HOW MICROORGANISM

CAUSE DISEASE AND IMMUNE

EVASION OF MICROBES

PRESENTED BY:
SANTOS, CARLA RIZA
CUERPO, MHELMAR JAY
PANTUA, HAZILLE
HOW MICROORGANISMS CAUSE DISEASE
Infectious agents establish infection and damage tissues by any of
three mechanisms:
• They can contact or enter host cells and directly cause death of infected cells.
Microorganisms can cause toxins, tissue degradation, and damage, causing
ischemic necrosis and mediated destruction of infected hepatocytes.

• Oncogenic viruses, like HPV and EBV, stimulate cell growth and survival
through various mechanisms, including hijacking cell cycle control, anti-
apoptotic strategies, and insertional mutagenesis. Bacterial damage to host
tissues depends on bacteria's ability to adhere, invade, or deliver toxins.
Pathogenic bacteria have virulence genes grouped together in pathogenicity
islands, with a few genes determining a bacterium's harmfulness. Plasmids and
bacteriophages carry virulence between bacteria.

• They can induce host immune responses that, although directed against the
invader, cause additional tissue damage. Thus, the defensive responses of the
host can be a mixed blessing, helping to overcome the infection but also
contributing to tissue damage.
MECHANISMS OF VIRAL INJURY
Viruses can directly damage host cells by entering them and replicating at the host’s
expense. The manifestations of viral infection are largely determined by the tropism of the
virus for specific tissues and cell types. Tropism is influenced by a number of factors.

• Host receptors for viruses.

Viruses have surface proteins that bind specific host cell proteins, allowing entry
into cells. HIV glycoprotein gp120 binds to CD4 and CXCR4 receptors, while host
proteases may be required for binding.

• Specificity of transcription factors.

The virus's replication depends on lineage-specific transcription factors
recognizing viral enhancer and promoter elements. For instance, the JC virus
replicates in oligodendroglia in the central nervous system, not neurons or
endothelial cells.

• Physical characteristics of tissues.

Host environment and temperature influence tissue tropism, with enteroviruses
reproducing in the intestine due to resistance to acids and bile, and rhinoviruses
infecting upper-respiratory tract cells.
Once viruses are inside host cells, they can damage or kill the cells by a number
of mechanisms
• Direct Cytopathic Effects
Viruses can kill cells by preventing host macromolecule synthesis,
producing degradative enzymes, toxic proteins, or inducing apoptosis. Examples
include poliovirus blocking protein synthesis, HSV inhibiting DNA synthesis,
and triggering apoptosis through endoplasmic reticulum perturbations.

• Anti-viral Immune Responses

The immune system recognizes viral proteins on host cells, triggering
lymphocytes to attack virus-infected cells. Cytotoxic T lymphocytes (ctls)
defend against viral infections but can cause tissue injury, like hepatitis B
infection.

• Transformation of Infected Cells

Oncogenic viruses like HPV and EBV stimulate cell growth and
survival through various mechanisms, including regulating cell cycle, anti-
apoptotic strategies, and insertional mutagenesis.
MECHANISMS OF BACTERIAL INJURY

• Bacterial virulence is the ability of pathogenic bacteria to

adhere to host cells, invade, or deliver toxins. Pathogenicity
islands are clusters of virulence genes that determine a
bacterium's harmfulness. Plasmids and bacteriophages carry
virulence factors, including toxins or enzymes that confer
antibiotic resistance. Exchange of these elements can give
recipient bacteria a survival advantage or cause disease.
Plasmids or transposons encoding antibiotic resistance can
make therapy difficult. Carbapenemase genes have spread
among gram-negative bacilli, making them an urgent threat.
POPULATIONS OF BACTERIA ALSO CAN ACT
TOGETHER IN WAYS THAT ALTER THEIR
VIRULENCE.

• Quorum sensing
Bacteria regulate gene expression within large populations,
enabling specific genes like virulence genes to be expressed after high
concentrations. S. Aureus secretes auto inducer peptides, increasing
exotoxin production as bacteria grow.

• Biofilms
Biofilms form on host tissues or devices, making bacteria
inaccessible to immune mechanisms and increasing resistance to
drugs. They are crucial for infections like bacterial endocarditis,
artificial joint infections, and cystic fibrosis.
• Bacterial adherence to host cells
Adhesins are surface molecules that bind to host cells or extracellular
matrix. Different bacteria have different surface structures, such as S.
Pyogenes' protein F and teichoic acid binding to fibronectin. Pili,
filamentous proteins, have conserved stalks and vary in amino acids. E.
Coli strains have specific P pilus binding to uroepithelial cells, while N.
Gonorrhoeae's pili mediate adherence and host antibody response.

• Bacterial toxins
Toxins are bacterial substances that contribute to illness, classified
as endotoxins or exotoxins. Bacterial endotoxins are lipopolysaccharides
(LPS) found in gram-negative bacteria's outer membrane. LPS binds to
CD14 on host leukocytes and binds to toll-like receptor 4, promoting cell
activation and inflammatory responses. Benefits of LPS include protective
immunity, increased cytokines, and costimulatory molecules. However,
high levels can lead to septic shock, coagulation, and acute respiratory
distress syndrome. Exotoxins are secreted proteins that cause cellular
injury and disease, classified by their mechanism and site of action.
• Enzymes
Bacteria secrete enzymes (proteases, hyaluronidases, coagulases,
fibrinolysins) that act on their respective substrates in vitro, but their
role in disease is understood in only a few cases. For example,
exfoliative toxins are proteases produced by S. Aureus that cleave
proteins known to hold keratinocytes together, causing the epidermis
to detach from the deeper skin.

• A-B toxins:
Toxins with two components alter intracellular signaling or
regulatory pathways. These toxins have an active (A) component
with enzymatic activity and a binding (B) component that binds
cell surface receptors and delivers the A protein. The effect
depends on the binding specificity and cellular pathways affected.
Anthrax toxin has two alternate A components, edema factor and
lethal factor, mediating specific pathologic effects.
• Super Antigens
Stimulate very large numbers of T lymphocytes by binding to
conserved portions of the T cell receptor, leading to massive T
lymphocyte proliferation and cytokine release. The high levels of
cytokines lead to capillary leak and the systemic inflammatory response
syndrome. Superantigens made by S. Aureus and S. Pyogenes cause toxic
shock syndrome.

• Neurotoxins
Produced by Clostridium botulinum and Clostridium tetani inhibit
release of neurotransmitters, resulting in paralysis. These toxins do not
kill neurons; instead, the A domains cleave proteins involved in secretion
of neurotransmitters at the synaptic junction. Tetanus and botulism can
result in death from respiratory failure due to paralysis of the chest and
diaphragm muscles.
• Enterotoxins
Affect the gastrointestinal tract causing varied effects, including
nausea and vomiting (S. Aureus), voluminous watery diarrhea (V.
Cholerae), and bloody diarrhea (C. Difficile).
• Chronic Inflammatory Diseases
In the development of inflammatory bowel disease, an important
early event may be compromise of the intestinal epithelial barrier, which
enables the entry of both pathogenic and commensal microbes and their
interactions with local immune cells, resulting in inflammation. The cycle
of inflammation and epithelial injury may be an important component of
the disease, with microbes playing the central role.
• Cancer
Viruses, such as HBV and HCV, and bacteria, such as H. Pylori, that
are not known to carry or to activate oncogenes are associated with
cancers, presumably because these microbes trigger chronic inflammation
with subsequent tissue regeneration, which provides fertile ground for the
development of cancer.
Injurious Effects of Host Immune Responses
As mentioned earlier, the host immune response to microbes can
sometimes be the cause of tissue injury. A few examples of types and
mechanisms of injury are as follows:

• Granulomatous inflammation. Infection with M. Tuberculosis results in a

delayed hypersensitivity response and the formation of granulomas, which
sequester the bacilli and prevent its spread, but also produce tissue damage
(caseous necrosis) and fibrosis.

• T-cell–mediated inflammation. Damage from HBV and HCV infection of

hepatocytes is due mainly to the immune response to the infected liver cells
and not to cytopathic effects of the virus.

• Innate immune inflammation. Pattern recognition receptors bind to

pathogen-associated molecular patterns (PAMPS) and to damage-associated
molecular patterns (DAMPS) released from damaged host cells, activating the
immune system and leading to inflammation.
• Humoral immunity. Poststreptococcal glomerulonephritis can develop
after infection with S. Pyogenes. It is caused by antibodies that bind to
streptococcal antigens and form immune complexes, which deposit in renal
glomeruli and produce nephritis.

IMMUNE EVASION BY MICROBES

Humoral and cellular immune responses that protect the host from
most infections are discussed in. Not surprisingly, microorganisms have
developed many means to resist and evade the immune system these
mechanisms of escaping the immune response are important determinants of
microbial virulence and pathogenicity.

ANTIGENIC VARIATION
Neutralizing antibodies prevent microbes from infecting cells and
killing pathogens. They use genetic mechanisms for antigenic variation, such
as low fidelity viral RNA polymerases, reassortment of genomes, gene
rearrangement, and gene-specific surface antigens in borrelia, trypanosoma,
and S. Pneumoniae serotypes.
MODIFICATION OF SURFACE PROTEINS
Host cationic antimicrobial peptides, like defensins,
cathelicidins, and thrombocidins, protect against invading microbes
by binding to the bacterial membrane and killing. Bacterial
pathogens avoid killing by creating surface molecules that resist
binding.

OVERCOMING ANTIBODIES AND COMPLEMENT

Host defense involves coating bacteria with antibodies or
complement protein c3b for phagocytosis by macrophages. M.
Tuberculosis activates the complement pathway, allowing
monocytes to uptake the organism, allowing replication. Many
bacteria use cells as a "hideout" to escape antibodies and
complement, and listeria monocytogenes can manipulate cell
cytoskeletons.
RESISTING PHAGOCYTOSIS AND BACTERIAL KILLING IN
PHAGOSOMES
Phagocytosis and killing of bacteria by neutrophils and macrophages is
crucial host defense against extracellular bacteria. Bacteria causing pneumonia
or meningitis have carbohydrate capsules that prevent neutrophils from
phagocytosis. Surface proteins inhibit phagocytosis, while macrophages kill
bacteria through phagolysosome fusion. Legionella produces listeriolysin O and
phospholipases to degrade phagosome membranes, allowing bacteria to escape.
Additionally, bacteria produce proteins that kill phagocytes, prevent migration,
or diminish their oxidative burst.

ESCAPING THE INFLAMMASOME

The cytosolic inflammasome is an innate immune response to microbes,
triggered by microbial products. It leads to caspases, pro-inflammatory
cytokines, and cell death called pyroptosis. Bacteria like yersinia and salmonella
express virulence proteins that inhibit inflammasome formation, suppress
caspase activation, block signaling pathways, and limit bacterial protein access.
DISRUPTION OF INTERFERON PATHWAYS
Viruses have developed various strategies to combat interferons (ifns),
which are mediators of early antiviral defense. Some viruses produce soluble
homologues of IFN receptors, blocking ifns' actions or inhibiting JAK/STAT
signaling. RIG-I, a host cytoplasmic pattern recognition receptor, inhibits
IFN signaling, overcoming host defense. Some viruses encode cytokines,
chemokines, or receptors that inhibit immune responses. Additionally, viruses
block apoptosis, allowing them to replicate, persist, or transform infected host
cells.