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Chapter 1

Hidden Enemies Around Us

Humans have lived with infectious microbes since our very first beginnings and they have been, for most of our history, one of humanity's biggest preoccupations. Fortunately for us, modern science has had many shining successes against infections. To understand these successes, as well as our ongoing vulnerabilities to pathogens, we need to look at where we've come from, and where we are now.

Louis Pasteur's "germ theory," which originated in the 1870s, marked the dawn of our modern-day approach to microbes by illuminating for the first time the immense landscape of microscopic infectious pathogens that were behind the most problematic diseases of the time. It was a turning point after which medics and scientists began to develop and use hygiene principles and antimicrobial agents to prevent infection. Improvements in sanitation, water treatment, and pasteurization that were subsequently adopted have saved millions of lives and are still vital today. But despite these advances, the leading causes of death in the early 1900s remained infectious diseases, especially pneumonia and tuberculosis. Smallpox, cholera, diphtheria, and polio were also widespread. Average life span was just forty to fifty years in part because childhood infections were frequently fatal, and infections we now consider minor could lead to sepsis and death.

Against this background, it's no wonder that the first licensed vaccines in 1914, and first widely distributed antibiotics in 1928, were hailed as miracles of modern medicine. The decades that followed World War II were a golden age for vaccine and antibiotic development, culminating in the complete eradication of smallpox, near-eradication of polio, and the ability for people to live their lives unencumbered by the fear of catching diseases that could cause paralysis, brain damage, blindness, and death. The control over infectious diseases was such that their cumulative mortality rates dropped from 797 to just 36 per 100,000 people per year between 1900 and 1980. This allowed scientific and medical attention to shift to what then seemed like more pressing concerns: chronic diseases such as heart disease, diabetes, and cancer.

Aside from the tremendous difference that these medical advances made, what's also remarkable about this is that it is only relatively recently in human history, and only really in industrialized countries, that infectious diseases have taken a back seat. Of course, COVID-19 thrust infections back to the forefront, highlighting the potential for new pathogens to emerge and wreak havoc across the world. Prior to that, though, it's arguably in part down to sheer luck that prior outbreaks such as SARS and Ebola never completely took hold on our shores. And these emerging diseases are not the only reason for growing concern and interest in new antimicrobial solutions. There's increasing recognition that some pathogens can contribute to chronic symptoms and the chronic diseases that we normally consider separate from infectious ones. The scientific community is also sounding alarm bells over the ever-growing incidence of antimicrobial resistance. COVID-19 dramatically changed the collective concern around infectious diseases. But the reality is that protecting ourselves against infectious disease has always been important. The current world of infectious, disease-causing microbes is still quite vast.

Today's Infectious Microbes

The primary types of infection-causing microbes are bacteria, viruses, parasites, and fungi.

Bacteria

Bacteria are independently living, single-celled organisms that are generally large enough to be identified under a light microscope. Most bacterial infections can be successfully treated with antibiotics. Common types of bacteria that can cause human infection when they proliferate are staphylococci and streptococci. Normally, these infections are localized at a particular site in the body, such as the throat, gums, sinuses, ears, lungs, skin, urinary tract, digestive tract, or genitals, but if they infect the blood, it causes a widespread infection called septicemia. Rarely, bacteria can cross into the central nervous system and cause meningitis. Other types of bacteria include borrelia burgdorferi, which causes Lyme disease. Harmful bacteria are also the cause of most instances of food poisoning.

Viruses

Viruses are much smaller than bacteria and operate quite differently. They cannot exist independently since they don't have their own cellular structure; instead, they are tiny fragments of genetic code that must insert themselves into the living cells of humans or other organisms (including bacteria) in order to survive. They can infect any part of the body. Viruses cannot be treated with antibiotics, and there are relatively few antiviral drugs available. Common types of human-infecting viruses are flu viruses (influenzae), cold viruses (such as adenoviruses or coronaviruses), varicella zoster virus, which causes chicken pox and shingles, herpes simplex virus, Epstein-Barr virus, which causes mononucleosis, and cytomegalovirus. New viral strains have emerged as potential, serious threats in recent years, including severe acute respiratory syndrome (SARS-CoV-1 and SARS-CoV-2, the latter virus the cause of COVID-19), Middle East respiratory syndrome (MERS), Ebola, West Nile virus, and Zika virus.

Fungi

Fungi can exist as simple celled organisms or branching structures made up of several cells. Fungal infections can occur at any location of the body and can usually be treated with antifungal medications. Fungal infections are usually relatively mild, such as skin ringworm, athlete's foot, oral thrush, or vaginal candidiasis. However, rarely, and particularly in people whose immune systems are compromised, fungal infections can compromise essential organ functions and become life-threatening. Valley Fever, caused by Coccidioides fungi, is one example of this.

Parasites

Most parasitic infections affect people living in tropical and subtropical countries, but several can also occur in Europe, North America, and other parts of the world. Parasites range in size from those visible only with a microscope to those that are visible even to the naked eye. Intestinal parasites that are relatively common in the United States include pinworm (Enterobius vermicularis), hookworm (Ancylostoma duodenale and Necator americanus), Giardia lamblia, and Entamoeba histolytica.

Microbes with Insidious Effects

In addition to the acute effects they can cause, there is another, more insidious side of infectious diseases known to occur in those who suffer later or long-term effects from infections. These can occur well beyond the first acute stage of illness in one of three ways:

Reactivation after a period of dormancy: Herpes simplex virus, for example, which can cause cold sores around the mouth, can lie dormant in the facial nerves only to later reactivate and cause new outbreaks during a period when the immune system is weakened. Varicella zoster, the virus that can cause chicken pox, lies dormant in the body after the initial infection and can become active again many years later to cause shingles (herpes zoster), a painful, blistering skin rash. Reactivations usually occur when the immune system is compromised. Sometimes medications compromise our immune system. Other times, our immune system can be compromised by stress, poor diet, or aging.

Chronic infection "syndromes": Several infections can produce long-term symptoms lasting months or years after an initial infection in some (but not all) infected individuals, often baffling medical doctors and leading to clusters of symptoms described as syndromes. Symptoms can range from fatigue, brain fog, headache, sleep disturbance, and pains to digestive issues and more. Sometimes these are mild and manageable. Other times they can significantly impact quality of life and work productivity. Epstein-Barr virus (a member of the herpes virus family that by some estimates up to 90 percent of us have encountered, and that can cause mononucleosis or "mono"), human herpesvirus-6, and Borrelia burgdorferi and other tick-borne illnesses can all lead to persistent symptoms in some individuals. As can SARS-CoV-2: long COVID is the term that was quickly adopted for chronic COVID-19 symptoms lasting more than a few weeks.

Contribution to other chronic diseases: Some delayed effects of infections can relate to diseases we normally think of as noncommunicable, or "chronic" diseases. Latent Chlamydia pneumoniae, a major cause of bacterial pneumonia and bronchitis, for instance, is thought to be able to promote arterial plaque formation and potentially contribute to heart disease due to its ability to enter the bloodstream and settle in other sites such as the lining of blood vessels. Epstein-Barr virus is implicated in triggering some autoimmune diseases and increases the risk for certain types of cancer. Herpes simplex, the virus that causes cold sores and genital herpes, is implicated in the later development of some instances of dementia and Alzheimer's disease. Almost all cervical cancers, as well as some genital cancers and cancers of the throat, are caused by human papillomavirus infections.

Infections and Autoimmune Disease

Several microbial infections are thought to play a role in the development of autoimmune disease in susceptible individuals. What makes someone susceptible isn't yet well defined but is understood to include a combination of genetics, environment (i.e., diet and lifestyle factors), and an immune system that is already under stress and not fully resilient. Some potential infectious triggers implicated in autoimmune diseases include:

Type 1 diabetes: rotaviruses, rubella, influenza, mumps.

Rheumatoid arthritis: Porphyromonas gingivalis (a common cause of oral gingivitis), Escherichia coli, Epstein-Barr virus.

Systemic lupus erythematosus (lupus): Epstein-Barr virus, parvovirus B19, cytomegalovirus, hepatitis C virus.

Sjšgren's syndrome: Epstein-Barr virus, herpes simplex virus, hepatitis C virus.

Autoimmune thyroid disease: Epstein-Barr virus, Yersinia entrocolitica, Bartonella henselae, influenza, herpes viruses, hepatitis C virus.

Multiple sclerosis: Epstein-Barr virus, Mycoplasma pneumoniae, Chlamydia pneumoniae.

Emerging data also implicate SARS-CoV-2 in the development of autoimmune reactions.

Pathogen Resistance to Current Medicines

In addition to the acute and long-term health effects of infections, one of the biggest threats to our control of harmful microbes is antimicrobial resistance. Resistance occurs when a bacteria, virus, fungi, or parasite changes in a way that makes it unharmed by the medications we normally use to kill them. This renders them much more difficult to treat, and in some cases not treatable at all-these microbes are known as "superbugs." Current examples of resistant microbes include certain species of Staphylococcus ("staph"), salmonella, tuberculosis, candida, and Clostridioides difficile ("C. diff"). Our exposure to these bugs can occur through foods, plants, animals, soil, air, other people, and public places, especially (and unfortunately) health centers.

Antibiotics, for example, used to be a trusted tool against bacterial infections, but now medical professionals are seeing increasing antibiotic resistance from more and more bacterial types. More than 2.8 million people in the US become sick due to antibiotic-resistant bacteria each year, at a cost of over $55 billion annually, and the number is growing. Just one of several drug-resistant bacteria, methicillin-resistant Staphylococcus aureus (MRSA), kills more Americans annually than emphysema, HIV/AIDS, Parkinson's disease, and homicide combined. These bacteria can cause resistant infections of the urinary tract, intestines, lungs, and other organs.

The reasons behind this increase in resistant microbes are several, but all come down to the fact that higher medicine usage rates mean a higher chance that bugs develop resistance. Recent data from the US Centers for Disease Control and Prevention (CDC) show that we are prescribed an equivalent of 838 antibiotics per 1,000 people in the United States each year. The vast majority are prescribed by primary care physicians for respiratory infections, many of which are actually viral rather than bacterial and therefore not treatable with antibiotics. This kind of overuse in medical, and also veterinary, practice has accelerated the resistance problem. Improper use, such as dosing too low, or stopping a course of antibiotics early is also problematic, since it increases the chance that the harmful bacteria survive the treatment and develop the capability to resist the medication.

Another driver has been the widespread preventive use of antibiotics in livestock and fish farming. In fact, the total agricultural use of antibiotics exceeds human use. Approximately 60 percent of the antibiotics used in food production are the same antibiotics that we rely on to prevent or resolve human infections, making the risk to human health even greater.

Compounding the problem is the stark reality that the development pipeline for new antimicrobial medications is concerningly thin. While around one new human infectious disease is discovered each year, there haven't been any entirely new classes of antibiotics discovered since the 1980s. Most antibiotics used today were identified during the 1940s to 1960s. One reason for this is that it's just not that attractive a business model for private enterprises. To develop one new antibiotic, there's the high cost of development, over $1.5 billion by some estimates. Then there's the problem that new drugs have a high risk of being soon rendered ineffective due to new antimicrobial resistance. This means that new drugs either have a blunted life span or they have to be used sparingly in order to preserve their effectiveness.

Although many experts are working on trying to solve these problems, the outlook for our continued ability to control harmful bacteria with medications is still shaky. In addition to untreatable illnesses, the World Bank estimates that, without new drug breakthroughs, antimicrobial resistance could cause up to 10 million deaths per year by 2050. Other estimates are similarly bleak. Scientists have called the situation "desperate," and "one of the most pressing threats to human health." The reality for us as individuals is the growing threat of catching a germ that can't be treated medically, and that the use of antimicrobial medications will have to be increasingly reserved only for the most needed situations. It's likely that milder infections will increasingly be left to run their natural courses without pharmaceutical antimicrobial treatment.

The Unique Problem of Emerging Viruses

While most nonresistant bacterial infections can, for now, still be countered by antibiotics, relatively few antiviral drugs exist. Have you ever wondered why? The answer lies in the different way that viruses are structured and operate. Viruses, without their own complete cellular structures, rely on their ability to "break into" their host's cells, incidentally through pathways already used by essential biochemical molecules, and hijack that cell's operational machinery-machinery that includes DNA or RNA replication (a way to reproduce genetic information) so the virus can make lots of copies of itself to send out to infect other cells. This overlap between viral functions and normal cell operations means that most of the viral targets that drugs could attempt to block would simultaneously block functions critical to our own healthy cells. It's not just that killing viruses is hard. The challenge is to kill viruses without harming our own cells. It's not all doom and gloom, though. There have been some notable antiviral successes such as for human immunodeficiency virus (HIV), hepatitis B, and hepatitis C-but standard medical care for most viruses is to treat the symptoms only until the individual's immune system (hopefully) dispenses with the unwelcome invader.

Vaccines have been our best defense against some viruses; the measles vaccine, for instance, is 97 percent effective at preventing infection to this highly contagious disease. However, for many other viruses, it's much harder to develop effective vaccines in part because, as the virus replicates, it churns out mutated copies of itself that then form different strains of the original virus. Vaccines developed to target one strain don't automatically work against others. Influenza (flu) viruses, for example, develop new strains each year, which makes predicting vaccine targets challenging and is why flu vaccine effectiveness rates as low as 40 percent to 50 percent are still considered a success.