Transcript Antibiotics - Curriculum Support

Microbial evolution and
infectious disease
Dr Sham Nair
Department of Biological Sciences
Faculty of Science
Macquarie University
[email protected]
Definitions
Microbes: microorganisms
 Pathogens: microbes that causes disease
 Host: usually multicellular organisms that harbour
microbes
 Epidemics: localised disease outbreaks that affect
a number of people in a population.
 Pandemics: disease outbreaks that occurs over a
very large area.

DNA – the thread of life
• DNA – deoxyribonucleic
acid
• All cells contain DNA
• Encodes all phenotypic
traits
• A language of 4 alphabets
(A, T, C and G)
http://www.myheritageimages.com/H/storage/blogs/genealogyblog/MH_DNA
_redblue_jan09.jpg
Mutations: changes to the script of life
Mutations are changes to DNA sequences.
 Most mutations have no impact.

 Mutations result in natural genetic variations in
populations.
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Natural selection acts on genetic
variations
Natural selection acts on mutations (Gould
and Keeton,Biological Sciences, Norton
Publishing, 1996)
Beneficial
mutations
propagate in a
population as a
result of sexual
reproduction
Host-microbe interactions

The human body contains about 1013 human cells and
also about 1014 microbial.

A place to call home: a human host is a nutrient-rich,
warm (constant temperature) and moist environment.
Hence, microbes love to colonize and survive in/on our
bodies.
Good bugs

Many infecting microbes remain unnoticed.

Many bacteria play important roles in human
physiology.
 Intestinal bacteria help digest food and provide essential
nutrients (Vit K)
 They are also essential for proper development of the
gastrointestinal tract in infants.
 Normal skin flora help prevent infections.

Disease is NOT the inevitable outcome of a hostmicrobe interaction
Immunity to infections
Physical barriers prevent the entry of most microbes
into the human body.
 Invading pathogens are confronted with a vast array of
anti-microbial weapons.
 Anti-microbial peptides
 Antibodies
 Microbe-destroying cells (white blood cells)

Infectious diseases

Infectious diseases cause about one-third of all human
deaths in the world (more than all forms of cancer
combined).

Antibiotics and vaccinations were very successfully in
controlling infectious diseases.

“It is time to close the book on infectious diseases.”
U.S. Surgeon General (1965)
Pathogen evolution and virulence genes

Pathogens evolve rapidly, while multicellular
organisms evolve slowly.
 Whereas humans and chimpanzees have acquired a 2%
difference in genome sequences over about 8 million years of
divergent evolution, poliovirus manages a 2% change in its
genome in 5 days, about the time it takes the virus to pass
from the human mouth to the gut!
Different strains of E. coli may differ by as much as
25% in their genomes.
 Genes that contribute to the ability of an organism to
cause disease are called virulence genes.

Pathogen evolution I
Acquiring new virulence genes bacteriophages
Cholera epidemics
http://www.mansfield.ohio-state.edu/~sabedon/images/phage_attack_t_001_001.jpg
http://images.clipartof.com/small/5725-Sick-Man-Sitting-In-A-Chair-Clipart-Illustration.jpg
http://dhiez.files.wordpress.com/2008/05/cholera.jpg
(1961)
(1817-1923)
(1991)
Evolution of
pathogenic
Vibrio
Pathogen evolution II
Errors during viral replication
Errors during viral replication –
Human Immunodeficiency Virus

HIV infects human white blood cells and causes the
immune system to collapse (AIDS – Acquired Immune
Deficiency Syndrome).

HIV is an RNA retrovirus and acquires on average one
point mutation every replication cycle

Resistance to anti-viral drugs rapidly appears in
patients undergoing chemotherapy.

The most virulent type of HIV, HIV-1, may have
jumped from chimpanzees to humans as recently as
1930.
Evolution of drug resistance in HIV
In a just a few
weeks, 3TC
resistant HIV
made up 100%
of the virus
population in
each case.
Evolution of the HIV
Pathogen evolution III
Horizontal Gene Transfer
Horizontal Gene Transfer
Horizontal gene transfer often causes
rapid evolution in bacteria.
 Once a bacterium acquires a new set
of virulence-related genes, it may
quickly cause human epidemics.
 Yersinia pestis, for example, is a
bacterium endemic to rats and other
rodents; it first appeared in human
history in 542 A.D. 25 million people
died of the plague.

http://www.bio.hbnu.edu.cn/wdwsw/newindex/
tuku/MYPER/zxj/zxjimage/97241a.jpg
Antibiotic resistance
Antibiotics, which kill bacteria, comprise the
most successful class of interventions that cure
rather than treat infections.
 The rapid evolution of pathogens, however,
enables bacteria to develop resistance to
antibiotics very quickly.
 It takes only a couple of years before resistance
to newly developed antibiotics is observed.
 It took 15 years for vancomycin resistance to
develop – development of the superbug (MRSA).

Antibiotic abuse and resistance
Persistent and chronic misuse of antibiotics can
eventually result in the evolution of antibiotic-resistant
pathogens.
 Antibiotic-resistant Shigella flexneri originated in this
way.
 In Brazil, antibiotics are available without physician’s
prescription. More than 80% of the strains of S. flexneri
found in infected Brazilian patients are resistant to four
or more antibiotics.
 Antibiotics misuse in agriculture: an antibiotic closely
related to vancomycin was used in cattle feed in Europe;
the resulting resistance in the normal flora of these
animals is widely believed to be one of the original
sources for vancomycin-resistant bacteria that now
threaten the lives of hospitalized patients.

Natural drug resistance
Bacteria commonly exchange genetic material across
species boundaries.
 Drug-resistance genes come from environmental
reservoirs, where they play an important part in the
competition between microorganisms.
 Natural resistance to 7 or 8 antibiotics in clinical use
already exist in unexposed soil bacteria.
 Microbes can draw upon this world-wide and essentially
inexhaustible source of genetic material to acquire
resistance.

Pathogen evolution IV
Genome recombinations in different hosts
Influenza epidmics – recombination
betwwen flu viruses?
http://www.drugdevelopmenttechnology.com/projects/fludase/images/1-influenza.jpg
H: hemagglutinin
N: neuraminidase
Strains: e.g. H1N1
Most recent epidemic: swine flu
• Bird and human
flu viruses have
been mixing in
pigs (“triplereassortant”
viruses).
• The immediate
ancestors of
swine flu virus
have been
present in pigs for
about a decade.
http://chickenoreggblog.files.wordpress.com/2009/06/swinefluevolution1.jpg
• The virus made
the leap to
humans around
January 2009.
Human evolution
 Constant exposure to pathogens has
strongly influenced human evolution.
 2 examples:
 Malaria and sickle cell anemia
 Resistance to HIV infections
Malaria





Malaria is a strong selective pressure on human
populations, especially in areas of Africa.
It is caused by the parasite, Plasmodium falciparum.
Sickle-cell anemia is a genetic disease that causes red
blood cells to deform and dysfunction.
The malarial parasites grow poorly in the deformed red
blood cells from either sickle-cell patients or healthy
carriers, and, as a result, malaria is seldom found among
carriers of this mutation.
For this reason, malaria has served to maintain the
otherwise deleterious sickle-cell mutation at high
frequency in these regions of Africa.
Malaria and the selection for
sickle cell anaemia allele
http://www.bswuiuc.net/tutinf/sickle/introduction/image002.jpg
Resistance to HIV infections

Early in an infection, most of the viruses use CCR5 as a co-receptor,
allowing them to infect macrophages.

As the infection progresses, mutant variants arise that now use
CXCR4 as a co-receptor, enabling them to infect helper T cells.

Individuals fortunate enough to carry a defective Ccr5 gene are not
susceptible to HIV infection.
Conclusion 1
• Host-pathogen interactions results in a constant arms race
for survival – this contributes to both host and pathogen
evolution: the Red queen hypothesis
• Pathogen evolution is not directed at harming the host –
sometimes, disease is the result of our immune responses to
infection.
• It is in the pathogens’ interest to keep the host alive.
THEORY OF THE RED QUEEN
(the Red Queen from
Alice Through the Looking
Glass was forced to
constantly run against a
howling gale. She made no
headway, but had to run
all the time simply to
stop from being blown
backwards) (http://www.1st-artgallery.com/thumbnail/188618/1/Alice-AndThe-Red-Queen,-Illustration-From-Through-TheLooking-Glass-By-Lewis-Carroll-1832-98-FirstPublished-1871.jpg)
Conclusion 2

Natural selection is an editing process rather than
a creative process.
 E.g. a drug does not create resistant pathogens, but
selects for resistant individuals already present in the
population

Natural selection favours genetic variations in a
population that provide an advantage in the
current, local environment.
“There is grandeur in this view of
life … [in which] endless forms
most beautiful and most
wonderful have been, and are
being, evolved.”
Charles Darwin
The Origin of Species