Transcript HOST and the MICROBE

HOST and the MICROBE
Rontgene M. Solante, M.D.
Internal Medicine- Infectious Disease Specialist
Department of Medicine
Section of Infectious Diseases- UERMMMC
Definitions
1. Infection:
establishment of a microorganism on or within a host;
may be short-lived, most often asymptomatic, or
subclinical signs of altered pathophysiology
2. Infectious Diseases:
an interaction of the microbe with the host, causing
damage and altered physiology on the host, resulting in
clinical signs and symptoms of the disease
3. Pathogen:
any microorganism that has the capacity to produce
disease (not all pathogens has the capacity to cause
disease in the same populations).
Definitions
1. Principal pathogens:
microbes that regularly causes disease in some
proportions of susceptible individuals with apparently
intact defense systems
e.g. Streptococcus pneumoniae
Staphylococcus aureus
2. Potentially pathogenic microbes:
= non-commensals
= doesn’t usually cause disease in those with intact
immune system
= cause severe disease in hospitalized or
immunocompromised host
e.g. Pseudomonas aeruginosa
Microbial Pathogenicity
1. Virulence:
quantitative measure of pathogenicity or the likelihood
of causing disease
e.g. encapsulated pneumococci are more virulent
than noncapsulated
2. Virulence factors
refer to the properties of a microbe that enable itself to
establish within a host and enhance its potential to
cause disease
Microbial Pathogenicity
3. Opportunist organisms
= microbes with a capacity for sustained multiplication
in human, and cause disease to individuals with
underlying chronic disease or compromised immune
status
= outcome is determined by the status of the host
= ability to be transient pathogens in a normal host
(“just passing through’)
e.g. a. fungal infections (Candida albicans) =
immunosuppresive cancer chemotherapy
b. protozoal infections (Pneumocystis carinii)=
HIV (+) individuals
“Normal Flora” Advantages
 Prevent overgrowth of pathogenic organisms
 Skin: fatty acids
 Gut: release bacteriocins, colicins and metabolic
waste; compete with others for living space,
produce vitamins B and K
 Vagina: lactobacilli maintain acid ph
“Normal Flora” Disadvantages
 Potential for spread during procedures or
trauma: intestinal perforation, skin breaks,
dental extraction
 Person is vulnerable during periods of
decreased immunity, change in environmental
conditions
Attributes of Microbes to be Pathogenic
1. Microbes have an interractive group of
complementary genetic properties that promote
interaction to its host. This is in the form of
“genetic traits” called phenotypes.
2. Microbes should have the capacity to breach
normal host anatomic, cellular, or biochemical
barrier that ordinarily prevent entry by other
microrganisms.
= motility
= chemotactic properties, adhesive structures
Attributes of Microbes (Pathogens)
3. Microbes is be able to pass thru the “normal host
defense” mechanism thru the following microbial
factors:
= antiphagocytic capsule
= elaboration of toxins and enzymes
= immune specific proteases and iron
(e.g. IgA proteases of Haemophilus influenzae)
= iron sequestration mechanisms (N. gonorrehae)
Attributes of Microbes (Pathogens)
4. Microbes has the ability to multiply upon reaching
its specific niche (blood, lungs, tissues, etc) and the
potential to be transmitted to a new susceptible host.
- this determine the outcome of the events, either in
the form of alteration of host physiology and tissue
damage or death of the host
Pathogens/microbes= Complex and highly
adapted organisms?
Microbial Adherence
 Initial interaction of a pathogen w/its host
 Route to invasion by intracellular parasites
 First step in host cell killing and toxin delivery
Microbial Adhesins
 Surface structures that anchor the
microorganism to tissue, promote cellular entry
and elicit host responses
Pili (fimbriae)
Flagella
Hemagglutinin
Surface glycoprotein
Glycosaminoglycans
Viral capsid protein
Lectins
Lipids
Avoidance of Phagocytosis of Microbes
 Release toxin that destroys phagocyte
 Prevent opsonization by releasing protein
 Prevent contact by capsule, etc.
 Inhibit fusion of phagolysosome
 Organism escapes into the cytoplasm and replicates within
the phagocyte
 Resists killing by producing antioxidants, etc.
EVASION STRATEGIES OF PATHOGENS
Strategy
Elicit minimal response
Example
HSV latent stage
Evade effects of
response
Depress host response
Mycobacteria in
granulomas
HIV destroys T cells
Antigenic change
Viruses, spirochetes
Rapid replication
Viruses, bacteria, protozoa
Survive in weakly
responsive persons
Genetic heterogeneity
Mediators of Tissue damage and
disease
 Viruses: down-regulate MHC molecule
production, make proteins that interfere with
interferon, decrease cytotoxic T cell recognition of
infected cells, etc.
 Bacteria: toxins (enterotoxin, exotoxin,
endotoxin)
Survival of microbe in host
 Concealment of antigen
 Privileged sites (CNS, joints, testes, placenta, cysts, host DNA)
 Mimicry (e.g., streptococci and cardiac muscle)
 Antigen uptake
infection during embryonic life, production
of large amts of antigen, exploit gaps in immune
repertoire, upset balance between antibody and TH1 and
TH2
 Tolerance:
Microbial biofilms
 Matrix enclosed bacterial
populations that adhere to a surface,
interface or each other
 Responsible for dental plaque, clogged
water pipes, form on synthetic
medical implants
 Leads to altered metabolism,
production of extracellular
virulence factors
 Decreased susceptibility to
antibiotics by forming an exclusion
barrier or directly complex with them
HOST FACTORS in INFECTIONS
1. There are specific host factors that influence
likelihood of acquiring infectious diseases.
a.
b.
c.
d.
e.
f.
Age= elderly and infants (altered immune response)
immunization history
prior and coexisting illnesses (e.g. diabetes)
level of nutrition (e.g. malnutrition)
pregnancy state
emotional state (e.g. depression)
HOST FACTORS in INFECTIONS
2. External host factors such as environment,
geography and behavior.
Examples:
a. geography/environment = P. falciparum malaria
bearing Aedes mosquito in mountainous and coastal
areas
b. geography= antibiotic-resistant malaria are common in
highly endemic areas (Phils, Africa, Indonesia)
c. behavior = acquisition of sexually transmitted diseases,
IV drug use hepatitis B and C
HOST FACTORS in INFECTIONS
3. Medical care (hospital, healthcare facilities)
and medical devices
a. contact of pathogens during hospitalization
b. breach of the skin during insertion of
intravenous devices and surgical incisions
c. alteration of the normal flora or commensals
with use of antibiotics
d. treatment with immunosuppressive drugs such as
cancer chemotherapy
HOST FACTORS in INFECTIONS
4. Genetics:
e.g., MHC genes (class II and leprosy), sickle cell
gene and malaria
Host Receptors
 Host molecules or ligands that microbial adhesins bind to for
adherence
Sugars
Ig superfamily
Growth factors
Integrins
Extracellular matrix
component
Transport proteins
Complement receptor
Host response
 Cellular immunity
 Humoral immunity:
 Antibodies: recognize and bind to foreign antigens, impede
function of organism, facilitate its removal
 Complement: adhere and disrupt
 Phagocytic cells: engulf, kill and digest
 Reticuloendothelial system: monocyte derived
phagocytic cells that clear circulating organisms in liver,
spleen, kidney, LN, brain
Interaction with phagocytes
 Activation of phagocytes is a key step in initiating
inflammation and migration of additional phagocytes into
affected sites
 Microbial factors that interact w/ phagocytes: LPS of gram
(-) bacteria, lipoteichoic acid of gram (+), etc.
1. Attachment by
nonspecific receptors
3. Lysosome fusion & killing
2. Pseudopodia forming
a phagosome
4. Release of microbial
products
Phagocytosis
Macrophages
 Produced in bone marrow, tissues
 Killing mechanism: oxidative, nitric oxide, cytokines
 Activated by TNF, IFNγ, IL-4, GM-CSF, microbial products
 Secretes lysozyme, cytokines, etc.
Neutrophils
 Produced in the bone marrow
 Killing mechanism: oxidative and nonoxidative
 Activated by TNF
 Secretes lysozyme
 Deficient states: CGD, myeloperoxidase, chemotactic,
Chediak-Higashi
T helper (TH) cells
 TH1 subset: mediate chronic inflammatory reactions (e.g.,
tuberculosis)
 IL-2, IFNγ
 TH2 subset: help B cells make antibody
 IL-4, IL-5, IL-6
Cytotoxic T lymphocyte
 Carries out both antigen specific recognition and killing of
target cell
 Recognition is associated with Class 1 MHC
 Killing mechanism: leakage due to insertion of perforin,
DNA fragmentation, apoptosis
Extracellular Killing
 Natural killer cells: cytotoxic cells that attach to the
surface of virally infected cells and release granules that enter
cells through pores and lead to programmed cell death or
apoptosis
 Eosinophils: important against helminths, produce major
basic protein, perforins and O2 metabolites that damage the
cells
Febrile response
 a complex physiologic reaction to disease involving a
cytokine mediated rise in the core temperature, generation
of acute phase reactants, activation of numerous physiologic,
endocrinologic and immunologic systems.
 Due to infection, malignancy, collagen vascular disease, etc.
Host response to infection
 Outcome of infection depends on the balance
between an effective response that eliminates a
pathogen and an excessive inflammatory
response
 Cytokine production: stimulate inflammatory
response
 Abscess or granuloma formation
 Local or systemic inflammation
Acute inflammatory response
 Opsonization: engulfment by phagocytic
cells facilitated by opsonins (C3B)
 Margination: PMNs align alongside blood
vessel wall
 Chemotaxis: marginated PMNs attracted to
site of C3B coated bacteria
bacterium
C3B
C3bBb
C5
C3b
C5a/C3a
MC
C3b receptor
Chemotactic
factors
Vascular
permeability
mediators
Acute inflammatory reaction
C3
RESPONSE TO PATHOGENS,
“CROSS-TALK” AMONG CELLS
BACTERIA
DENDRITIC CELL
NEUTROPHIL
MACROPHAGE
NECROTIC CELL
NECROTIC CELL
APOPTOTIC CELL
INFLAMMATORY
PRODUCTS
APOPTOTIC CELL
CD4 T CELL
ANERGY
ANERGY
Th1
Th1
Th 2
Th 2
- Hotchkiss. N Engl J Med 2003; 348(2):135-50
Innate immune system
Soluble factors Lysozyme,
complement, acute
phase reactants
Cells
Phagocytes, NK cells
Adaptive immune
system
Antibody
T lymphocytes
Response to microbial infection
1st contact
2nd contact
+
+, nonspecific, no
memory
+
+++, specific
memory, resistance
improved by
repeated contact
HOST and MICROBES :
Symbiosis or Opportunistic
Relationship?