Immunity against Microbes

Introduction:
• Defense against microbes is the main function of the immune system, where different microbial
targets are fought by its various arms.
• In order to appreciate the multitude of roles played by different immune system components in
this task, one might study them according to microbial nature in terms of relative structural
complexity:
- Acellular (viruses which can’t reproduce outside living cells) and Unicellular Microbes
(prokaryotic: bacteria, eukaryotic: protozoa, yeasts).
- Multicellular Microbes (helminths .
• In addition to the nature of the target, the immune response mechanisms themselves also show
immense variation.
• They can be innate (quick response/ no memory) or adaptive (long response/ memory/ specific),
and the immune cell role may be frontline (contacts the microbe) or supportive (support the
frontlines).
• Knowledge of immune response against infection may help in identifying the evasive mechanisms
microbes adopt whilst causing disease as well as designing strategies for artificial induction of
immunity through vaccination.

Immunity Against Acellular and Unicellular Microbes:

• Immunity against acellular and unicellular microbes may be studied according to the nature of
their initial encounter with immune cells:
- Extracellular Microbes: where free microbes located outside host cells are attacked by
immune cells.
- Intracellular Microbes: where immune cells start attacking body cells hosting microbes inside
their cytoplasm.
• Note that the above classification scheme means that the immune system may attack the same
type of microbe differently according to its location (e.g. free virions vs. viruses within the host
cell). Also, note that ‘intracellularity’ here does not apply to the microbes still within immune cell
phagosomes.

Immunity Against Extracellular Microbes:

• Professional phagocytes (i.e. neutrophils and monocytes-macrophages) identify microbial
products, swallow them, then kill them intracellularly.
• Pattern recognition receptors (PRRs) (e.g. TLRs (toll like receptors), mannose receptors,
scavenger receptors, complement) as well as antibodies aid in this process through opsonization
and stimulation of killing activity.
• Receptors on phagocytes which help mediate opsonization are:
- Complement receptors CR1 and CR3: which identify various C3 derivatives.
- immunoglobulin receptors FcγRI and FcγRIIa: which identify IgG1 and IgG3.
• T-independent antigens are non-protein molecules (e.g. polysaccharides, lipids) which induce
antibody production without TH cell help.
• Such antibodies are usually produced in the spleen (people who had undergone splenectomy are
more susceptible to these pathogens), and they are important in opsonizing polysaccharide-rich
 encapsulated bacteria (e.g. Streptococcus pneumoniae, Neisseria species.) also they will not
produce memory like protein molecules.
• The body can’t recognize non-protein the same way as protein molecules (protein molecule are
capable to activate T helper cells while non-protein can’t).
• Besides bacteria, phagocytosis and intracellular killing is important in facing different types of
unicellular microbes outside host cells, including fungi (e.g. Candida species) as well as protozoa
(e.g. Plasmodium species., Toxoplasma species.).
• Through activating the complement system, formation of the membrane attack complex (MAC)
is important for killing bacteria with thin cell walls (e.g. Neisseria species) as well as enveloped
extracellular virions.
• The complement system may be activated through the classical pathway (through IgG1, IgG2,
IgG3 or IgM action), alternative pathway, or lectin pathway.
• The mere binding of the antibody to microbial molecules necessary for pathogenesis (e.g. surface
structures, toxins) would protect against them through steric hindrance (i.e. antibody-mediated
neutralization). This is mostly done through IgG, IgM, or IgA (especially in mucosal surfaces).
• The inflammatory response happens due to complex interaction between inflammatory cells (i.e.
immune cells (leukocytes or dendritic cells), platelets and endothelium) and inflammatory
mediators.
• The degree and type of contribution of each component depends on the initial tissue injury, thus
determining the eventual character of this response and its outcome.
• Among the responses mediated by cells of the innate immune system are:
• Chemokine secretion: by macrophages, which helps in chemotaxis.
• Secretion of IL-1, IL-6 and IL-23: by macrophages and dendritic cells, thus stimulating the
development of ILC3s and TH17 cells. This may be in response to PRRs that identify β-
glucans on fungal surfaces (e.g. TLRs, dectins).
• Secretion of IL-12: by macrophages and dendritic cells, thus stimulating the development of
ILC1s and TH1 cells.

Innate immunity Adaptive immunity

Frontline Phagocytosis Antibody-Mediated Neutralization

Complement-Dependent Lysis (neutralize microbial target (ex:
virus/bacterial toxin))

Supportive Supportive Functions of: TH Cell Function

• Neutrophils & Monocytes Macrophages.
• Mast Cells, Basophils & Eosinophils
• Innate Lymphoid Cells (ILCs)

Note: Neutrophils & Monocytes-Macrophages can be supportive AND frontline through phagocytosis.
• Various TH cell subsets also play different roles in terms of the immune system mechanisms they
favor when facing extracellular microbes:
- TH1 cells (similar to ILC1): develop in response to IL-12 and they mainly produce IFNγ and
express CD40L. They are potent activators of macrophage function, especially when they
 encounter microbes that are resistant to intracellular killing (e.g. Mycobacterium tuberculosis,
Mycobacterium leprae, Histoplasma species). This might lead to granulomatous inflammation
with destructive effects on nearby host tissues.
- TH2 cells (similar to ILC2): which secrete IL-4 and IL-5, thus inhibiting macrophage function
whilst switching antibody isotype to IgE and IgG4. Though that may be beneficial against
helminths, a poor TH1 over TH2 response may prove detrimental to the host whilst dealing with
some protozoa (e.g. Leishmania species).
- TH17 cells (similar to ILC3): develop in response to IL-1, IL-6 and IL-23 and secrete IL-17, thus
recruiting neutrophils and stimulating inflammation and tight junction function. This
response is important for fighting off bacteria as well as Candida spp...) Especially in mucosal
tissues.

Immunity against Intracellular Microbes:

• If the microbe happens to be found within the cell’s cytoplasm, the aforementioned mechanisms
become useless to fight it.
• This applies not only to virus-infected cells, but in the case of some other microbes as well (e.g.
Listeria monocytogenes, Cryptococcus neoformans (yeast), Plasmodium species, Toxoplasma
species. (protozoa)).
• In these cases, some immune cells are prompted to form pores in the plasma membrane of the
infected cell, which will in turn cause:
• Osmotic lysis.
• Induction of apoptosis: either through the action of granzymes (entering through the pores)
or membrane bound FasL and TNF.
Both of those mechanisms may be performed by:
- Innate immune system: through the action of NK cells and monocytes-macrophages. They
would perform antibody-dependent cellular cytotoxicity (ADCC) through IgG1 and IgG3 binding
to the FcgRIII molecules on their surface through their Fab region.
- Adaptive Immune system: through TC cells.
• The innate and adaptive arms complement each other in fighting intracellular microbes; while
the adaptive arm through cytotoxic T cells attacks the infected cells which express class I HLA
(MHC) molecules, but if the microbes shut down their expression, the innate arm targets those
cells.
• The main cytokines which mediate and support immunity against intracellular microbes are the
interferons (IFNs).
• They are divided into different types (e.g. type I, type II) with different modes of action (e.g.
direct antiviral intracellular action, stimulation of HLA class I expression), but they all share
functional relation with the TH1 cell subset and related cells (e.g. ILC1s, NK cells, TC cells).

The doctor said about the peak incidence of innate

and adaptive and the innate is faster response and
the cells involved. in (a)

←the virus here is extracellular microbe

←the virus here is intracellular microbe

in the first box we conclude that the cell successfully
phagocyte the microbe so the phagocytosis as a
mechanism of killing the extracellular microbe was
successful process but if the microbe escape the
phagosome the mechanism will change from
extracellular to intracellular and because of that the body
will activate the CD8+ cytotoxic T lymphocyte to kill the
infected cell.
So the same microbe could be intracellular or
extracellular according to the place of it, and according to
that the immune response will change.
Immunity against Multicellular Microbes:
• The main effector immune cells which attack helminths are the eosinophils.
• They are supported by the TH2 cell subset and mast cells, which produce:
• IL-5: which stimulates eosinophil production from the bone marrow.
• IL-4: which stimulates the production of IgE, which would then bind to both the parasitic
surface and the eosinophils’ FcεR. This would cause the eosinophils to degranulate onto the
parasite, thus attacking its tegument (parasite ‫ )الغشاء الخاجي لل‬and nervous system.

Microbial Evasion of the Immune System:

• In response to the aforementioned attack options of the immune system, microbes have adopted
myriad mechanisms to evade the immune system and avoid destruction by it:
• ‘Hit and Run’ Raid: where infection, replication and shedding all take place quickly before
adaptive immunity defenses come into play (e.g. common cold, rotavirus).
• Inaccessibility: where infection takes place in an immune-privileged area which prevent the
immune system to get there (e.g. rabies).
• ‘Silent Infection’: where microbial antigens are not displayed on the host cell’s surface (HLA).
This happens with herpes simplex virus (HSV) and cytomegalovirus (CMV).
• Molecular Mimicry’: where microbial antigens mimic host antigens, thus leading to poor
immune response (e.g. Mycoplasma pneumoniae).
• ‘Antigenic Variation’: where the change in the microbial antigenic makeup limits if not
altogether cancels the value of immunological memory in mounting increasingly stronger
immune responses. Examples include HIV, influenza viruses (i.e. antigenic shift and drift with
these mechanisms the influenza could change its genetic material and so their proteins),
rhinoviruses, Trypanosoma brucei, Plasmodium species, Escherichia coli, and Neisseria
gonorrhoeae.
• ‘Antigenic Shedding’ (e.g. Entamoeba histolytica which get rids of its antigens).
• Nonspecific, Nonproductive ‘Switch-On’ of Lymphocytes as with polyclonal activation of T
cells (by superantigens) or of B cells due to staphylococci.
• Presence of Fc Receptors on Microbe or Induced on Host Cell: would cause nonspecific
binding of IgG antibodies in an ‘upside-down’ direction (e.g. some streptococci).
• Antibody Destruction (e.g. Neisseria gonorrhoeae, Haemophilus influenzae).
• TH Cell Destruction (e.g. HIV).
• ‘Exhaustion’ of TC Cell Response (long-standing activation of these cells which leads to
upregulation of inhibitory receptors or inhibition of their function) (e.g. HIV, viral
hepatitis).
• Encouraging T-reg Cell Formation (e.g. Leishmania spp.). It will suppress the immune
system.
• Cytokine Inhibition: as with poxviruses and Epstein-Barr virus (EBV).
Vaccination:
• The main idea behind vaccination is allowing the immune system to develop immunological
memory against a specific pathogen whilst avoiding contracting disease because of it.
• The nature of the pathogen would determine the chances of success of developing a vaccine, as
such factors as latency, antigenic variation and animal reservoirs would make those chances
significantly lower.
• From an immunological point of view, vaccines may be divided into:
- Live attenuated vaccines: where the germ is administered in a weakened state without killing
it. This method has a number of advantages:
o Microbial replication ensures sustained antigen delivery to the body.
o Enhancement of antigen binding to MHC class I molecules: due to intracellular microbial
replication, thus maximizing Tc cell response.
o Preferential antigen concentration in the target tissues.
However, the use of live attenuated vaccines poses two main problems:
o Immunodeficient patients may develop disease even due to weak microbes.
o Possible reversion of the microbe to its pathogenic, wild-type form which can the disease with
its full pathogenic potential.
Examples include: the BCG, measles, mumps, rubella, oral polio and varicella vaccines.

- Inactivated Vaccines: where the microbe is killed before administration. This eliminates the
risks of live attenuated vaccines but reduces its beneficial effects (e.g. Injectable flu and polio
vaccines, rabies).

- Subunit Vaccines: where the vaccine is prepared from a certain microbial portion which would
induce the formation of protective antibodies against the whole microbe (e.g. HBsAg (hepatitis B
surface antigen), human papilloma virus (HPV) which can cause cervical cancer in women).

- Conjugate Vaccines: If the microbial antigen is a weak immunogen, it may be bound to an

adjuvant to stimulate the immune response (e.g. Haemophilus influenzae type b, pneumococci,
meningococci).

- Toxoid Vaccines: where the microbial toxin is weakened before administration to the host (e.g.
diphtheria, pertussis, tetanus).

- Experimental Vaccines: have been designed for effective delivery of genes coding for microbial
antigens to the inside of the host cells, thus hopefully eliciting a better cell-mediated immune
response. These genes may be delivered using either lipid micelles or viral vectors.
Helpful videos:
https://www.youtube.com/watch?v=fHzs9FcnkdE
https://www.youtube.com/watch?v=kuaClgGHyZ4
questions:
1- which of the following evasive mechanisms is used by poxvirus?
a) (hit and run) raid
b) Cytokine inhibition
c) Inaccessibility
d) Encouraging T-reg cell formation
e) Exhaustion of cytotoxic T cell response
2-to which vaccine type does the rabies vaccine belong?
a) Live attenuated vaccine
b) Subunit vaccine
c) Toxoid vaccine
d) Conjugate vaccine
e) Inactivated vaccine
3- which of the following antibody isotypes cannot activate the classical complement pathway?
a) IgG3
b) IgM
c) IgG4
d) IgG1
e) IgG2
4- which microbe uses antigen shedding to evade the immune system?
a) Plasmodium
b) Mycoplasma pneumoniae
c) Trypanosoma brucei
d) Entamoeba histolytica
e) Leishmania
5-to which vaccine type does the human papilloma virus (HPV) belong?
a) Live attenuated vaccine
b) Subunit vaccine
c) Toxoid vaccine
d) Inactivated vaccine
e) Conjugate vaccine

Answers: 1-b 2-e 3-c 4-d 5-b