Molecular Cell Biology

Prof. D. Karunagaran

Department of Biotechnology

Indian Institute of Technology Madras

Module 10
Cell biology of Infection

Lecture 2
Bacterial Pathogenesis

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• Bacteria are small, microscopic organisms
• They are prokaryotes
• Only a few species of bacteria cause infection and disease in humans
• Bacteria are classified accordingly
• Those which cause disease and replicate only in host cells are called “Obligate
pathogens”
• Those which replicate in an environmental reservoir such as soil or water and
cause disease only in susceptible host are called “facultative pathogens”
• Those which are benign and have latent ability to cause disease in a immune-
compromised host are called “Opportunistic pathogens”
• Disease causing bacteria carry virulent genes or factors which produce
substances that help the bacteria to survive, multiply and destroy the host

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Phagocytosis helps bacteria to enter host cell

• Phagocytosis is the process by which macrophages engulf the bacteria and

destroy them
• But in a few cases bacteria survive and replicate in macrophages
• One among them is Mycobacterium tuberculosis
• These bacteria acquired through inhalation into the lungs and phagocytosed by
alveolar macrophages
• In some cases, macrophages of healthy individual with assistance from adaptive
immunity contain infection within a lesion called “tubercle” and calcified
• Bacteria in the lesion have the ability to cause disease even after years when the
individual immune system weakens

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Nonphagocytic entrance for bacteria

• Bacteria express adhesion molecules that help them to adhere to the cell
adhesion protein in the cell used for cell –cell communication
• Examples:Yersinia pseudotuberculosis expresses invasin that binds to β1
integrins;Listeria monocytogenes expresses a protein that binds to E-cadherin
• This action of bacteria fools the cell to spread over the adhesive surface of their
surface resulting in the phagocytosis of the bacteria, a mechanism known as
Zipper mechanism of invasion.
• Second mechanism involves injection of molecules into the host cell cytoplasmic
system via type III secretion system.
• This activates Rho family-GTPases leading to actin polymerization and other
bacteria secreted molecules interact directly with cytoskeletal molecules.
• These lead to dramatic localized ruffling on the cell surface resulting in large actin
protrusion production which fold over and traps bacteria within endocytic vesicles
called “macropinosomes”
• This is also known as Trigger mechanism which is followed by certain bacteria
like Salmonella enteric

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Alteration induced by bacteria in host cell

• After endocytosis, bacteria use specific mechanisms to survive or evade lysis in

phagolysosome environment
• Trypanosomacruzisecretes hemolysin that forms large pores in phagosomal
membrane leading to disrupting the membrane and bacteria are released into the
cytosol
• Bacteria continue to secrete hemolysin to lyse phagolysosome to survive at the
acidic pH
• Hemolysins are degraded by host proteasomal machinery
• Intracellular bacteria prevent lysosomal fusion and use a specific mechanism to
import nutrients from host cytoplasm
• Some bacteria create their own membrane enclosed compartments that are not
involved in host cell trafficking but allow nutrients

Bacterial movement inside the cell

• Viscosity of the cytoplasm and organelles prevents movement of bacteria in the

crowded environment
• Some bacteria induce nucleation and assembly of cell actin filaments at one pole
of the bacterium
• These growing filaments generate force and push the bacteria in the cytoplasm
at a rate of about 1μm/sec
• New filaments form at the rear of every bacterium and are left behind like a
rocket trail as the bacterium advances. Depolymerization occurs within a minute
or so as they encounter depolymerizing factors in the cytosol.
• When bacteria reach the membrane, they move outward inducing the formation
of a protusion at the tip of bacteria which is engulfed by the neighboring cell
cytoplasm without exposing the bacteria to the immune activated external
environment

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 • GTPase Cdc42 activation by growth factors or signals can cause activation of a
protein called N-WASp that activates ARP complex that can induce nucleation of
new actin filament
• Bacteria like L.monocytogenes directly bind to and activate ARP complex via
surface proteins
• Some bacteria like Wolbachia use microtubules for transmission from mother cell
to daughter cell or it can be found in eggs during chromosomal segregation

Immune response during bacterial infection

• During extracellular bacterial infection, humoral antibody production by plasma

cells in lymph nodes and submucosa of respiratory and gastrointestinal tract is
induced
• Antibodies remove bacteria, inactivate bacterial toxins
• Antibodies bind to surface antigen of the bacteria along with complement system
and it results in opsonization of the bacteria increasing the phagocytosis of
bacteria
• In certain gram negative bacterial infections, complement system directly lyse the
bacterial cells
• Antibody mediated activation of complement system can induce localized
production of immune effectors molecules that lead to amplified immune
response
• Intracellular bacteria can activate natural killer cells during the early stage but
induces cell-mediated immune responses more specifically by cytokines secreted
by CD4+ T cells that can activate macrophages to kill the ingested pathogens

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 Study Questions

1. What are different types of bacteria?

2. Write a note on bacterial entry into host cell
3. Yersinia pseudotuberculosis uses
a) Trigger mechanism b) Zipper mechanism c) proton pumps d) none of the
above to enter the cell
4. Match the following

Wolbachia Trigger mechanism

Trypanosomacruzi E-cadherin

Salmonella enteric hemolysin

Listeria monocytogenes microtubule

5. ______________directly binds to and activate ARP complex via surface protein