Bennett Lorber

Bennett Lorber is the Thomas M. Durant Professor of Medicine and Professor of Microbiology and Immunology at Temple University School of Medicine, Philadelphia, Pa.

Author Profile--Lorber: Infectious Diseases, Teaching, and Painting-Playing 15 Guitars for a Hobby

Summary
● During the past few decades, our understanding of human-microorganism interactions changed fundamentally as we learned infectious agents can give rise to chronic illnesses.
● Mild or asymptomatic infections sometimes trigger damaging immune system responses that account for chronic diseases; in some cases, vaccines can prevent or ameliorate those damaging effects.
● Several infectious agents, including parasites, are associated with psychiatric and other disorders of the central nervous system.
● Other infectious agents are tied to kidney and heart disease, obesity, and cancers.

Imagine if debilitating arthritis were due to an anaerobic bacterium that lives in our mouths. What if heart attacks were due to a transmissible bacterium or autism to a virus? What if vaccines could prevent these and other chronic illnesses?

Human interactions with microbes are various, complex, and wondrous. Sometimes the interaction produces an acute illness that we recognize as an infectious disease. One of the most extraordinary features of my professional life caring for people with infections has been the recognition of new microbes and diseases about which to learn and be concerned. During my career, more than 50 new pathogens or infectious diseases have been described, including HIV/AIDS, Legionnaires' disease, Lyme disease, Clostridium difficile colitis, the Ebola fever virus, community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA), vancomycin- resistant enterococci (VRE), the virus responsible for severe acute respiratory syndrome (SARS), and a novel bunyavirus in China that produces fever and thrombocytopenia.

During the past few decades, a fundamental change has taken place in our understanding of human-microorganism interactions. We are learning that transmissible agents might cause chronic illnesses that were not thought to have anything to do with infectious processes. In some instances, becoming infected is a sine qua non for developing a chronic illness. In others, illness can occur without infection, but infection increases the risk of that illness. In still other cases, an immune response that continues after a short-lived infection produces chronic health problems.

"New truths become evident when new tools become available," said Nobel laureate Rosalyn Yalow. For instance, the microscope enabled biologists to recognize the cellular nature of life and to visualize bacterial pathogens. More recently, the polymerase chain reaction and other tools of molecular biology enabled microbiologists to identify pathogens without growing them. New technologies put us in the midst of a scientific revolution.

Infectious Agents Associated with a Range of Chronic Illnesses

For decades medical students were taught that peptic ulcers were due to an excess of acid. No stomach acid, no ulcer was their mantra. Thus, physicians treated ulcer patients with antacids and, later, with other medicines that block acid production. Ulcers healed but commonly recurred; sometimes surgery was necessary to stop acid production. Now we know that infections with the bacterium Helicobacter pylori lead to peptic ulcers, which can be healed and recurrences prevented with antibiotic treatments, a discovery that eventuated in the 2005 Nobel Prize for Medicine. Talk about a paradigm shift!

More than infection is at work here, and the host genetic makeup certainly plays an important role in determining whether an infection, even when mild or asymptomatic, leads to ulcers or any number of other chronic illnesses.

Consider rheumatoid arthritis, which affects young adults, produces stiffness and pain in multiple joints, and may lead to disabling joint deformities. Patients with this systemic disease have more periodontal disease than usual. They also produce antibodies to cyclic citrullinated peptides that are thought to play a role in the pathogenesis of arthritis. The anaerobe Porphyromonas gingivalis, which is a major contributor to periodontitis, produces arginine proteinases that enable these bacteria to survive in gingival crevices. One such enzyme, peptidylarginine deiminase, converts arginine to citrulline. Investigators speculate that P. gingivalis makes citrullinated antigens that then serve as systemic immunogens resulting in rheumatoid arthritis among genetically susceptible individuals.

Meanwhile, Guillain-Barre´ syndrome remains the major cause of acute neuromuscular paralysis worldwide. The bacterium Campylobacter jejuni is strongly associated with this condition. For example, patients with Guillain- Barre´ frequently report experiencing diarrhea with fever a week or two before the onset of this ascending paralysis. Even in the absence of gastrointestinal illness, C. jejuni is found in stool specimens from as many as one-fourth of patients at the onset of neurological symptoms. Circulating antiganglioside antibodies can be detected in many individuals following C. jejuni infection. Here is an instance in which an intestinal bacterial infection apparently leads to an immune response that attacks another part of the body, the central nervous system.

Infectious Agents Associated with Central Nervous Disorders

Other infectious agents can also affect the central nervous system. For instance, children affected by pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) typically experience a dramatic onset of obsessive-compulsive disorder (OCD) following Group A streptococcal pharyngitis. Among children with longstanding OCD, antimicrobial prophylaxis to prevent Group A streptococcal infections prevents exacerbations of OCD. This condition may reflect autoimmunity from molecular mimicry.

Physicians proposed an infectious cause of multiple sclerosis (MS) at least as early as 1884. One more modern agent proposed as a cause of MS is human herpesvirus 6 (HHV-6). In 1988, HHV-6 was established as the cause of roseola, a common childhood infection. An integral feature of HHV-6 is that it often infects the central nervous system (CNS), usually without causing symptoms. Further, HHV-6 encodes a protein similar to part of the myelin protein that coats human nerves. In autopsies of the CNS of MS patients, HHV-6 DNA associates more closely with parts of the brain afflicted with MS-related plaques than with normal white matter. Perhaps MS is the result of molecular mimicry following HHV-6 infections.

Another etiological candidate for MS is the Epstein-Barr virus (EBV). In a large, case-controlled study of U.S. military personnel, those who developed MS were seropositive for EBV when blood samples were collected, a mean of four years before the onset of MS. Moreover, initial EBV titers were higher among those who went on to develop MS than among those who did not. However, a similar relationship did not hold for another herpesvirus, namely cytomegalovirus, implying that MS may be connected to specific viruses rather than an underlying immune dysfunction. Yet, EBV is rarely found in areas of MS brain damage. One possibility is that the virus triggers an immune response that begins outside the CNS, activating CD8_ T lymphocytes having one receptor for a viral peptide and another for CNS-specific myelin peptide. If correct, EBV need not invade the CNS to produce MS.

Some infections produce obvious behavioral changes. For instance, mice infected with Toxoplasma gondii develop specific behavioral changes that increase their risk for being eaten by cats, which are the definitive host of this parasite. In this case, parasite-infected mice lose their aversion to cat odors, along with their ability to discriminate between familiar and novel components of the environment, thus becoming easy prey for cats.

Similarly, a recently described picornavirus makes honeybees more aggressive than usual when it infects their CNS. Only those bees whose brains are infected by the virus will attack hornets dangled outside the hive. Other bees that flee from threatening hornets prove to be virus free.

Bornaviruses have a similar affect by increasing the aggressiveness of the horses that they infect, but such infections typically progress to paralysis, then death. Bornavirus infections of the CNS, which are not so deadly in humans, are linked with schizophrenia, bipolar disorder, major depression, and autism. When bornaviruses infect neonatal rats in experiments, the resulting disturbances to the brain resemble those seen in humans with autism, and include abnormal taste preferences, sleep disturbances, sensorimotor alterations, and social deficits. Meanwhile, another line of investigation links some forms of autism to clostridial species producing toxins in the bowel.

Infectious Agents Tied to Kidney and Heart Disease, Obesity, and Some Cancers

Bacterial infections can give rise to hemolyticuremic syndrome (HUS), an illness seen mostly in children and one that is characterized by anemia, low platelet numbers, and kidney failure. HUS is the most common cause of acute renal failure in otherwise healthy U.S. children, many of whom require dialysis to survive. Most cases follow an acute diarrheal illness in which the stools typically are bloody, whereas fever is absent. Two epidemics of diarrhea during the early 1980s linked enterohemorrhagic Escherichia coli O157:H7 to patients who consumed pathogen-contaminated hamburgers from fast-food restaurants. This microorganism causes symptomatic infections in which as many as 10% of infected children under the age of 10 develop HUS. Some of them require short-term dialysis, while others need kidney transplants.

Infectious agents also might play a role in atherosclerosis, a risk factor for heart attacks. Atherosclerosis was long regarded as a passive process in which lipids are deposited in blood vessel lumen walls-with obstruction in the case of coronary arteries leading to heart attacks. However, coronary artery disease proves to be an active process, and inflammation plays a major role in pathogenesis. Asymptomatic healthy individuals who have elevated levels of C-reactive protein, a sign of inflammation, are at increased risk for heart attack. Individuals with periodontal disease also have an increased risk of coronary disease.

Meanwhile, other infectious agents might play a role in ischemic heart disease, including Chlamydophila pneumoniae, a common cause of respiratory infections. These bacteria are found in diseased coronary vessels and are linked seroepidemiologically to heart disease. Some investigators argue that Chlamydophila induces nonspecific inflammation. However, the amino acid sequence of an outer membrane protein of C. pneumoniae shows homology to heart muscle peptide. Moreover, introducing that bacterial protein into mice results in perivascular inflammation. Additionally, monocytes infected with C. pneumoniae up-regulate genes with proinflammatory functions, including some that are associated with atherosclerosis. Nonetheless, secondary-prevention clinical trials, in which antibiotics targeting C. pneumoniae were administered to those who had experienced one heart attack, failed to prevent a second event.

Viral infections might contribute to obesity. For instance, when infected with human adenovirus 36 (Ad-36), chickens, mice, monkeys, and marmosets develop excessive visceral fat compared with their uninfected counterparts. Along these lines, obese humans are more likely to have antibodies to Ad-36 than do those who are not obese. Ad-36 enhances differentiation of cells that form adipocytes in vitro.

In the case of obesity it might not be one organism but populations, or relative proportions of populations of microorganisms, that affect weight levels. Gut flora help break down otherwise indigestible components in foods. Putting gut flora from a normal mouse into a germ-free animal increases body fat without any increase in its consumption of food. Sequencing of genes in stool samples to monitor human gut microbial ecology indicates that the microbiota of obese individuals, through an increased capacity to harvest energy from the diet, differs from that of lean people.

Finally, infectious agents can give rise to a number of cancers. Examples include T-cell leukemia/lymphoma due to the HTLV-1 retrovirus; cervical and anal cancer due to human papilloma virus; liver cancer due to hepatitis viruses B and C; Hodgkin's Disease, Burkitt's lymphoma, and primary CNS lymphoma due to EBV; and stomach cancer due to H. pylori.

About 15 years ago, the use of a newly developed molecular biology tool, representational difference analysis, led to discovery of the virus now known as HHV-8 and defined its role as the cause of Kaposi's sarcoma, the skin cancer that plagued many victims early during the AIDS epidemic. Recent investigations indicate that some strains of Bacteroides fragilis, among the most prevalent species in the human intestine, produce an enterotoxin that may be an important factor in the development of colon cancer. Vaccines against hepatitis B and HPV reduce the incidence of liver and cervical cancer, respectively.

Conclusion

When I was a medical student, we could not imagine stomach ulcers being cured with antibiotics or viruses causing vaccine-preventable liver and cervical cancers. There is every reason to believe that science will continue to propose links between chronic illnesses and infections. Over time, some will not be confirmed and will fade from memory. For instance, the idea that nanobacteria cause kidney stones has not been sustained. However, other links between infectious agents and degenerative, inflammatory, malignant, and even hereditary diseases likely will be proved true and, in turn, might provide opportunities for preventing disease through immunization, an exciting prospect to contemplate.

SUGGESTED READING

de Smit, M. J., Brouwer, E., Vissink, A., and A. J. Van Winkelhoff. 2011. Rheumatoid arthritis and periodontitis; a possible link via citrullination. Anaerobe 17:196-200.

Goverman, J. M. 2011. Immune tolerance in multiple sclerosis. Immunol. Rev. 241:228-240.

Hansson, G. K. 2005. Inflammation, atherosclerosis, and coronary artery disease. N. Engl. J. Med. 352:1685-1695.

Lorber, B. 1996. Are all diseases infectious? Ann. Intern. Med. 125:844-851.

Lorber, B. 2005. Infection and mental illness: do bugs make us batty? Anaerobe 11:303-307.

Sears, C. L., Pardoll, D. M. 2011. Perspective: alpha-bugs, their microbial partners, and the link to colon cancer. J. Infect. Dis. 203:306-311.

Turnbaugh, P.J., Gordon, J. I. 2009. The core gut microbiome, energy balance and obesity. J. Physiol. 587:4153-4158.