An Interview with Professor Manuel Varela: Carl Eberth and Salmonella:

Jun 30, 2018 by

Michael F. Shaughnessy –

1) Professor Varela, thank you for sharing your expertise about microbiologists and various issues in that realm. Can we start with the issue of “salmonella” and work from there? What exactly IS salmonella and why do we hear so much about it?

Historically, the term “salmonella” has been popularly used to refer to either the bacterial pathogen or the infectious disease caused by the microbe.  I will briefly describe both the microbe and the disease here.

First, in precise scientific terms, the microbe, a bacterial pathogen, is quite often called by its species name Salmonella enterica, using a binomial classification scheme referring to the genus Salmonella and the specific epithet enterica.  The microbe has a rod-shaped conformation, called a bacillus, and its cell wall matrix is Gram-negative in its biological nature. The S. enterica bacterium is facultatively anaerobic, meaning that it may grow with and without the presence of atmospheric oxygen. Furthermore, the microbe may be able to utilize one or more sugars via fermentation machinery, consisting of various enzyme proteins that in turn make up a variety of metabolic pathways, all starting with glycolysis, the oxidative breakdown of sugar substances.

The microbe’s cell wall also has specific chemical constituents tied to it that make S. enterica potentially dangerous to individuals who may consume foods or drink contaminated with the bacterium. One notorious chemical example is a bacterial cell wall component called lipid A, also known as endotoxin, a potent virulence factor in disease development. This lipid A endotoxin causes acute and severe symptomology in salmonellosis patients. In fact, S. enterica harbors a variety of pathology-inducing virulence factors, and the microbe even has a specialized protein-based transport and secretion system to move its virulence factors to the insides of the human host cells. Collectively, these virulence factors play a role in mediating cellular toxicity and disease pathology in salmonellosis patients.

Incidentally, the S. enterica bacterial microbe has a unique nomenclature system, stemming largely from scientific studies of its cell wall structures. Cell wall structural variations between the numerous related S. enterica bacteria account for their classification into distinctive serotypes or serovars, based on serologic behavioral differences. These serotypes or serovars number in the thousands. Prior to the development of these serotype or serovar distinctions, the Salmonella bacteria were assigned with specific epithet names based on the serological classification scheme.

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However, closer examination of the bacteria at the molecular genomic level showed that many of these species were actually the same one. Anyhow, the commonly accepted nomenclature scheme will include the genus and the specific epithet, followed by the relevant serovar or serotype designation. As an example, what used to be called, for instance, “Salmonella typhi,” considered now an incorrect form, is now more appropriately classified scientifically as “Salmonella enterica serovar Typhi.”  After the full name has been provided in a given scientific publication, the name will then be shortened simply to S. Typhi, the specific epithet being tacitly assumed. The naming system, however, can be confusing to those who might expect the term Typhi to be the specific epithet rather than as the more accurate serovar-based system.

Second, with respect to the infectious disease aspect of “salmonella,” the more modern term for the ailment is called salmonellosis. The pathological condition of salmonellosis may be further sub-categorized as certain disease subsets, depending on the particular type of ailment.  For example, typhoid fever has been the historically-used term to describe a so-called enteric fever of salmonellosis. Another salmonellosis disease sub-category is called septicemia, which describes the growth of the bacteria in a patient’s blood, and a third sub-category is called gastroenteritis, also known as enteritis.

I think that there are several reasons why we often hear so much about S. enterica and salmonellosis.  First and foremost, the microbe represents a critical public health concern, as it is the causative agent of serious and severe infectious disease in humans and in other animals. Second, with respect to its epidemiological parameters, salmonellosis occurs in staggering numbers of disease cases and deaths yearly and on a worldwide scale. Third, contamination of different foods occurs without warning, resulting in sporadic infectious disease outbreaks. This latter outcome often severely affects numerous aspects of the food industry, complete with recalls of affected food items and in economic losses, in terms of both sales and productivity, not to mention detrimental enhancements in healthcare costs.

2) Now, who was Carl Eberth and what did he have to contribute to our understanding and treatment of salmonella?

Dr. Carl (or Karl) Joseph Eberth, considered to be a pioneer bacteriologist and pathologist, was born in Würzburg, Germany on the 21st day of September in the year 1835.  His father was an artist, and he died when Carl was still young, in his teen years. The resulting loss in income led young Carl to become one of the breadwinners in the household by constructing silhouette cutouts for later sale. Despite the financial hardships, Eberth took his doctorate (M.D.) at the University of Würzburg, under the direction of Prof. Heinrich Müller in 1859 studying the microorganism called Trichocephalus dispar, a type of whipworm.

Eberth had the good fortune to have studied then under excellent scientific mentors, such as Albert von Kölliker and Heinrich Müller, both of whom were renowned muscle histologists; Eberth also studied under Prof. Franz von Leydig, a noted anatomist and zoologist. Interestingly, Eberth was a protégé of Dr. Rudolf Ludwig Karl Virchow, known also as the father of pathology. Thus, great mentors and teachers aided Dr. Karl Eberth, and he was no doubt able to ascend to the heights of one of the greatest discoveries in typhoid fever history, as a direct consequence of these mentorships.

Eberth’s prime discovery of great importance was that he had been the very first scientist ever to have observed the so-called “typhoid bacillus” in culture in 1880.  While on the faculty as a professor of pathology at the University of Zurich, Switzerland, Eberth studied several pathological tissue types, namely, spleen and lymph nodes that he had obtained from human patients who had had the typhoid fever. In the patients’ diseased tissues, Eberth found the bacilli bacteria, whereas the bacillus failed to show itself in the tissues of patients with diseases other than the typhoid fever.

One particular criticism that emerged as a result of Eberth’s published works lies in the fact that he had claimed that the typhoid bacillus formed an endospore structure, which later studies demonstrated that it had not. As of this writing, the finding of a Gram-negative bacterium that also forms endospores has been hitherto unheard of, perhaps possibly due to the fact that microbiologists simply have not yet examined all possible microbes in the Earth’s microbiome to have definitively found such an organism.

Eberth had named the rod-shaped bacterium as Eberthella typhi. For a short while, the microorganism had been referred to as Eberth’s typhoid bacillus or the Eberth Bacillus.  Confirmation of Eberth’s claim that his organism was a cause of typhoid fever emerged out of the work of George Theodor August Gaffky in 1884. Soon after, the organism was referred to as the Gaffky-Eberth bacillus.

The typhoid bacterium had then been renamed Salmonella typhi in 1900 by Dr. Joseph Léon Ligniéres, in order to commemorate Dr. Daniel Elmer Salmon, who together with Theobald Smith, had been the first to isolate the bacillus organism in 1885 from hogs who had been sick the so-called hog cholera. As I explained above, the modern name for the typhoid bacillus is Salmonella enterica serovar Typhi, amongst the numerous other serovars.

Dr. Eberth became a professor of anatomy in the field of pathology at the University of Zurich in Switzerland in 1869.  He later moved in 1881 to become professor of comparative anatomy and chair of histology at the veterinary medical school at the University of Halle, Germany, until he retired in 1911.

Dr. Ebert died on the 2nd day of December in the year 1926, at the age of 91 years.

3) I may be wrong, but apparently, typhoid fever and salmonella are linked somehow- can you explain this relationship?

In short, the microbe Salmonella enterica is the primary causative agent of the typhoid fever.  The ailment is one of several types of salmonelloses experienced by individuals who may have acquired the infectious microbial agent.

The clinical symptoms of the typhoid or enteric fever ailment commence gradually, usually about 10 – 14 days after consuming the microbe-contaminated food.  The first classical symptom is fever, but may be accompanied by one or more conditions like anorexia, a headache, pain in the muscles (called myalgia), and a vague feeling of discomfort or uncomfortability, called malaise.

One of the prime methods for the acquisition of the S. enterica microbe by a patient is referred to as the so-called fecal-oral route of transmission from contaminated foods to the individual. This means that the food consumed by the patient had been contaminated by another individual, perhaps an asymptomatic carrier, who prepared the food and likely inadvertently infused the food with the microbe after going to the bathroom and inadequately washing or perhaps not washing their hands afterwards.

 

Typically, the types of foods that may be microbe-contaminated with S. enterica involve dairy foods, eggs and poultry, such as chicken. Good hand-washing practices, proper food-handling, and sufficient cooking with heat are good protective measures that help to prevent food contamination and inadvertent consumption of potentially contaminated food items by human individuals. Salmonellosis prevention efforts may also include a vaccine, which is used primarily in regions where the disease is endemic.

Eberth’s efforts started the work towards the treatment of salmonellosis by identifying a suitable target, the microbe. While modern treatment of enteritis does not involve chemotherapeutic antimicrobial agents, as such treatment tends to prolong the illness, antibiotics are indicated for other forms of salmonellosis. Such antimicrobial agents include cephalosporin, a cell wall synthesis inhibitor, chloramphenicol, a protein synthesis inhibitor, ciprofloxacin, a nucleic acid synthesis inhibitor and which is a member of the class of drugs called fluoroquinolones, and trimethoprim-sulfamethoxazole, a two-drug combination, both of which are antimetabolites.

4) What other discoveries or research did Carl Eberth make or what else was he involved with during his lifetime?

In addition to having been the first to observe the Salmonella enterica bacterium in the tissues of typhoid fever patients, Eberth is also credited for a couple of other scientifically based findings.  For example, Eberth coined the term “Eberth’s Lines” referring to the so-called lines that are typically observed under the microscope when the silver-nitrate chemical is used to stain heart muscle cells, often also called cardiac, or myocardial, cells.

Another discovery made by Dr. Eberth lies in his histological observation of a certain pathological tissue, the so-called “Eberth’s Perithelium,” which apparently consists of a mesh of blood capillaries that are in turn covered by an underdeveloped layer of connective tissue cells.

5) What have I neglected to ask?

Typhoid fever has wreaked havoc throughout many millennia, affecting countless millions of lives in history.  A little known case involving the typhoid fever, however, happened to a child by the name of Cécile Pasteur, 12-year old daughter of Prof. Louis and Madame Marie Pasteur.  The story has been told that after little Cécile died in Chambéry of the dreaded feverous ailment on the 23rd of May in 1866, the loss had greatly affected both her parents Louis and Marie for the rest of their own lives. This incident had made matters worse because their other daughter, 9-year old Jeanne, had earlier succumbed to the typhoid fever in Arbois on the 10th of September in 1859, and little 2-year old Camille Pasteur had died of liver cancer in 1865 on the 11th of September. Prof. Pasteur’s later work was to result in his establishment of the so-called germ theory of disease, in which germ microbes, like Salmonella enterica, were agents of infectious disease, such as in this case the typhoid fever.

Another interesting story regarding typhoid fever lies with a rather infamous historical figure by the name of Mary Mallon, known notoriously also as “Typhoid Mary.”  At the beginning of the 20th century, Ms. Mallon had been a cook for a family with children in a small town known as Oyster Bay, New York. Several of the family members succumbed to an outbreak the typhoid fever in the household.  Shortly after the outbreak, Ms. Mallon had somehow mysteriously disappeared.  Hired to investigate the typhoid fever outbreak incident in the household, one Mr. George Soper, located the missing Ms. Mallon.

What followed next depends on whom you would choose to believe.

According to Soper, Mallon was personally belligerent and uncooperative, refusing to be tested and to voluntarily agree to have her gall bladder surgically removed, to prevent further transmission. According to Mallon, Soper was unfairly accusatory and unreasonable in expecting a person to give up freely what she considered her own healthy tissue (she explained she did not have typhoid fever).  Neither party was feeling particularly in a capitulating mood, and an impasse was thus established. Soper had Mallon incarcerated. Public outrage ensued, and Mallon was released from jail after public pressure, whereupon she disappeared again. She was later reportedly discovered to be employed as a cook in a hospital.  Mallon had, apparently, chosen to ignore repeated requests to cease working as a cook. Ms. Mallon had had the extremely unfortunate chance to have been an asymptomatic carrier of the microbe that causes typhoid fever in a very public set of circumstances. With public support diminishing, Mallon was placed under house arrest, a quarantined condition of sorts, for the remainder of her life.

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