Virulence

Table of Contents

The Merriam Webster dictionary defined virulence as a pathogen or microorganism’s ability to overcome a host’s defenses and cause damage or disease.

Another version describes it as a measurement of hostility, highly infectious, malignant, or deadly. There are so many definitions of this word, mainly when referring to a microorganism.

Well, simply put, virulence is a state of been pathogenic or the degree of pathogenicity of a pathogen or as the intrinsic nastiness of a pathogen. Pick one; they all reflect the same meaning.

All pathogens, including bacteria, viruses, fungi, and others, can all avoid a host defense and reproduce in or out of the host.

They all can also cause damage to the host either locally, at the entry point of infection, or a distinctive point by the production of toxins and using the host’s circulatory system as a transport system or the entire body of the host. (a host is a cell or organism which harbors another organism or biological entity, usually a parasite).

But these abilities vary between microorganisms and even between species. It is the degree to which an organism can execute these abilities referred to as the Virulence of an Organism.  

The degree of virulence of a pathogen is directly proportional to that pathogen’s ability to cause disease despite host resistance mechanisms.

An eminent American microbiologist, Theobald Smith, once developed an expression, P=NV/R, for the probability of a host developing an infection. In his presentation, he stated that P represented the probability of a host developing a disease.

It is directly proportional to the N, the number of pathogenic organisms encountered, and V the organism’s virulence, and inversely proportional to the resistance R of the host.

Using this expression, it became biologically possible to calculate and measure a parasite or pathogen’s virulence degree. Virulence is influenced by numerous variables such as the number of infecting pathogens, route of entry into the host’s system, nonspecific and specific host defense mechanism, and virulence factors of the pathogen.

Virulence Scale

A degree to which an organism is pathogenic is known as virulence, and the ability of an organism or a microbial agent to cause disease is called pathogenicity.

The degree of virulence is on a continuous spectrum. At one end of this spectrum are organisms that are not harmful, avirulent and at the other end are organisms that are highly deadly or virulent.

The highly virulent organism at the top of the spectrum will likely cause a disease whenever they are introduced into a host, and some may even cause multi-organ and system failure in healthy hosts or individuals.

Less virulent pathogens may only initially cause an infection, and this may not cause severe illness. Low virulent pathogens are most likely to present mild signs and symptoms of a disease, such as mild fever, headaches, and muscle aches.

Some cases might even be asymptomatic (not showing any symptoms at all).

An instance of a highly virulent microorganism is Bacillus anthracis, the bacteria that is responsible for causing anthrax. It can produce various forms of the disease, depending on the route of transmission, either through the skin, inhalation, or ingestion.

The deadliest form of anthrax is inhalation anthrax. After inhaling B. anthracis spores, they germinate, and an active infection develops, and the bacteria release potent toxins that cause edema (building up of fluid in tissues), hypoxia, and necrosis (cell inflammation and death).

Below is a list of selected foodborne pathogens and their ID50 values in humans as determined from epidemiologic data and studies on human volunteers (ID50 – the number of pathogen cells required to cause an active infection in 50% of inoculated animals).

ID50 for Selected Food-borne Disease
PathogenID50
Viruses Hepatitis A virus Norovirus Rotavirus  10 – 100 1 – 10 10 – 100
Bacteria Escherichia coli, enterohemorrhagic (EHEC) E. coli, enteroinvasive (EIEC) E. coli, enteropathogenic (EPEC) E. coli, enterotoxigenic (ETEC)   Salmonella enteric serovar Typhi S. enteric serovar Typhimurium Shigella dysenteriae Vibro cholera V. parahemolyticus  10 – 100 200 – 5000 10,000,000 – 10,000,000,000 10,000,000 – 10,000,000,000     <1,000 ≥1 10 – 200 1,000,000 100,000,000
Protozoa Giardia lamblia Cryptosporidium parvum  1 10 – 100

It is important to note that the pathogenic infective dose or number does not necessarily correlate with the disease severity, and the active infective dose for a person can vary, depending on some factors such as age, route of entry, immune status, and environmental and pathogenic-specific factors such as susceptibility to the acid pH of the stomach.

Virulence Factor

There are several categories of factors that contribute to the virulence of a pathogen. These factors are collectively known as virulence factors. As previously stated, some pathogens are more virulent than others.

This is due to the unique virulence factors produced by pathogens individually. These factors determine the severity and extent of the disease they may cause.

The virulence factors of a pathogen are encoded by genes that can be identified using a microbiological technique called the molecular Koch’s postulates. When the genes encoding virulence factors are deactivated, the virulence factor is diminished.

Some significant classes of virulence factors that contribute to the virulence of a pathogen include:

  1. Virulence factors for Adhesion or attachment (flagellate, pill, adhesins)
  2. Virulence factors for invasion (Bacterial Exoenzymes and Toxins) are either integral components or toxic materials, endotoxins and exotoxins, secreted into body tissues, e.g., TSST-1, the toxic shock syndrome toxin).
  3. Virulence factors for survival in the host’s body system (invasins, enzymes that damages host tissues and convert them into bacterial nutrients. Enzymes such as Hemolysins, elastases, and nucleases).
  4. Virulence factors for defense against the host’s immune mechanisms such as the glycocalyx and other surface components such as capsule formation prevent phagocytosis and attack by the host’s cellular immune response.

There is enough evidence suggesting that virulence factors are initiated after a certain critical mass of cells has become established. Much of the virulence of pathogens is under Quorum Sensing control.

Quorum Sensing is a communication system established by pathogens that allows specific processes to be controlled, such as virulence factor expression, biofilm formation, stress adaptation mechanisms, and production of secondary metabolites.

Quorum Sensing equips pathogens with a strategic ‘attack-defense system’ as their number increases. For instance, when the human system recognizes a pathogen’s presence, an active inflammatory immune response (including protective macrophage and neutrophil mobilization) is the usual consequence.

The strategy of biofilm formation is, therefore, one of stealth. Suppose the bacterium was to liberate virulence factors early in the infection process. In that case, the body system could respond with its entire armamentarium of defenses when the bacterium is in its vulnerable state.

By delaying the release of such factors until enough cells exist and a thick EPS matrix (Extracellular Polymeric Substance) is established, biofilm avoids the significant challenges of the host response to infection.

A Bacterial Case Study: Pseudomonas aeruginosa

One of the best-studied biofilm pathogens is the opportunist bacterium P. aeruginosa.

This bacterium can prosper in a vast range of habitats such as plant surfaces, soil, burn-injured human tissues, wounds, unbroken skin surface, and on the lungs of persons who have inherited the autosomal recessive hereditary disease cystic fibrosis.

This ability possessed by this bacterium to survive in such different environs is a consequence of the genetic versatility and its ability to respond to other environmental cues by producing gene products conducive to its existence in each habitat.

In a case of burns and lung infection, the production of virulence factors will facilitate:

  • Protection against host defenses
  • Adhesion to host tissue
  • Ability to convert host resources to bacterial advantage.
  • The ability to convert host resources into toxins.

P. aeruginosa secretes virulence factors in each of the above categories, and although some of these may be constitutive, many are under Quorum Sensing control.

Adherence and Attachment

P. aeruginosa produces both pili, which serve as adhesins binding the cells to the cellular surface, and flagella enables the bacterium to closely approach the mucus membrane surface that attachment can occur. These are the significant virulence factor for adhesion.

Protection and Bacterial Surface Components

P. aeruginosa strains isolated from the lungs of patients with chronic cystic fibrosis are of a mucoid phenotype. This means the cell masses are encased in a thick slimy coat of an exopolysaccharide called alginate.

In experimented studies with rats’ subjects, P. aeruginosa (non-mucoid strains) were used to infect rats. It was later observed that in the tissues of the infected rats, the bacterium rapidly converted to a mucoid phenotype.

Conversion of Host Resources and Invasins

P. aeruginosa produces a variety of enzymes, the function of which are to degrade hosts tissues, thereby providing nutrient materials and breaching host defensive barriers enabling the spread of the pathogens from the initial point of infection.

Two of the enzymes are elastase A and elastase B (products of LasA elastase and LasB elastase gene respectively). Elastin is a protein that accounts for as much as one-third of the protein of lung tissues and these enzymes (elastase A and B) have the capability of degrading this material (elastin).

Destruction of this protein causes the production of hemorraghic lesions, and alongside elastin, proteases, immunoglobins, lysozyme, and complement proteins are also degraded reducing the effectiveness of host defense mechanisms.

Toxin

P. aeruginosa secretes a number of toxins including exotoxin A, a byproduct of the toxA gene. This toxin is physiologically related to the diphtheria toxin and inhibits protein synthesis.

Although with all these virulence factors, P. aeruginosa is still not very successful at overcoming physical barriers such as the skin and gaining access to host tissues.

And when P. aeruginosa enters the body system, it is not effective at avoiding host defense mechanisms. These two intrinsic factors of the bacteria, as pointed out by Passador and Iglewski are the reasons why P. aeruginosa is capable of only invading only hosts with some compromising disability like wounds, burns, hereditary predisposition, and immune deficiency.

According to Passador and Iglewski, 1995, in healthy persons, the normal first line of defenses of the human body is sufficient to prevent Pseudomanas aeruginosa infection.

It is only when Pseudomanas reaches a critical quorum that the virulence factors are expressed but by the time it reaches, the organism is capable of dealing with host defenses because it has by this time developed a fully capable biofilm.

So initially in the early stage of infection, Pseudomanas is dormant and “hides out”, thus failing to trigger the aggressive host responses typically initiated by more virulent pathogens.

A Viral Case Study: COVID-19

A virus with the world’s largest-ever known impact on the human race is Covid-19; this is primarily due to its infectiousness. The virus’s virulence factor contributes largely to its increased level of infectiousness, currently being studied intensely.

One of its known virulence factors is the nutritional status of the host. This factor is common among viruses since the immune defenses that need to be mounted against a viral infection can be energetically expensive.

Another Covid-19 famous virulence factor is the host’s host’s health status- more senior individuals and persons with immune dysfunctions appear to be susceptible to Covid-19.

Last but not least, the known virulence factor of Covid-19 (associated with most coronaviruses) is related to T-cells. In most patients of Covid-19, there is a fall in CD4 T cells production following infection as conditions worsen. Scientists believe this to be the most critical virulence factor of the virus.   

Virulence and Treatment

Searching for treatment approaches for pathogens is a constant war. Especially in this age of antibiotic resistance, it is increasingly becoming frequent that more virulence factors are identified at the molecular and genetic level, which opens up the possibility of targeting virulence factors as a form of treatment against pathogens.

Many manufactured antibiotics that do not target virulence factors kill both pathogenic (harmful) and commensal (not harmful) bacteria, resulting in adverse side effects.

Since commensal microorganisms will not likely share a pathogenic virulence factor, drugs targeting virulence factors can theoretically prevent many harmful outcomes.

Subsequently, infections related to biofilm factors are not always treated by antibiotics and could instead be treated with VFD (virulence factor-related drugs).

Conclusion

Many factors determine the outcome of a pathogen-host relationship. The host must live in an environment filled with a diverse population of pathogens.

Because of the gravity of the infectious-disease problems, scientists, particularly microbiologists, strive to understand the host’s natural immune mechanisms so that prognostic improvements in resistance to bacterial and viral infections may be possible.

Although viruses are not similar to bacteria in terms of structure, some of the properties contributing to their virulence are similar. Massive efforts have been expended on research to identify and categorize the virulence factors of pathogenic bacterial and viral infections and hence allow physicians to interrupt the pathogenic mechanisms of virulent pathogens.     

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