all invaders and infected cells have been destroyed, the immune system soldiers that once multiplied so quickly decline in number. Inﬂammation subsides, and symptoms gradually disappear. But certain memory B and T cells remain, to remember how to attack the invader if it returns.
Even with all these physiological weapons at our disposal, microbes occasionally manage to outsmart our immune sentries or elude detection. One reason is that microbes evolve rapidly and humans do not, giving the germs an advantage over our immune defenses. Moreover, if our defense system is impaired in any way—either by an inherited condition or because we’ve been exposed to certain environmental toxins or medical treatments that suppress immunity—we are more susceptible to infection.
Failing to Protect: Immune Dysfunction Spells Trouble
For all its highly evolved mechanisms for identifying and ﬁghting off the daily onslaught of germs, the immune system sometimes fails to provide the protection we need. Because the system is so complex, relying on a battalion of specialized units (in the form of T cells, B cells, macrophages, and an arsenal of antibodies and other biochemicals) to perform speciﬁc defense tasks and to coordinate with one another, dysfunction in any one of these units can render the entire system inadequate.
One might compare the immune system to the U.S. Department of Defense. When waging a war, the Defense Department relies on all of its forces—Army, Navy, Air Force, Marines, as well as specialized intelligence units, paramilitary forces, antiterrorist teams, and so on—to work together in a coordinated fashion to defeat the enemy. It also relies heavily on its weapons—bombs, missiles, guns, tanks, battleships, warplanes, and so forth. As with the immune system, the effectiveness of the war machine as a whole depends largely on the ability of each component to efﬁciently fulﬁll its individual role. If a reconnaissance plane spies an enemy battalion approaching, but it can’t get the message to troops on the ground, or if the troops don’t have the ammunition or armor they need to fend off the attack, the enemy is free to wreak havoc.
In the same way, if any one component of the immune system is not up to par, germs can quickly get the upper hand. This is the case in immune deﬁciency diseases (IDDs), which result when one or more parts of the immune system are missing or defective.
|A computer model shows the two intertwined strands of nucleotides that form the “double-helix” structure of DNA, which contains the body’s genetic code. With few exceptions, including sperm and eggs, every cell in the human body contains the complete DNA information of an individual. Robert Guy, NCI|
An IDD can be inherited or acquired through an infection (such as HIV) or illness, or it can result as a side effect of certain immunosuppressive medical treatments, or treatments that suppress natural immune responses. Acquired immunodeﬁciency syndrome (AIDS) is the best-known immune deﬁciency disease (“Special Focus: AIDS,” page 32), but there are many other less well-known and less prevalent examples. Some cancer treatments, including chemotherapy drugs, radiation, and high doses of a group of medicines called steroids, can weaken the immune system and render a person more vulnerable to infection.
When the Problem Is Your Genes
Primary immune deﬁciency (PID) diseases are the result of an inherited genetic defect that interferes with the immune system’s normal development in one way or another. More than eighty different PID diseases have been identiﬁed, each one producing a constellation of symptoms depending on which piece or pieces of the defensive system are faulty. Symptoms of individual diseases can range from mild or nonexistent to devastatingly severe. About 25,000 to 50,000 Americans have been diagnosed with a severe form of primary immune deﬁciency disease, but there are probably many thousands more who have milder forms.
One of the most common of these diseases, affecting about 1 in 600 Americans, is selective immunoglobulin A (IgA) deﬁciency. IgA is a particular type of antibody that defends against infections at mucous membranes that line the mouth, airways, and digestive tract. IgA deﬁciency results when B cells do not mature properly and fail to produce IgA antibodies at the levels required. Many people with the deﬁciency remain healthy; others may suffer recurrent infections of the ear, sinuses, or lungs.
| A child with severe combined immunodeﬁciency disease (SCID), also called “bubble boy” disease, is extremely susceptible to infection because of a malfunctioning immune system. He would not survive outside carefully controlled environments, such as the enclosed area pictured here. © Laurent / Photo Researchers, Inc.|
Living in a Bubble
Far less common is severe combined immunodeﬁciency disease (SCID), sometimes called “bubble boy” disease, which affects about one child in a million and is usually fatal. Infants born with this inherited condition have dramatic abnormalities in both innate and adaptive immunity, leaving them utterly defenseless against infections of any type and necessitating that they remain in a germ-free environment (the plastic “bubble” in which such children often must live acts as a barrier to infectious microbes).
At least a quarter of SCID cases are linked to a defect in a gene that speciﬁes the genetic code for a particular enzyme, adenosine deaminase (ADA). The absence of ADA interferes with metabolic processes within the cell, setting off a cascade of molecular events that are particularly lethal to T and B cells. Scientists have tested controversial gene therapy approaches to treating SCID, with the goal of replacing the missing gene and restoring production of ADA. While this approach has proven successful in some cases, treated children died as a result of complications from the therapy, prompting an end to clinical trials until scientists conduct further laboratory research.
|This image shows a cancer cell dying. Scientists who work on cancer treatments have to find ways to target cancer cells without damaging the healthy cells that surround them. NCI|
Targeting Tumor Cells
In addition to defending us against germs, the immune system identiﬁes and attacks cancerous tumor cells. When a normal cell turns cancerous, many properties of the cell change, and these changes, some of which occur on the surface of the cell, are recognized by the immune system as antigens. The dendritic cells, for example, recognize dying cancer cells and process them to make their antigens more conspicuous to T cells. Under normal circumstances, the immune system ﬁghts back to contain and neutralize the cancer. However, if the immune system is defective in some way, or tumor cells are so widespread or so fast-growing that the immune defenses are overwhelmed, cancer cells can develop and thrive.
A great deal of research is now directed at developing immune therapy for cancer. Sometimes referred to as cancer vaccines, these approaches seek to bolster the immune system’s response to tumor cells. A number of research groups are using various strategies to “pump up” tumor-killing immune cells or to increase levels of speciﬁc types of antibodies that can seek out and destroy tumor cells. The National Cancer Institute, part of the federal government’s National Institutes of Health, is the main agency responsible for coordinating and funding clinical trials testing cancer immune therapy.
Inducing Disease: “Friendly Fire” from the Immune System
Like tragic cases of “friendly ﬁre” on the battleﬁeld of war, sometimes the immune system mistakenly attacks “self” tissue. This self-attack can cause symptoms that range from the annoyance of a runny nose, as in allergies, to the devastating progressive degeneration of joints and organs associated with rheumatoid arthritis.
A disease in which the immune system attacks the body is called an autoimmune disorder. Autoimmune disorders comprise at least 80 different conditions that together affect 5 to 9 percent of Americans, or between 14 million and 22 million people. The misdirected attack on self tissue may target one or several body parts, depending on the disease. For example, in type 1 diabetes the immune system zeroes in on the pancreas, damaging cells that secrete the hormone insulin and rendering the body inefﬁcient at processing glucose (a type of sugar). In multiple sclerosis, the objects of attack are cells in the central nervous system (the brain and spinal cord), particularly those in myelin, the fatty substance that sheathes nerve ﬁbers and enhances the transmission of nerve signals. In psoriasis, skin cells are targeted. Systemic lupus erythematosus, on the other hand, is an example of a non-organ-speciﬁc autoimmune disease: organs and tissues throughout the body may be affected, and different people experience different sets of symptoms.
No Tolerance for Self
Each autoimmune disorder is associated with a unique combination of health problems. All of them seem to result from the malfunctioning of immune tolerance mechanisms. “Tolerance” refers to the process by which the developing immune system normally eliminates any immune cells that are autoreactive—that is, immune cells that mount a response to the body’s own tissue.
Tolerance is a multilayered system, with a series of checks and balances built in to prevent self-attack from either innate or adaptive immune cells. In some cases, the self-reactive cells are removed or deleted. In other cases, they are silenced by immune cells called regulatory or suppressor cells.
Unfortunately, the process is somewhat leaky, and each of us ends up having a subpopulation of autoreactive immune cells ﬂoating around our body. If at some point in our life we are exposed to a microbe that happens to carry antigens resembling those on a particular organ—a situation immunologists call molecular mimicry—then the self-reactive cells that slipped through the checkpoints of tolerance mistakenly take aim at the body, striking out against the very tissue that they are supposed to be defending. Some scientists reason that such a scenario may trigger multiple sclerosis, for example.
A combination of many factors, inherited and environmental, increases one’s susceptibility to autoimmune disease. On the genetic side, scientists are trying to identify the speciﬁc genes involved in various disorders, but that search has proved difﬁcult because these disorders do not appear to result from single genetic defects. Rather, it is likely that a combination of genes, each of which may increase one’s vulnerability, interact with environmental and lifestyle factors to produce disease. Environmental risks for autoimmune disease may include exposure to certain toxins or chemicals that are in the air, the ground, or the food we eat, or to certain viral infections.
For reasons that are not clear, autoimmune disorders strike women more than men. Some scientists believe the female hormone estrogen may contribute to this increased incidence among women, but estrogen’s role in immune function is complex and still being sorted out.
In 2002 the National Institutes of Health committed $51 million to a ﬁve-year research initiative aimed at unraveling the puzzle of autoimmune disorders. The plan, which established nine Autoimmune Centers of Excellence at large academic research institutions, funds both basic research on the underlying biology of these disorders and clinical trials to test potential treatments. The goal is to speed the translation of scientiﬁc discoveries about the basic biology of autoimmunity into new therapies that will beneﬁt patients.
Sneezing and Wheezing
Though they are not technically autoimmune disorders, allergies and asthma also result from an inappropriate immune response. An allergic reaction occurs when normally harmless substances, such as pollen or chemicals in pet dander, trigger an immune response. In people prone to allergies, the response produces an overabundance of the antibody called IgE, or immunoglobulin E, which in turn triggers plasma cells in the blood and mast cells in the skin, tongue, lungs, nose, and intestinal tract to release histamine, a biochemical that produces common allergy symptoms.
|Asthma can be triggered by allergies or exposure to pollutants such as cigarette smoke. The inhalers used by people with asthma stave off inﬂammation caused by these triggers. Karen Phillips, Benjamin Reese|
|This diagram shows the stages of the body’s response to the presence of an allergen (allergic response). Interleukins are proteins that help regulate the immune system, particularly the interaction among white blood cells, or leukocytes. B cells recognize the allergen and produce antibodies. A reaction follows, producing the symptoms commonly referred to as allergies. Adapted from NIAID, NIH|
Asthma results when mast cells in the lungs and airways are provoked into producing histamine as a result of contact with an allergen, or because of some other precipitating factor such as exercise. The airways can become constricted, causing the difﬁcult breathing, wheezing, and coughing that are typical of an asthma attack. Without treatment, asthma can be deadly. Although the overall number of deaths from asthma is low, at least 17 million Americans have asthma, and its prevalence appears to be increasing. Researchers are trying to understand why.
Losing Battles: Why the Immune System Can’t Beat Every Enemy
You may be wondering why, if the immune system is such an efﬁcient germ-killing machine, so many people are sick with the ﬂu at certain times of the year. Or why, if our immune system can ﬁght off cancer cells and other life-threatening illnesses, it can’t protect us from the common cold. Why do we hear so much in the news these days about “new” viral diseases (such as West Nile, SARS, and bird ﬂu) and resurging “old diseases” (such as tuberculosis, malaria, and whooping cough)?
Despite the remarkable efﬁciency of the normally functioning immune system, people who manage to escape unscathed from every infectious microbe they encounter are rare. The highly adaptable nature of germs means that new threats are always emerging as microbes reinvent themselves, learn to outsmart our medicines, and jump from other species to humans.
Adapting to Change
Perhaps the biggest reason our immune systems can’t seem to keep up with every “bug” out there waiting to infect us is a simple one: microbes are more adaptable to changing environments than we are. Bacteria, parasites, and viruses replicate rapidly in response to environmental pressures and, while doing so, alter their structures in subtle ways that make them undetectable to the immune system.
Flu viruses are among the most changeable of microbes; the genes that compose them are in a continual state of ﬂux and reassortment. This is why last year’s ﬂu vaccine is unlikely to protect fully against this year’s dominant strain (or strains) of ﬂu, and why the ﬂu vaccine is reformulated every year. It is also why, without immunization, we are more likely to catch the ﬂu: since the virus has morphed into a new composition, our immune system doesn’t recognize it, and we end up suffering the classic symptoms: fever, chills, muscle aches, and fatigue. These symptoms are the result of our immune system trying to rid the body of the virus.
Annually, many Americans come down with the ﬂu and an average of 20,000 to 40,000 people die from it. The elderly, young children, and people whose immune systems are compromised are most at risk for serious complications from the ﬂu.
The common cold, like the ﬂu, is the result of a viral infection, usually called a rhinovirus. Scientists have identiﬁed more than 110 different strains of rhinovirus and at least another hundred viruses that cause colds in humans. Nearly half of all adult colds are of unknown origin, which makes the sought-after “cure for the common cold” a distant goal. School-age children get colds most often, probably because they are in such close proximity to one another. Children have an average of six to ten colds a year, compared with adults’ two to four a year, on average. People over 60 have even fewer colds—less than one a year, on average—which may simply reﬂect the fact that many older people have less day-to-day contact with other people who could infect them with a cold virus.
Pandemics and Emerging Microbes
Every few decades a particularly virulent strain of the ﬂu emerges and produces a pandemic, an epidemic that occurs across a wide geographic area. The last ﬂu pandemic occurred in 1968, and many scientists believe we are long overdue for the next. Global health experts are keeping a close watch on bird ﬂu (also known as avian ﬂu), which many fear might produce a pandemic. First identiﬁed in chickens, this ﬂu strain began causing alarm because it was found in humans for the ﬁrst time in 1997, and by 2005, many dozens of human cases had been documented in several countries.
What Are “Emerging Microbes”?
One of the biggest subjects in contemporary microbiological research (the study of microbes) is that of “emerging microbes.” In the last two decades alone, more than thirty newly recognized infectious diseases have emerged, including AIDS, toxic shock syndrome, Lyme disease, hantavirus, hepatitis C, and SARS. In most cases, these diseases are not really new, but rather their incidence is rising more rapidly than ever, making them an ever greater threat to humans. Also of concern are old diseases that are now re-emerging, even though they were mostly wiped out thanks to improved public health measures and widespread immunization. Tuberculosis is one example.
Driving the spread of these diseases is increasing globalization, with the growing world population traveling greater distances than ever before, carrying disease-causing microbes with them. Climate changes and the widespread logging of Earth’s forests are also factors in the spread of infectious diseases to new geographic areas and populations.
Public health experts are particularly concerned about the appearance of new strains of bacteria that are resistant to treatment with antibiotics, the “wonder drugs” of the last century that have saved many millions of lives. Fueling this dangerous trend is the widespread use of antibiotics, which are often inappropriately prescribed for people who have viral infections (antibiotics kill bacteria, not viruses). The problem stems from the innate adaptability of bacteria: Because bacteria evolve and replicate so rapidly— dividing every few hours or so—they can reshufﬂe their genes with each division, creating strains that stubbornly resist treatment with standard antibiotics in the penicillin family. A great deal of current research is focused on the molecular tricks that bacteria use to outwit antibiotics, an area that has progressed rapidly thanks to new tools that enable researchers to unravel the genetic code of resistant microbes.
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| The recent incidence of bird ﬂu among humans has increased the importance of research into the disease. Tests of a vaccine have shown promise, though as of summer 2005 it was not ready for public use. Rob Flynn|