Microbiology, Lec 22.

Mechanisms and evolution of diseases.

Pathogenesis

Despite all of these defenses we have been discussing some organisms can invade our bodies and cause disease. So let's talk about pathogens in a general sense for a while. Disease causing organisms can be classified as Obligate, Accidental or Opportunistic.

Accidental Pathogens are organisms such as Clostridium tetani that is very common in soils and lives quite happily there and only causes diseases under unusual circumstances (e.g. via a puncture wound).

Obligate Pathogens are organisms that cannot survive for long outside of the human body. An example that we will discuss later is Neisseria gonorrhoeae, the causal agent of gonorrhea.

Opportunistic Pathogens are organisms that can only cause disease in an immuno-suppressed person or under unusual circumstances, e.g. skin infections caused by Pseudomonas aeruginosa when the normal skin microbiota is disrupted.

We also will be referring to the degree of virulence of different pathogens. Virulence is a relative term, a highly virulent organism is one that can cause an acute infection. Virulent organisms must either produce really nasty toxins or be very invasive (or both!).

Aspects of virulence:

Infectivity - Ability of the pathogen to establish a focal point of infection
Invasiveness - Ability of the pathogen to spread to other tissues
Toxigenicity - Ability of the pathogen to produce toxins

Virulence can be measured experimentally by determining the lethal dose 50 (LD50).....

See Fig. 29.2

Steps in the infection process

Transmission, Attachment & Colonization, Invasion & Growth, Evasion and Damage.

I. Transmission (see pgs. 728 - 731)

Airborne e.g. Flu Virus, Mycobacterium tuberculosis,
Contact e.g. person-to-person (direct) contact, e.g. AIDS
Vehicle e.g. via fomites (=inanimate objects)
Vector-borne e.g. via ticks, fleas etc.

II. Attachment & Colonization

Before a pathogen can cause infection it must attach to a specific tissue. Most nasty diseases start when organisms adhere to mucosal surfaces inside the respiratory, gastrointestinal or genitourinary tracts. Most pathogens have very specific mechanism for attachment to the specific mucosal surfaces that they colonize. For example E. coli strains that attach to glycoproteins on mucosal cells in the urinary tract have different lectins on their fimbriae than E. coli that cause intestinal infections. This type of specificity also is one reason that pathogens of one animal species usually do not infect other animals. If a pathogen cannot adhere, then it cannot colonize and infect.

See Fig. 29.3 and Table 29.3 After adherence, some pathogens simply colonize the mucosal surface and cause damage via the release of toxins (e.g. Vibrio cholerae, Corynebacterium diphtheriae). Other pathogens must penetrate the surface to cause their harm.............

III. Growth

All pathogens must grow in order to cause disease and nutrients for such growth usually comes from the disruption of host cells. Table 29.4 shows just some of the enzymes that allow bacteria to disrupt tissues (and thereby gain food) and invade their host.....

Pathogens also have other virulence factors, many of which are plasmid encoded (see Table 29.4).

VI. Evasion of Host Defenses

Avoidence of the Immune Response
Many bacteria have mechanisms for avoiding our immune system once they have entered our bodies. Some pathogens can also avoid the immune system by actually living inside macrophages (e.g. Mycobacterium tuberculosis,). More about such critters next week.

Many bacteria also exhibit phase variations once they are in the body. One example is phase variation in fimbriae. Remember from lec. 4 and lec. 21 that fimbriae are involved in attachment and that they are antigenic and can elicit an immune response. A single bacterium can have several distinct types of fimbriae genes and recombination among such genes is common. Thus, some bacteria (e.g. E. coli) can change its fimbriae after infection and thus not be affected by antibodies to its original fimbriae.

V. Toxigenicity

Toxins

Endotoxins are part of the lipopolysaccharide (LPS, Fig. 3.29), specifically the Lipid A is the toxic part of the LPS and the polysaccharide helps to solubilize the lipid (remember, the polysaccharide is also antigenic; lec. 21). Endotoxins are released when gram - bacteria are lysed. They are not very toxic in low doses but can lead to internal hemorrhaging in high doses.

Exotoxins. Exotoxins are protein toxins (usually Dimeric, see Fig. 29.4) that we will see a lot of over the next few weeks.
Discuss differnce between the roles of exotoxins in "Intoxications" vs. "Infections".

e.g. Food intoxication caused by Saphylococcus aureus vs. Food-borne infection caused by e.g. Salmonella.

Most exotoxins fall into one of the following categories:

1) Enterotoxins - cause dysentery; e.g. cholera toxin, or the related E. coli toxin discussed above.

2) Neurotoxins - disrupt nerve impulses; e.g. tetanus and botulinum toxins

3) Cytotoxins - inhibit protein synthesis, e.g. diphtheria toxin

.

Entry of exotoxins into cells - see Fig. 29.4

Many exotoxins are plasmid or viral borne

Table 29.5

Viulence plasmids

Show plasmid pCG86 from E. coli

117,000 bp
has Tra genes (is infectious)
codes for 2 exotoxins as well as resistance to 2 antibiotics

Exotoxins coded by lysogenic phage
"lysogenic conversion"

e.g. Beta phage of Corynebacterium diphtheriae
Other examples: See Table 29.5

Evolution of Hosts and Pathogens.

Before we go any further into our exploration of diseases I want to say a few things about where diseases come from and how they evolve.

It is true of many diseases that the longer a population is exposed to a disease, the less susceptible that population is to the disease. Over the short term (months to years) this is due to the fact that more and more people become immune to the disease (see lec. 21). Over the long term (years to many generations), however, this is due to evolution of both the host and the pathogen. Natural selection tends to weed out extremely virulent pathogens, because if they kill all of their hosts, then they too will go extinct. Simultaneously, hosts that are more resistant to a prevalent pathogen (because there has been selection for hosts with more responsive immune systems to the specific pathogen) are more fit and therefore leave more offspring. Thus, through evolutionary time specific pathogens tend to become less virulent to their hosts and hosts become more resistant to their pathogens. It is even thought that some mutualistic relationships evolved from former antagonistic ones via a progression like this...

.

Pathogenic ----> Commensalistic --?--> Mutualistic

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As an illustration of a transition from a virulent pathogen to a commensal, I will tell you the story of rabbits in Australia.

Rabbits were first introduced to Australia from England in 1859. Because they had no natural enemies they soon became major pests, competing with native wildlife and sheep. Finally in 1950 an enterprising scientist isolated a Myxoma virus that caused a not-very-serious disease in a species of Brazilian rabbits. When this virus was brought to Australia (remember it was a brand new disease to those descendants of English rabbits) it was extremely virulent towards them. Within a year,99.9% of all the rabbits in Australia died from the disease.

Over the following 20 years, Australian scientists closely monitored the co-evolution of this new disease and the rabbits of Australia. The main finding of these studies was that the virulence of the virus decreased each year and the non-immunological resistance of the rabbits increased each year. Finally after about ten years the number of rabbits in Australia increased back up to about 20% of their pre-virus levels.

Two important points about the above story.

1) The long-term change in the rabbits was genetic, i.e. more resistant rabbits were selected for.

2) It took about ten rabbit generations (assuming 1 generation per year) for the rabbits and virus to reach a equilibrium in which the rabbit was quite resistant and the virus was almost avirulent.

Let's quickly review that with an overhead.

Of course not all diseases evolve exactly like the rabbit/myxoma case. Co-evolution is a back and forth process that can lead to a balance, as in the rabbit/myxoma case, or to either the pathogen or the host gaining advantage at any point in time.

Emerging Infectious Diseases

One reason that I started with the rabbits is that it is pertinent to how and why new diseases keep cropping up - especially lately. One reason that new diseases are turning up is that the human population on earth is still growing exponentially (show graph of human pop. growth) and therefore people are increasingly encountering new microbes and viruses in nature. For example 13 new serious viral diseases have been reported in the last 20 years, including the Ebola virus and HIV (read pg. 732 and Tables 35.3 and 36.1). The study of emerging infectious diseases is a rapidly expanding field of medical microbiology.
Here is a link to an article about emerging infectious diseases caused by organisms such as E. coli.