coevolution, evolution, and medicines - part 2

what is Mycobacterium tuberculosis?

the causative agent of tuberculosis

transmitted by airborne droplets

what are. themajor virulence factors for tuberculosis?

mycolic and cord factor

what is mycolic?

lipid component of the bacterial cell walls

provides resistance to antibiotics and immune response

what is a cord factor?

glycolipid that prevents the fusion of the lysosome and phagosome

also contributes to the granuloma formation

a hydrolytic organelle

what is the pathogenesis of Mycobacterium tuberculosis?

latent phase and active phase

what happens in the latent phase for Mycobacterium tuberculosis?

• after inhaling M. tuberculosis, bacteria settle in lungs and will be ingested by macrophages

• bacteria will grow slowly and multiply within the macrophages → granuloma

• infection remains localized  (can stay in this stage for many years or even a lifetime

what happens in the active phase of Mycobacterium tuberculosis?

• aging, malnutrition, overcrowding and stress can reduce the strength of the immune system and allow reactivation of dormant bacteria

• granulomas get bigger, lesions in the lungs and bacteria are relreased into the airways

  • coughing up blood, chest pain, fever/fatigue-chronic tuberculosis often results in more serious; potentially fatal

how do humans counter Mycobacterium tuberculosis?

use antibiotics; combination isoniazid (block formation of mycolic acid) and rifampin (inhibits RNA polymerase)

use vaccination; using an attenuated strain of M. bovis (BCG) can effectively prevent tuberculosis

How do the pathogens evolve to obtain the resistant genes?

through spontaneous mutations, improper treatments, and horizontal gene transfers

What is KatG?

encodes catalase-peroxide enzyme in M. tuberculosis

converts isoniazid into its active, toxic form that kills the pathogen (highest efficiency)

what are the results from mutations in the KatG gene?

prevents the conversion, making the drug ineffective

isoniazed-resistance strain

what is rpoA?

encodes for RNa polymerase in M. tuberculosis

what happens when there are mutations in the rpoA?

mutations in this gene alter the RNA polymerase enzyme which prevents rifampin from binding

rifampin-resistance strain (overuse of antibiotics)

what is MRSA (Methicillin-resistant Staphylococcus aerus)?

common gram-positive skin bacterium that can cause a wide range of infections

what are the major virulence factors of MRSA?

hemolysins, leukocidins, coagulase

what is hemolysins?

lyses red blood cells

what are leukocidins?

destroys certain leukocytes

what is coagulase?

converts fibrinogen to fibrin (clot formation)

creates barrier from immune system to attack

what’s the pathogenesis of MRSA?

• can enter through an open wound and cause a systemic infection (non toxic shock syndrome) (multiple organ failure)

  • can resist many antibiotics which may complicate the treatment process

what’s the evolution of MRSA?

• initial strain of S. aureus was sensitive to penicillin

• horizontal gene transfer (Hgt) allows the pathogen to obtain the gene for penicillinase to inactive penicillin

• methicillin used to fight → pathogen developed resistance → can resist many beta-lactam antibiotics

what did humans use to counter MRSA?

antibiotics: vancomycin → blocks cell wall synthesis and does not have a beta-lactam antibiotic

some cases are asymptomatic

normal flora

how can staphylococcus aureus resist many different antibiotics?

through horizontal gene transfer allowing the pathogen to pick up beneficial genes

• transformation (“naturally competent”)

• staphylococcus cassette chromosome mec

what is mecA?

a transpeptidase that has no affinity for beta-lactam antibiotics (penicillin)

allows for continuation of transpeptidation

enables cell wall synthesis in the presence of penicillin

what is staphylococcus cassette chromosome mec (SCCmec)?

mobile genetic element

contains mecA

what is pseudomonas aeruginosa?

major opportunistic gram-negative bacterial pathogen

commonly form biofilms

very common in hospital settings

what are the major virulence factors in pseudomonas aeruginosa?

lipopolysaccharides

flagella (motility)

type IV pili (attachment)

what are lippolysaccharides?

component of the bacterial cell wall that can generate inflammation → vigorous immune response

what is the pathogenesis for pseudomonas aeruginosa?

for high risk individuals → immunocompromised: enter bloodstream → septic shock

cystic fibrosis patients: enter lung → pneumonia

what’s the evolution of pseudomonas aeruginosa?

originated in diverse soil and aquatic environments that gained the ability to infect over time due to genetic changes

can become pathogenetic through adaptive radiation which allows it to evolve after entering a host (lung)

what does pseudomonas aeruginosa require to survive?

iron

how does pseudomonas aerunosa adapt to the lack of iron?

it undergoes mutations that allow it to produce new proteins that are important for surviving and adapting to this new environment with less iron (lung) → resulting in new strains

how does pseudomonas aeruginosa pick up beneficial genes?

when it is in a biofilm, it can interact and pick up beneficial genes from other bacteria and can pass the beneficial genes to other bacteria

however, when it is in a biofilm, it is hard to get rid of but easy to go through transformation

how do humans counter pseudomonas aeruginosa?

asympotomatic in immuno-competent patients

treatments: combinations of multiple antibiotics and vary depending on the site of infection

• beta-lactam antibiotics (block cell wall synthesis)

• aminoglycoside (streptomycin blocks translation)

• quinolone (ciprofloxacin blocks DNA replication)

what is a hypermutator?

an organism with a significantly increased genome-wide mutation rate due to environmental pressure to gain new traits

what can pseudomonas aeruginosa have a high risk of becoming?

hypermutator

how can pseudomonas aeruginosa become a hypermutator?

due to defects in the DNA repair systems (methyl-directed mismatch repair system)

• the chronic lung environment is harsh

• nutrient limitations

• oxidative stress

• constant antibiotic pressure

• creates a strong positive selection for bacteria that can adapt quickly

what mechanisms are used by pseudomonas aeruginosa to fight the immune system and antibiotics?

• high motility (flagellated)

• being in a biofilm makes it easier to exchange DNA with other bacteria to gain beneficial genes using a pilus

• possesses a plasmid that encodes for a transport protein that can pump antibiotics out of the cell (“efflux pumps”)

• mutations in genes that alter the target of the antibiotics (bacterial ribosomes)

what is plasmodium falcuparium?

a protozoan that is spread by mosquitoes (vector)

infects the liver and RBCs

causes malaria

what are the virulence factors/pathogenesis for plasmodium falciparium?

PfEMP1 allows infected cells to bind tightly to the lining of the blood vessels in the brain (preventing them from being cleared by the spleen)

constant lysis of RBCs by the merozoites leads to a very high fever

brain swelling → seizure/coma → death

what is the evolution of plasmodium falciparium?

most likely evolved from ape malaria parasites through a recent zoonotic transfer (from gorilla to humans)

over time, a genetic bottleneck event is believed to have taken place to reduce the parasite population, creating a homogenous genetic population that infects mainly mosquitoes

how do humans counter plasmodium falciparium?

treatments: artemisinin (damage the proteins in the parasite)

prevention: mosquirix vaccine given to individuals in high risk areas

how does plasmodium falciparium counter the immune system and antimicrobial drugs?

pathogen can exist in many forms; each form can express different surface antigens, making it difficult for the host immune system to recognize

large population increases the chance that beneficial mutations will occur and spread rapidly

why is plasmodium falciparium considered an endemic disease?

pathogen is from a specific species of mosquitoes that lives in certain regions of the world so it can’t possibly spread as a pandemic