Early perspectives on pathogens generally assumed that pathogenicity andvirulence were inherent properties of microorganisms, however it was laterdemonstrated that these are not absolute (1).
The term ‘pathogenicity’ commonlyrefers to the capacity of a microorganism to cause damage in a host. This essay will focus on bacteria and viruses. The former areunicellular organisms that replicate themselves autonomously, while viruses arecomposed of a DNA or RNA core and replicate only within the cells of livinghosts. This essay will examine the various factors behind a microorganism’spathogenicity, in particular how initially harmless microorganisms can becomepathogenic, and how environmental changes, genetic evolution and mutations, aswell as the pathogen’s life cycle and survival strategy, can influencepathogenesis. Firstly, it is important to understand the nature of the host-microbial relationshipwhen studying the origin of pathogenicity.
This relationship can be defined bythree types of symbiotic associations. Commensal microbes live harmlessly in oron the host’s body; mutualism implies reciprocal benefits for both microbes andhost; whilst in parasitism, the relationship benefits only the parasite. Astrain of micro-organisms can be categorised depending on its genomiccomplement, the makeup of the microbiome, the host’s genetics as well as otherenvironmental factors (2).
In particular, a closer study of commensal relationships sheds light ona first category of pathogens. Some microorganisms in the human body are infact not pathogenic, as they form part of the human ecosystem and even ensureprotection. For instance, the intestinal microflora has the ability tointerfere with pathogens and prevent infection – by exogenous pathogens orovergrowth of endogenous pathogenic agents. If stable, its members produceantimicrobial substances, such as short-chain fatty acids or bacteriocins, thushindering the growth of microorganisms entering the system via contaminatedfood or water (3).
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However, bacteria in our normal flora can become harmful if thisstability is disrupted, through the weakening of the immune system orenvironmental changes – for instance if bacteria can access a sterile part ofthe body (4). A good example would be peritonitis,in which case bowel perforation, caused by trauma, disease or a surgicaloperation, results in infection: bacteria from the intestinal flora penetrateinto the peritoneal cavity. Decreased oxygen supply and poor circulation leadto the formation of an abscess, and subsequently induce the growth of varioustypes of bacteria from the intestinal microflora (E coli, Bacteroides or Colstridium) (3). Therefore, it becomesclear that these microorganisms, initially harmless to the host, canpotentially become endogenous pathogens. Conversely, in some cases the absence of bacteria in the normal floracharacterises the latter as pathogenic. The suppression of part of the normalflora – in most cases as a result of antibiotics – disrupts its balance, thusfavouring overgrowth of potentially pathogenic agents.
For example, vaginallactobacilli produce antimicrobial substances – bacteriocins, hydrogenperoxide, acetic acid and lactic acid – to lower the vaginal pH and create ahostile environment for pathogens (5). Therefore, the suppression of this typeof bacteria would increase vaginal pH and induce the replacement oflactobacilli 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 pathogenicif it disrupts the hosts’ homeostasis. Furthermore, the study of pathogenicity implies the examination of thepathogen’s life cycle. The latter consists in various stages: colonizing thehost; finding a nutritionally compatible niche in the host’s body; avoiding andbypassing the host’s immune responses; replicating; exiting and infecting a newhost (4).
At each stage, pathogenic bacteria –relying on the host primarily fornutrition – encounter selective pressures. They have to adapt themselves inorder 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 pathogenicstrains of microorganisms.
For example, H.influenzae and S. pneumoniaecompete against each other for the same host niche – the respiratory tract: thelatter expresses a neuraminidase (NanA), which prevents the former from evadingthe host’s immune surveillance by desialylating its surface, thus contributingto pathogenesis (7). In addition to this, a pathogen’s transmission mode and survivalstrategies suggest its ability to spread effectively. In the case of the herpes simplex, viral replication occursat the site of the primary infection.
Neurons transport a virion to the dorsalroot ganglia: viral replication is then followed by latency (8). The lesions onthe genitalia, containing the virus, increase the efficiency of the latter’sdirect spread from one host to another through coitus, thus giving it aselective advantage (4). Furthermore, this virus has developed strategies toevade and impair host immunity, thus allowing it to remain in the body: viralevasion molecules specifically target components of innate an acquiredimmunity, such as natural killer cells, antibody or complement proteins (9).HSV-1 encodes immunoevasins (glycoproteins gC and gE) that impair antibody andcomplement responses, thus explaining the virus’ ability to generate recurrentinfections. Such examples challenge traditional views of pathogens as hostileorganisms, whose only purpose is to harm the host.
As a matter of fact, inducinga disease-state presents no advantage for the pathogen: the host is a source ofnutrients, 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 directmanifestation – for instance through interferons – of our immune systemattempting to destroy pathogens. As part of its life cycle, a bacteria or a virus experiences geneticevolution, which determines its pathogenicity and is therefore at the origin ofpathogenesis.
The acquisition of genes is made through horizontal transfer and givesorganisms advantages in their ecosystem. Distributed genes, as opposed to coregenes, are considered as the main determinants of pathogenicity: this isreferred to as the ‘distributed genome hypothesis’ (10), which states thatvirulence traits are acquired through horizontal gene transfer, and that theconstant recombination of distributed genes amid strains is used to circumventthe 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 geneticheterogeneity due to mutations of its genome and the reassortment of the latterduring mixed infections with variant influenza viruses (11). These variationscan be observed in the two glycoproteins of the virus, hemagglutinin andneuraminidase, thus explaining its epidemiologic success (11). Non-pathogenic microorganisms can evolve into pathogenic forms throughthe acquisition of virulence genes. The latter encode proteins – virulencefactors – and are gathered in either pathogenicity islands or virulenceplasmids (12).
These encode toxins and other proteins that can increase thevirulence of the microorganism. The genetic material is transferred from onebacterium to another, thus creating new genotypes: DNA can be transferredthrough transformation, conjugation, transposition or transduction. In thelatter case, bacteriophages (bacterial viruses) carry virulent genes andtransfer genetic material by infection. This offers an explanation forevolution from non-pathogenic forms to pathogenic forms.
For example,non-pathogenic strains of Vibrio choleraeexist in aquatic ecosystems; through the acquisition of a toxin(toxin-co-regulated pilus), followed by an infection with a filamentousbacteriophage, it obtains the genes encoding cholera toxin (13). However, genetic evolution also occurs in the host, and host mutationscan directly influence microbial pathogenicity. In particular, combinations ofdifferent bacterium and host genes can result in pathogenesis. For example, mutationsin the human CFTR gene, and thesubsequent 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, predatesthe establishment of chronic infections (15). The early-infecting strains arenonmucoid and fast growing.
However, during chronic infection, geneticadaptation to the environment and mutations can be obvserved in P. aeruginosa genes, especially in the mucA gene, allowing a transition from anonmucoid to mucoid phenotype (15).Therefore, many parasites can become pathogenic due to changes in thehost’s health, or if they infect an ‘unnatural’ (new) host: this ischaracterised by unbalanced pathogenicity.Bacteria that are non-pathogenic in a healthy host may become pathogenicif a specific host gene is defective, in which case the infection can becomelethal.
It is therefore important to observe the hologenome as a whole andaccount for all the possible interactions between microbial and host genes. In conclusion, simplistic views of pathogens have always referred to thelatter as hostile microorganisms, whose fundamental goal is to harm its host. Infact, many bacteria from the normal flora are essential to the protection ofthe human body from external pathogens. However, disruptions in the stabilityof this ecosystem can result in commensal microorganisms becoming harmful tothe host and provoke pathogenesis. Furthermore a pathogen has a life cycle: throughvarious stages, it is confronted to an interspecies arms race, and must spreadas effectively as possible. Therefore, the disease-state induced by themicroorganism in the host is only a by-product of the former’s survivalstrategy. Genetic evolution can favour the pathogen’s evasion from the host’simmune system, thus allowing it to replicate and spread.
In addition to this,microorganisms can generate virulence by acquiring virulence genes or adaptingto host mutations. Thus, pathogenesis appears as the result of complexinteractions between a microbe and its environment.
