Early perspectives on pathogens generally assumed that pathogenicity and
virulence were inherent properties of microorganisms, however it was later
demonstrated that these are not absolute (1). The term ‘pathogenicity’ commonly
refers to the capacity of a microorganism to cause damage in a host.

This essay will focus on bacteria and viruses. The former are
unicellular organisms that replicate themselves autonomously, while viruses are
composed of a DNA or RNA core and replicate only within the cells of living
hosts.

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This essay will examine the various factors behind a microorganism’s
pathogenicity, in particular how initially harmless microorganisms can become
pathogenic, and how environmental changes, genetic evolution and mutations, as
well as the pathogen’s life cycle and survival strategy, can influence
pathogenesis.

 

Firstly, it is important to understand the nature of the host-microbial relationship
when studying the origin of pathogenicity. This relationship can be defined by
three types of symbiotic associations. Commensal microbes live harmlessly in or
on the host’s body; mutualism implies reciprocal benefits for both microbes and
host; whilst in parasitism, the relationship benefits only the parasite. A
strain of micro-organisms can be categorised depending on its genomic
complement, the makeup of the microbiome, the host’s genetics as well as other
environmental factors (2).

 

In particular, a closer study of commensal relationships sheds light on
a first category of pathogens. Some microorganisms in the human body are in
fact not pathogenic, as they form part of the human ecosystem and even ensure
protection. For instance, the intestinal microflora has the ability to
interfere with pathogens and prevent infection – by exogenous pathogens or
overgrowth of endogenous pathogenic agents. If stable, its members produce
antimicrobial substances, such as short-chain fatty acids or bacteriocins, thus
hindering the growth of microorganisms entering the system via contaminated
food or water (3).

However, bacteria in our normal flora can become harmful if this
stability is disrupted, through the weakening of the immune system or
environmental changes – for instance if bacteria can access a sterile part of
the body (4). A good example would be peritonitis,
in which case bowel perforation, caused by trauma, disease or a surgical
operation, results in infection: bacteria from the intestinal flora penetrate
into the peritoneal cavity. Decreased oxygen supply and poor circulation lead
to the formation of an abscess, and subsequently induce the growth of various
types of bacteria from the intestinal microflora (E coli, Bacteroides or Colstridium) (3). Therefore, it becomes
clear that these microorganisms, initially harmless to the host, can
potentially become endogenous pathogens.

Conversely, in some cases the absence of bacteria in the normal flora
characterises the latter as pathogenic. The suppression of part of the normal
flora – in most cases as a result of antibiotics – disrupts its balance, thus
favouring overgrowth of potentially pathogenic agents. For example, vaginal
lactobacilli produce antimicrobial substances – bacteriocins, hydrogen
peroxide, acetic acid and lactic acid – to lower the vaginal pH and create a
hostile environment for pathogens (5). Therefore, the suppression of this type
of bacteria would increase vaginal pH and induce the replacement of
lactobacilli by several pathogens (usually G.
vaginalis), leading to an infection known as bacterial vaginosis (6).

In that sense, an infectious agent could be characterised as pathogenic
if it disrupts the hosts’ homeostasis.

 

Furthermore, the study of pathogenicity implies the examination of the
pathogen’s life cycle. The latter consists in various stages: colonizing the
host; finding a nutritionally compatible niche in the host’s body; avoiding and
bypassing the host’s immune responses; replicating; exiting and infecting a new
host (4).

At each stage, pathogenic bacteria –relying on the host primarily for
nutrition – encounter selective pressures. They have to adapt themselves in
order to compete with other microorganisms and protect from predation. However,
these adaptations are likely to induce pathogenicity at a later stage (2). The
‘intermicrobial arms race’ is partly responsible for the creation of pathogenic
strains of microorganisms. For example, H.
influenzae and S. pneumoniae
compete against each other for the same host niche – the respiratory tract: the
latter expresses a neuraminidase (NanA), which prevents the former from evading
the host’s immune surveillance by desialylating its surface, thus contributing
to pathogenesis (7).

In addition to this, a pathogen’s transmission mode and survival
strategies suggest its ability to spread effectively. In the case of the herpes simplex, viral replication occurs
at the site of the primary infection. Neurons transport a virion to the dorsal
root ganglia: viral replication is then followed by latency (8). The lesions on
the genitalia, containing the virus, increase the efficiency of the latter’s
direct spread from one host to another through coitus, thus giving it a
selective advantage (4). Furthermore, this virus has developed strategies to
evade and impair host immunity, thus allowing it to remain in the body: viral
evasion molecules specifically target components of innate an acquired
immunity, such as natural killer cells, antibody or complement proteins (9).
HSV-1 encodes immunoevasins (glycoproteins gC and gE) that impair antibody and
complement responses, thus explaining the virus’ ability to generate recurrent
infections.

Such examples challenge traditional views of pathogens as hostile
organisms, whose only purpose is to harm the host. As a matter of fact, inducing
a disease-state presents no advantage for the pathogen: the host is a source of
nutrients, and the pathogen’s only purpose is to survive in its environment.
Thus, disease in humans appears as a by-product of this need for survival.
Several symptoms we generally associate with disease are only a direct
manifestation – for instance through interferons – of our immune system
attempting to destroy pathogens.

 

As part of its life cycle, a bacteria or a virus experiences genetic
evolution, which determines its pathogenicity and is therefore at the origin of
pathogenesis.

The acquisition of genes is made through horizontal transfer and gives
organisms advantages in their ecosystem. Distributed genes, as opposed to core
genes, are considered as the main determinants of pathogenicity: this is
referred to as the ‘distributed genome hypothesis’ (10), which states that
virulence traits are acquired through horizontal gene transfer, and that the
constant recombination of distributed genes amid strains is used to circumvent
the host’s adaptive immune response by continually presenting novel antigens,
thus enhancing population survival. A good illustration of this process is the influenza virus: it presents genetic
heterogeneity due to mutations of its genome and the reassortment of the latter
during mixed infections with variant influenza viruses (11). These variations
can be observed in the two glycoproteins of the virus, hemagglutinin and
neuraminidase, thus explaining its epidemiologic success (11).

 

Non-pathogenic microorganisms can evolve into pathogenic forms through
the acquisition of virulence genes. The latter encode proteins – virulence
factors – and are gathered in either pathogenicity islands or virulence
plasmids (12). These encode toxins and other proteins that can increase the
virulence of the microorganism. The genetic material is transferred from one
bacterium to another, thus creating new genotypes: DNA can be transferred
through transformation, conjugation, transposition or transduction. In the
latter case, bacteriophages (bacterial viruses) carry virulent genes and
transfer genetic material by infection. This offers an explanation for
evolution from non-pathogenic forms to pathogenic forms. For example,
non-pathogenic strains of Vibrio cholerae
exist in aquatic ecosystems; through the acquisition of a toxin
(toxin-co-regulated pilus), followed by an infection with a filamentous
bacteriophage, it obtains the genes encoding cholera toxin (13).

 

However, genetic evolution also occurs in the host, and host mutations
can directly influence microbial pathogenicity. In particular, combinations of
different bacterium and host genes can result in pathogenesis. For example, mutations
in the human CFTR gene, and the
subsequent loss of a chloride channel, result in a genetic disease – cystic fibrosis
(14). A period of colonization with P.
aeruginosa, an opportunistic bacterium of cystic fibrosis patients, predates
the establishment of chronic infections (15). The early-infecting strains are
nonmucoid and fast growing. However, during chronic infection, genetic
adaptation to the environment and mutations can be obvserved in P. aeruginosa genes, especially in the mucA gene, allowing a transition from a
nonmucoid to mucoid phenotype (15).

Therefore, many parasites can become pathogenic due to changes in the
host’s health, or if they infect an ‘unnatural’ (new) host: this is
characterised by unbalanced pathogenicity.

Bacteria that are non-pathogenic in a healthy host may become pathogenic
if a specific host gene is defective, in which case the infection can become
lethal. It is therefore important to observe the hologenome as a whole and
account for all the possible interactions between microbial and host genes.

 

In conclusion, simplistic views of pathogens have always referred to the
latter as hostile microorganisms, whose fundamental goal is to harm its host. In
fact, many bacteria from the normal flora are essential to the protection of
the human body from external pathogens. However, disruptions in the stability
of this ecosystem can result in commensal microorganisms becoming harmful to
the host and provoke pathogenesis. Furthermore a pathogen has a life cycle: through
various stages, it is confronted to an interspecies arms race, and must spread
as effectively as possible. Therefore, the disease-state induced by the
microorganism in the host is only a by-product of the former’s survival
strategy. Genetic evolution can favour the pathogen’s evasion from the host’s
immune system, thus allowing it to replicate and spread. In addition to this,
microorganisms can generate virulence by acquiring virulence genes or adapting
to host mutations. Thus, pathogenesis appears as the result of complex
interactions between a microbe and its environment.

 

 

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