Immunity to infection

Department of Microbiology
College of Medicine
University of Baghdad

Assist Prof. Dr. Inas Al-Sharquie

2019-2020
 Learning objectives
 Identify the innate and adaptive mechanisms of defence
which operate against different types of microbes

 Describe the systemic inflammatory response

 Explain how the immune Response Against Bacteria

Can Cause Pathogenesis

 Recognize the microbial mechanisms of evasion from

immune response
 Disease-causing organisms
Organisms that cause disease are called pathogens.
What are the four major types of pathogen?

bacteria fungi

protozoa

virus
 How are pathogens spread?
Different pathogens have different transmission routes:

insect bites
food and water airborne droplets

direct contact indirect contact

 Immunity to Infection
• Immunity is the acquired ability to defend
against infection by disease-causing
organisms.
 Overview of your immune system
 First line of defence: Physical, mechanical and chemical barriers
that viruses, bacteria must cross.

 Second line of defence: Innate immune system (germline-

encoded receptors -- no adaptation to specific pathogens)
 Macrophages, neutrophils, natural killer (NK) cells.

 Third line of defence: Adaptive immune system (adapts to

defend against specific pathogens using variable receptors)
 B cells make antibodies that vary -- can make an antibody
specific for any new antigen
 T cells mediate cellular responses using variable receptors (T
cell receptors; TCRs).
 First line of defence
 What are the body's natural defence mechanisms?
 First line of defence
o Keratized epithelium
o Tight junctions
o Mucus flow by ciliated cells
o pH/chemicals
o Enzymes
o Antimicrobial peptides
o Bacterial commensal effects
 Innate immune responses
o Unchanged after exposure to a pathogen
o Immediate responses to infection
o Recognition of common bacterial components
o Phagocytosis and inflammation
o Activate the adaptive immune responses
Phagocytosis and inflammation
 Adaptive immune responses

o Specific recognition of individual antigens

o T and B lymphocytes
o Capable of improving the specificity of a
response
o Have a long Memory
Adaptive Immunity
 Bacterial Infections

• Bacterial Infection Involves the following steps

– Attachment
– Proliferation
– Invasion of host Tissue
– Toxin Induced Damage To Host Cells
 Defense against bacteria
Nonspecific defense
 Phagocytic cells (neutrophils, macrophages and
natural killer cells)
 Complement and Lysozyme

Specific defense
 Antibodies
 T lymphocytes
Early host responses to bacterial
infection
 Defense against bacteria
 Pyogenic response
 e.g. Staphylococcus aureus and Streptococuus pyogenes
are defended against by Pyogenic response
 Antibody, complement and neutrophils
 Often called Extracellular bacteria

 Granulomatous response
 e.g. Mycobacterium tuberculosis and Listeria
monocytogenes are defended against by Granulomatous
response
 Macrophages and CD4+(helper) T cells
 Often called Intracellular bacteria
 Extracellular bacteria
o Bacteria producing toxins (C.tetani, C.botulinum,
C.diphtheriae)
o Polysaccharide capsule (Streptococci, Neisseria,
Staphylococci)
o Extracellular bacteria do not invade cells.
o They cause disease by two principle mechanisms.
 They induce inflammation.
 Many of these bacteria produce toxins.
Endotoxins.
Exotoxins.
o Principal injuries of host responses to extracellular
bacteria are:
Inflammation
Septic shock

Streptococcus pneumoniae
 Extracellular bacteria
 Extracellular bacteria cause inflammation via Ab-and
complement-mediated mechanisms
 Extracellular bacteria
• Innate Immunity to extracellular bacteria
 Complement activation
 Activation of phagocytes and inflammation
 Innate lymphoid cells (ILCs)
ILCs secrete IL-7, IL-22 and GM-CSF. These
cytokines enhance epithelial barriers function and
recruit neutrophils to site of infection.
 Extracellular bacteria
• Adaptive Immunity to extracellular bacteria
 Humoral immunity is a major protective immune response
against extracellular bacteria, and it function to block
infection, to eliminate the microbes, and to neutralize their
toxins.
 Antibody-Mediated Mechanisms for
Combating Infection by Extracellular Bacteria
 Antibody-Mediated Mechanisms for
Combating Infection by Extracellular Bacteria
1. Antibody neutralizes bacterial toxins.
2. Complement activation on bacterial surface leads to
complement-mediated lysis of bacteria.
3. Antibody and the complement split product C3b bind to
bacteria, serving as opsonins to increase phagocytosis.
4. C3a and C5a, generated by antibody-initiated complement
activation, induce local mast cell degranulation, releasing
substances that mediate vasodilation and extravasation of
lymphocytes and neutrophils.
5. Other complement split products are chemotactic for
neutrophils and macrophages.
 Extracellular bacteria
• Adaptive Immunity to extracellular bacteria
 The protein antigens of Extracellular bacteria also activate CD4
helper T cells, which produce cytokines and express cell surface
molecules that induce local inflammation, enhance the phagocytic
and microbicidal activities of macrophages and neutrophils, and
stimulate Ab production.
 Injurious effects of immune responses to
Extracellular bacteria
 Excessive release of cytokines caused by M.O can result in
Inflammation and sepsis
• Predominant Cytokines Involved: IL-1 and TNF-
• Source: Macrophages
 Intracellular bacteria
o e.g Listeria, Mycobacterium, Brucella
o Intercellular bacteria have the ability to survive and even
replicate within phagocytes where they are inaccessible to
circulating antibodies.
o During the innate immune response to intracellular bacteria
phagocytes ingest and attempt to destroy.
o Intracellular bacteria are resistant to degradation within
phagocytes.
o Intracellular bacteria also activate NK cells, either directly or
by stimulating macrophages production of IL-12, a powerful
NK cell – activating cytokine

M. tuberculosis
 Intracellular bacteria
• Innate Immunity to intracellular bacteria
 Mediated by phagocytes and NKs
• Adaptive Immunity to intracellular bacteria
 T Cell mediated immunity
Injurious effects of immune responses
to Intracellular bacteria
– Intracellular Bacteria Cause Granulomas: if intracellular
pathogens are not quickly eliminated, the persistent recruitment
and activation of macrophages and T cells to an infected tissue
can result in the formation of granuloma
• Extensive Tissue Damage
• E.g.Tuberculosis
• Tuberculosis (Mycobacterium tuberculosis)
– Macrophages ingest M. tuberculosis But Cannot Digest It
– Eventually Burst Releasing Bacilli
– Macrophages and TH1 Cells Form Granulomatous Lesion
A granuloma develops…
Continuous activation of
macrophages induces the
macrophages to adhere
closely to one another,
assuming an epithelioid
shape and sometimes
fusing together to form
giant, multinucleated
cells.
(e.g, Tuberculosis)
 Host immune responses to bacterial
infection and bacterial evasion mechanisms
 Bacterial evasion mechanisms
Sequestration: Staphylococci in bone

Antigen Shedding: Organisms that shed surface Ag

in abundance, e.g. Streptococcus pneumoniae, can
neutralize the Ab response at a distance.

Fc binding: Some Staphylococci produce a protein

that binds to the Fc fragment of IgG, and some
Streptococci produce a substance that binds to the Fc
of IgA. This inhibits the ability of the Fc fragment to
opsonize or activate complement.
 Bacterial evasion mechanisms
Resistance to killing: some organisms possess cell
walls that resist oxidative killing e.g. M tuberculosis.
Some Staphylococci produce catalase and can destroy
hydrogen peroxidase.

Escape from the phagosome. M Leprae enter the

phagosome but then escape from it into the cytoplasm.
 Bacterial evasion mechanisms
Inhibition of chemotaxis: the process by which
phagocytes are attached into sites of inflammation is
inhibited by several organisms, e.g Clostridium
perfringens, S aureus and some streptococci.

Blocking access of cells: e.g. staphylococci liberate a

coagulase which cause fibrin deposition and blocks
access to inflammatory cells.
 Viral Infections
 Obligatory intracellular pathogens
Influenza virus
 Use the nucleic acid and protein synthetic
machineries of the host cell.
 Infect a variety of cell populations by utilizing normal
cell surface molecules as receptors to enter cell.

 Pathogenesis
 Transmission
 Portal of entry
 Viral dissemination in the organism
(local infection, generalized infection)
 Course of infection (cells damaged)
 Defence against viruses
Nonspecific Defenses
 Interferons

Induction and action of interferon.

A: Virus infection induces the synthesis of interferon, which then leaves the infected cell.
B: Interferon binds to the surface receptor of an uninfected cell and induces the synthesis of
three new cell-encoded enzymes (antiviral proteins).
C: A new virion enters the cell, but viral replication is inhibited by the interferon-induced
antiviral proteins. One of these antiviral proteins is a ribonuclease that degrades mRNA, and
another is a protein kinase that phosphorylates an initiation factor that inhibits protein
synthesis.
 Defence against viruses
 Nonspecific Defenses
 Natural Killer cells
• They are called “natural” killer cells because they are
active without the necessity of being exposed to the
virus previously and because they are not specific for
any virus.
• NK cells are a type of T lymphocyte but do not have an
antigen receptor.
• They recognize virus-infected cells by the absence of
class I MHC proteins on the surface of the virus-
infected cell.
• They kill virus-infected cells by secreting perforins and
granzymes, which cause apoptosis of the infected cells.
 Phagocytosis
 Defence against viruses
Specific Defenses
 Antibodies
 Cell mediated immunity
• Examples Of Cell Mediated Immunity
– TH1, CTL Are the major participants
• TH1 Produce IFN-, IL-2, and TNF-
– IL-2 and IFN- activate NK cells (first line of defense)
• CTL (cytotoxic lymphocytes)
– Peaks 7-10 days post infection
– Eliminate virally infected cells
Defence against viruses
How does antibody inhibit viruses?
 Neutralization
 Lysis of virus infected cells in the presence of
complement
Virus evasion strategies
 Virus evasion strategies
Sequestration in inaccessible site: Wart papilloma
virus, Herpes Simplex Virus and Epstein-Barr
Virus.

Antigenic Drift and shift: Influenza Virus, Keeps

Changing Antigens
 Parasitic Infections
 In infectious disease terminology, “ parasitic infection” refers to
infection with animal parasites, such as protozoa and
helminthes.

 Parasites currently account for greater morbidity and mortality

than any other class of infectious organism, particularly in
developing countries.

 Principal innate response is phagocytosis; however many

parasites are resistant to phagocytosis and may even replicate
within macrophages.

 Phagocytes attack helminthic parasites and secrete microbicidal

substances to kill organisms too large to be phagocytosed.
 Parasitic Infections

Different parasites elicit distinct adaptive immune

responses.
Pathogenic protozoa have evolved to live within host
cells.
The principal defense mechanism against protozoa
that survive within macrophages is cell mediated
immunity, particularly macrophage activation by
TH1-derived cytokines
Defence against protozoan infections
 Most parasites can’t be completely eradicated by either innate or
adaptive  usually establish chronic infections in host
 Both humoral and cellular immunity
 Extracellular (Entameba, Giardia, Trichomonas)
 Antibodies, alone or with complement
(IgG – opsonize protozoa for phago and killing)

Entameba
Giardia Trichomonas
 Defence against protozoan infections
 Intracellular (Plasmodium, Trypanosoma,
Leishmania, Toxoplasma)
 Th1 lymphocytes and activated macrophages
Leishmania
Protozoa peptides/class II displayed by phago cells
activate mostly Th1 subset  Th1 make/secrete IFN-
gamma and TNF which activates killing of phagos

 CD8 T cells

Trypanosoma
 Defence against helminths
 Chronic persistent infection
 e.g flatworm (Schistosoma) and roundworm
(Ascaris)
 High morbidity, low mortality
 Reinfection
 Mast cells, eosinophils
 Th2 response, antibody IgE

Pathology:
 Formation of immunocomplexes
 Auto-antibodies, granulomas
 Allergic reactions
 Defence against helminths
 Mostly humoral immunity with IgE Ab that mediate
ADCC by eosinophils.
 Shed Ag from worms and displayed by class II phago
cells  activate CD4+ T cells of Th2 subset  Th2
makes IL-4  induces B cells to switch to produce IgE;
IL-5 stimulates prolife of eosinophils.
 Worm-specific IgE and IgG Ab coat worm and
eosinophils bind to Ab  activates eosinophils to kill
worm by exocytosis.
 High levels of IgE Ab and eosinophils in blood = sign
of worm infection.
 Defence against helminths
 Worms too large to be phago-ed which is why
eosinophils are involved
 Worm Ag bind mast cell or basophil bound anti-
worm Ab  triggers mast cell or basophil
degranulation with release of inflammatory
mediators  smooth muscle contraction and mucus
secretion  helps to expel worm
Defence against helminths
Role of Antibody in parasitic
infection
 Parasite evasion strategies
Sequestration: tapeworms in hydatid cyst integrated into
host DNA are inaccessible to the immune response.

Disguise: Schistosomas cover their surface with various

host proteins, e.g. blood group substances and HLA
proteins.

Antigenic variation – African trypanosomes have variant

surface glycoprotein (VSG) coat that can change via gene
conversion, rapidly multiply and cause waves of
parisitemia (parasites in blood) with each wave dominated
by a different VSG variant.
 Antigenic variation -
Trypanosome mechanism
 Parasite evasion strategies
 Antigen shedding: Shedding of surface Ag – that neutralize
the Ab response. (Plasmodium falciparum and Schistosoma
mansoni)
 Cleavage of immunoglobulin molecules: Protease that
cleaves IgA.(Trypanosoma cruzi)
 Inactivation of complement: Leishmania sp. eject MAC
(C5b-C9) from their cell membrane.
 Inhibition of attachment to phagocyte: Toxoplasma gondii
 Inhibition of phagocytosis: African trypanosomes
 Escape from phagosome: Trypanosoma cruzi enter the
phagosome but then escape from it into the cytoplasm.
 Parasite evasion strategies
 Resistance to killing: Leishmania produce a superoxide
dismutase and have an antioxidant effect.
 Inhibition of phagosome-lysosome fusion: Toxoplasma gondii
 Resistance to digestion: Some Leishmania produce a
lysosomal enzyme inhibitor (gp63).
 Inhibition of cytokines: Trypanosoma cruzi can inhibit IL-2
and TNF.
 Lymphocyte activation: Trypanosomes
 Lymphocyte suppression: malaria
 Fungal infections
Eukaryotes that tend to cause serious infections
primarily in individuals with impaired immunity .

Systemic disease in immunocompromised

individuals

Pneumocystis jirovecii (carinii) Aspergillus fumigatus

Candida albicans
 Fungal infections
Fungal diseases, or mycoses , are classified based on
the following criteria:
 Site of infection—superficial, cutaneous,
subcutaneous, or deep and systemic
 Route of acquisition—exogenous or endogenous
 Virulence—primary or opportunistic
 Defence against fungi
 The principal mediators of innate immunity against
fungi is the neutrophils, macrophages, and ILCs.
 Neutrophils liberate fungicidal substances, such as
reactive oxygen species and lysosome enzymes.
 They also phagocytose fungi for intracellular killing.
 Cell-mediated specific immunity is the major defense
against fungal infections.
 Th1 response (IFN-γ production to activate
macrophages)
 Th17 response
 Fungi evasion strategies
Inhibition of phagocytosis: Candida albicans

Production of a capsule: which inhibit phagocytosis

C. neoformans.

Dermatophytes suppress host T cell responses and

delay the cell-mediated destruction.
 Summary
Immunity to infection depends on a combination of
innate mechanisms (phagocytosis, complement, etc.)
and antigen specific adaptive responses (antibody,
effector T lymphocytes).

The immune system regulates which specific

responses predominate (humoral vs. cell-mediated)
based on the body compartment infected (intracellular
vs. extracellular) and on cytokine signals present at
initial antigen contact (Th1 vs. Th2 responses).
 Summary
The survival and pathogenicity of pathogens in a
host are critically influenced by their ability to evade
or resist protective immunity.

Tissue injury and disease consequent to infections

may be caused by the host response to the pathogen
and its products rather than the pathogen itself.
 Main References
• Abbas AK., Lichtman AH. And Pillai S. Cellular and
Molecular Immunology. 9th ed. Copyright 2018.
• Levinson W. Review of Medical Microbiology and
Immunology.13th ed. Copyright 2014, McGraw-Hill.
• Owen J., Punt J. and Stranford SH. KUBY
Immunology. 7th ed. Copyright 2013.
• Male D., Brostoff J., Roth DB. and Roitt IM.
Immunology. 8th ed. Copyright 2013.