What characteristics of bacteria enable them to become successful pathogens?

Introduction
Historically, bacteria have been the cause of some of the most deadly diseases
and widespread epidemics of human civilization. This is despite the fact that
most bacteria are harmless or beneficial. In this essay I will be describing the
characteristics which have enabled a significant pathogenic minority to wreak
such havoc on the human race.

What makes a pathogen ‘successful’?

A pathogen is defined as a microorganism capable of causing disease; a disorder
of structure or function in a human. The inherent ability of a pathogen to cause
such disorder is called its pathogenicity, and is quantified by virulence-the extent
of a pathology caused by a pathogen. Thus, a successful pathogen is one that is
virulent.

Measuring Virulence
Virulence is traditionally measured experimentally by raising the concentrations
of bacteria administered to test subjects by standard and small amounts until a
concentration consistently causing animal death (LD50) or disease (ID50) in half
the host population is reached. This is based on the observation that the
inoculum required to kill an animal after experimental infection varied
depending on the microbe, for example, Shigellosis can caused by as few as 10
bacteria whereas E.coli requires between 106-108.

What characteristics of bacteria enable them to be virulent?

To answer this question, one must examine exactly how bacteria cause disease in
the host; a process termed pathogenesis:

Adhesion to Disease
Transmission Evasion
cell surfaces symptoms

Transmission
Bacteria are extremely effective at moving from host to host. The wide range of
modes of transmission utilized by bacteria are illustrated in the table below.
Mode of transmission
Human to human- Clinical Example: Further details on
horizontal: transmission:
 Direct contact  Gonorrhea  STI
 Indirect contact  Dysentry  Fecal-oral
 Blood bourne  Syphilis  Transfused blood,
although screening
has greatly reduced
risk
Human to human-
vertical: Pathogen: Disease in Fetus:
 Transplacental  Treponema Pallidum  Congenital syphilis
  Within birth canal  E.Coli  Neonatal sepsis
 Breast milk  Staphylococcus aureus  Oral/skin infections

Animal to Human: Clinical Example: Portal of entry:

 Directly  Cat scratch fever  Cat scratch
 Insect vector  Lyme disease  Tick bite
 Animal excretion  Hemolytic-uremic  Cattle feces ingested
syndrome caused by in undercooked
E.coli hamburger
Non human to human: Clinical Example: Portal of entry:
 Water  Legionnaires disease  Water aerosol
 Fomite  Staphylococcal skin  Bacteria on an object
infection

Whether this high transmissibility is a virulent factor is a matter of significant

debate. It could be argued that transmission isn’t a component of virulence
(unless we are speaking on an epidemiological scale), as virulence is a measure
of the extent of a pathology caused by the microorganism once inside the host.
However, I would argue that transmission is a key aspect of being a successful
pathogen. This is due to the host-dependent nature of virulence as a term;
virulence isn’t an independent, microbial property, yet a dependent variable
contingent on the availability of a successful host. Essentially, the bacteria can
only be virulent once the host-bacteria complex has been formed. For this to
occur, the host must be exposed to the pathogen, and the greater the ease of
transmission, the greater the exposure.

Evasion
The ability of bacteria to avoid the hosts attempts to destroy it are essential to
their virulence, ergo their ability to become successful pathogens. Defense
mechanisms produced from millennia of competitive evolution ranging from
host mimicry to antigenic variation and recruitment of immune modulators
allow certain bacteria to subvert the immune system and survive within the
host-exerting a greater pathogenic effect.

Neisseria Meningitides
An excellent example of bacteria proficient in immune evasion is Neisseria
meningitides, whose survival strategy is having a highly adapted, diversity
generating capacity compounded with anti-phagocytic properties. These anti-
phagocytic properties are largely provided by a polysaccharide capsule
surrounding its cell wall, which prevents the phagocyte from adhering and
engulfing the bacterium. The importance of this capsule to the virulence of N.
Meningitides is illustrated clinically through the efficacy of its vaccine; which
contains capsular polysaccharides that induce protective anti-capsular
antibodies. This allows more effective phagocytosis to occur via opsonisation.
However, to circumvent such antibodies, some serogroups will incorporate sialic
acid into the capsule (B,C, W-135 and Y). This is a form of host mimicry, as sialic
acids are commonly found on several host cell surfaces, meaning the immune
system may gloss over the pathogen as ‘self’ instead of ‘non-self’.
The bacteria can also undergo capsule switching between serogroups, allowing
bacteria with non-sialic acid capsules (serogroup A) to obtain sialic acid
capsules, and meaning that closely related virulent meningococcal clones may
not be recognized by serogroup-specific immune-surveillance methods. This
applies to both specific vaccines, and natural protective immunity. The existence
of capsule switching has been proven experimentally by Swartley and Marfin in
1997, through the assumption that if capsule switching occurs, meningococci
must be naturally competent to undergo such a transformation. It was
postulated that conversion from one sialic acid expressing capsule serogroup to
another could be achieved by homologous recombination of the sequences
encoding the serogroup-specific capsule polymerase. The use of experimental
techniques including PCR, gel electrophoresis and southern DNA hybridization
revealed that serogroup B meningococci contained synD (encoding a key capsule
polysialyltransferase), which wasn’t present in serogroups C,Y and W-135
strains. SynD was then used to transform prototype serogroup C, Y and W-135
strains into serogroup B strains through creation and recombination with
chromosomal DNA containing synD, with acquisition of the adjacent synD
sequence confirmed by PCR and nucleotide sequence analysis of selected
transformants. Transformation occurred at a frequency of between 1*10^-5and
1*10^-7 per recipient. The ease with which this was achieved in vitro suggests
that similar could be achieved in vivo, especially when the extensive horizontal
gene transfer bacteria are capable of, combined with the selection pressure
having a capsule that the immune system could target would create, is
considered.
The antigenic variation provided by capsule switching is compounded by the fact
that almost every gene critical to host interactions and thus available as a target
for an immune response is phase variable-a process of reversible switching
between phenotypes via alternating expressed genes. This provides N.
meningitides with an extremely efficient method of evading host detection.
The importance of these properties in virulence is evidenced by the disparity of
virulence properties between in-vitro and in-vivo meningococci: suggesting that
host factors present in vivo modified the bacteria in such a way as to protect
them from host defenses

Staphylococcus Aureus
Staphylococcus Aureus is similarly well adapted in subverting the immune
system, however instead of avoiding detection like N. Meningitides, it instead
uses more direct methods of actively attacking defensive cells or using them
against themselves.
A prime example of this is its polysaccharide capsule, which will exploit
antibodies targeted against its fibronectin-binding proteins. The bound IgG
engages receptors on nearby platelet surfaces-causing platelet aggregation. The
bacteria will them produce coagulase, which accelerates the formation of a fibrin
clot from tis precursor fibrinogen. This combined with increased platelet
aggregation will form a thrombus, protecting the bacteria by walling off the
infected area.
Staphylococcus Aureus also subverts neutrophils, either directly attacking them
through cytolytic leukotoxins which form beta-barrel pores in the cytoplasmic
membranes of target cells causing leakage and lysis, or indirectly by degrading
extracellular traps. This neutrophil-driven response was observed
experimentally by Said-Salim B et al in 2005, through transcriptional microarray
analysis of mRNA from five strains of s aureus following ingestion by
neutrophils. The results showed that many known or suspected stress-response
genes were upregulated immediately after ingestion-including several
leukotoxins such as Hlg, indicating that S.Aureus targets neutrophils.
This response is an ‘example of how the pathogenesis has evolved to anticipate
host defenses and repurpose them for destruction of the immune system’.

Disease
Once a bacteria has been exposed to the host, and has evaded the immune
system, to truly be a successful pathogen it needs a mechanisms of upsetting host
tissue structure and function. There are two main mechanisms, invasion and
inflammation, and toxin production; both of which are usually precluded by and
dependent on bacterial adhesion to cell surfaces.

Adhesion to cell surfaces

Adhesion to cell surfaces is essential to virulence, as it is the first step in
overcoming the bodies last physical barrier-mucous membranes. It also
increases the tropism of the pathogen; the cells and tissues of a host which
support its growth.
Adhesion is facilitated by specialized structures such as pili, through specific
adhesion proteins that bind specific receptors on the epithelial component of
mucous membranes. For example, in N.Meningitides, type 4 pili mediate
attachment to the respiratory epithelium.
Adhesion doesn’t necessarily have to be static; certain serogroups of E.coli are
characterized by type 1 pili, which can adhere to the urinary tract but also act as
fimbriae to provide motility.

Invasion and Inflammation

The function of pili is predominantly adhesion, but is also extremely important in
facilitating invasion. This is typified within N.Meningitides, where type 4 pili
induce exploitation of host cell signaling pathways to promote uptake by host
cells, specifically invading neutrophils. The pili of E.Coli are similarly involved in
invasion of uroepithelial cells, causing UTIs. This phenomena was documented
by Mulvey MA in 1999, who noted that shortly after transurethral inoculation of
mouse bladders with type 1 piliated uropathogenic E.coli (UPEC), bacteria could
be found entering and within the large superficial epithelial cells lining the
luminal surface of the bladder. Upon examination using high resolution electron
microscopy and freeze fracture, it was revealed that the type 1 pilus tips
interacted directly with the luminal surgace of the bladder, facilitating intimate
contact with the host cells and invasion.
It is thought that this invasion provides the bacteria with a survival advantage
within the urinary tract. This hypothesis was also put to the test by Mulvey, who
determined using ex vivo fentamicin protection assays in which extracellular
bacteria are specifically eliminated, that between a 24-48h period after
inoculation, the majority of bacteria that continue to persist within the bladder
are intracellular. This is almost certainly due bacterially induced exfoliation of
superficial uro-epithelial cells, which are avoided by UPEC by invading into
deeper tissue. This observation has important clinical consequences, as the
ability of type 1 piliated UPEC to invade the bladder epithelium and persist, may
provide an explanation for the recurrent nature of UTIs.
UPEC illustrates the importance of invasion as a virulent factor not only due to
its use as a tool for access to the viscera, but also as an escape mechanism.
Upon invasion, both pathogens described in this section cause pyogenic (pus
producing) inflammation and associated pathology. Inflammation can also be
granulomatous, as is the case in mycobacterium tuberculosis.

Toxin Production
Toxins are the second major mechanism by which bacteria cause disease. There
are two types, and their features are outlined in the table below.
Property Exotoxin Endotoxin
Source Certain species of gram Cell wall of gram
positive and gram negative negative bacteria
bacteria
Secreted from cell Yes No
Chemistry Polypeptide Lipopolysaccharide
Mode of action ADP-ribosylation, Activates macrophages,
Superantigen, protease, complement and tissue
lecithinase factor
Toxicity High Low
Typical diseases Tetanus, botulism, diphtheria Meningococcemia, sepsis
by gram negative rods
Clinical Case Tetanus: LPS and LOS:
study  Produced by clostridium  Produced by both
tetani-spore forming gram Neisseria meningitides
positive rods and gonorrhea.
 Carried intra-axonally to CNS  Causes fever and
where it blocks release of hypotension-salient
inhibitory transmitters at the features of septic
spinal cord synapse by shock.
proteolytic cleavage of  Septic shock is one of
SNARE complex. the leading causes of
 Causes spasms and rigidity. death in ICU, with an
 Immunization with tetanus estimated mortality
toxoid is very successful as rate of between 30 and
there is no antigenic 50 percent.
variation.

Shock Toxic Shock: Septic Shock:

 Toxin in the bloodstream  Bacteria in the
bloodstream
 Blood cultures negative  Blood cultures positive.
In conclusion, bacteria’s highly adapted ability to expose themselves to the host,
evade its immune system and then cause disorder to its tissue structure and
function via adhesion followed by toxin release and invasion and inflammation
enable them to act as successful pathogens.