3. Introduction
The outcome of TB infection is highly variable and is
determined by the response of the immune system and
environmental variables, but a deeper knowledge of the
global genomic diversity in the MTBC suggests that
bacterial factors are also involved
Unlike other pathogens, MTB virulence is directly linked
to its transmission.
Thus its virulence can be measured through
(1) the ability of the bacteria to survive the host immune
response,
(2) their capacity to cause lung damage and
(3) to be successfully transmitted to infect a new host
4. Virulence
Considering the ability of Mtb to infect a variety of
mammalian hosts, manifest clinically in humans as
both latent and active infection, and dwell in the air
within modes of airborne particles to be transmitted
to naive hosts, it has evolved a variety of approaches
to establish infection and survive within a variety of
cells, tissues, and environments
5. VIRULENCE FACTORS
Cell envelope
Major constituent: mycolic acid
Mycolic acid is attached to glycolipids
Glycolipids are responsible for “cord formation” on
microscopy (grossly corresponds to granuloma
formation).
Catalase-peroxidase: resists host-cell oxidative
response
Sulfatides and trehalose dimycolate: triggers toxicity
Lipoarabinomannan (LAM): induces cytokines
6. Mycolic acid
Mycolic acids, long chain fatty acids ranging
between (C60-C90), are the primary constituents of
the inner leaflet of the outer membrane. Mycolic
acids are covalently linked to the arabinogalactan
layer or are present as free mycolic acid within the
capsule .
This region is also known as the mycomembrane
for the abundance of this lipid species.
In alveolar epithelial cells, mycolic acids inhibit
TLR2 leading to a decrease in IL-8 production.
7. •Free mycolic acids can activate the DAP12-
associated triggering receptor expressed on
myeloid cells 2 (TREM2) on innate immune cells,
which in turn increases MCP-1 production and
recruitment of Mtb permissive macrophages
•Overproduction of MCP-1 correlates with
susceptibility to ATB . Thus, regulation of
inflammation via IL-8 and MCP-1 is but one of
several mechanisms by which mycolic acids
influence host immunity
8. •Trehalose monomycolate and trehalose
dimycolate
TDM is also known as cord factor for mediating the formation
of long filaments or “cords”when Mtb is extracellular.
Monocyte-Inducible C-type Lectin (Mincle), a pattern
recognition receptor (PRR) present in macrophages and
dendritic cells, binds to the trehalose motif of TDM .This
interaction triggers SH2-domain-containing inositol
polyphosphate 5’ phosphatase 1(SHP-1) and Fc gamma receptor
IIB (FcγRIIB) leading to inhibition of phagosome arrest
Mincle also activates the PI3K-AKT-GSK3 signaling pathway
leading to the production of TNF-α, IL-6, and MCP-1 with
subsequent recruitment of monocytes and neutrophils.
9. •Phthiocerol dimycocerosates
PDIM is thought to mask pathogen-associated molecular
patterns (PAMPs) of Mtb, allowing the bacteria to evade
recognition by TLRs
After phagocytosis, PDIM is suggested to have a role in
membrane rupture
including both phagosome and mitochondria membranes
Though damaged phagosomes signal the host cell to initiate
degradative
autophagy, a cell-intrinsic host defence, PDIM also inhibits
MyD88 signaling, leading to a decrease in autophagy.
10. •Phenolic glycolipids
PGL may also modulate the immune system by antagonizing
the function of TLR2 , or by inhibiting inflammatory cytokine
activity by interfering with T-cell receptor signaling
•Polyacyl trehaloses
acyl trehaloses bind cell surface Mincle receptors, triggering a
signaling cascade that increases production of TNF-α and other
cytokines
11. Lipoarabinomannan (LAM)
Lipoarabinomannan (LAM) is a glycolipoconjugate
composed by an anchor mannosyl phosphate
inositol (MPI), a polysaccharide backbone and
diverse capping motifs species
12. Lipomannan (LM)
Lipomannan (LM) is a multiglycosylated lipid or
polymannosylated Phosphatidylinositol mannoside
(PIM). LAM and LM coexist in the mycobacterial cell
wall.
13. Phosphatidylinositol mannosides
(PIMs)
Phosphatidylinositol mannosides (PIMs) constitute a
substantial component of the cell envelope, precursor
of LAM and LM. PIM has a variable number of
mannose units and acylation, virulent species have
high order PIM (5 or 6 mannoses) that contribute to
the uptake of macrophages by mannose receptor
14. Trehalose-6,6´-dimycolate (TDM)
Trehalose-6,6´-dimycolate (TDM) also known as cord
factor, is the most abundant and toxic lipid in the
mycobacterial cell envelope. TDM is composed by two
polar trehalose head group where two mycolic acids
(MA) are esterified
15.
16. Macrophage phagolysosome
inhibition
When we’re exposed to Mycobacterium, There are
macrophages within the airway-
Find the Mycobacterium and engulf it
Phagocytose it and put it into a phagosome
Normally, phagosome should combine with vesicles
that contain lysosome
But tuberculosis can inhibit the phagolysosome. It
can’t break down the pathogen as easy .So, the
pathogen multiplies within multiple macrophages
18. HOST RISK FACTORS
Elderly
Children
Immunocompromised patients
Institutionalized patients
IV drug use
HIV or other immunodeficiencies
Travel to high-risk regions
19. TRANSMISSION
M. tuberculosis
transmission: respiratory droplets from patients with
active disease
M. leprae transmission:
Direct contact with lesions
Inhalation of infectious droplets
MAC transmission:
Inhalation into the respiratory tract
Ingestion into the GI tract
20. PATHOGENESIS
RESERVOIR
M. tuberculosis : humans are the only natural reservoir
M. leprae natural reservoir: armadillos
M. avium and M. intracellulare are found in water and
soil.
21. PATHOGENESIS
MTB pathogenicity, defined by its ability to cause disease in a
host organism, has co-evolved with its physiology as species.
Initial infection is mainly through respiratory tract, here the
alveolar macrophages are the most common cell type infected by
MTB and the inflammatory signals arising from infection
promote the influx of additional monocytes and macrophages,
which become infected as well.
Inflammation is required for initial control of infection but can
also cause extensive tissue damage
Moreover, the bacteria exploit the host inflammatory signals to
spread to other individuals. Because of that, it is believed that its
pathogenicity is likely to have evolved from its specific
adaptations to host immunity
22.
23. Tuberculosis is classified as one of
the granulomatous inflammatoy
diseases. Macrophages, epitheliod
cells, T lymphocytes, B
lymphocytes,
and fibroblasts aggregate to form
granulomas,
with lymphocytes surrounding the
infected macrophages.
When other macrophages attack
the infected macrophage, they
fuse together to form a giant
multinucleated cell in the
alveolar lumen. The granuloma
may prevent dissemination of
the mycobacteria and provide a
local environment for
interaction of cells of the
immune system.[
24. Recent evidence suggests that the bacteria use the
granulomas to avoid destruction by the host's immune
system.
Macrophages and dendritic cells in the granulomas are
unable to present antigen to lymphocytes; thus the
immune response is suppressed.
Bacteria inside the granuloma can become dormant,
resulting in latent infection. Another feature of the
granulomas is the development of abnormal cell death
(necrosis) in the center of tubercles.
To the naked eye, this has the texture of soft, white cheese
and is termed caseous necrosis
26. About 90% of those infected with M.
tuberculosis have asymptomatic, latent TB infections
(sometimes called LTBI), with only a 10% lifetime
chance that the latent infection will progress to overt,
active tuberculous disease.
In those with HIV, the risk of developing active TB
increases to nearly 10% a year. If effective treatment is
not given, the death rate for active TB cases is up to
66%.
27. PATHOGENESIS OF
M.TUBERCULOSIS
Pathogen- Mycobacterium tuberculosis (most
common)
Usually, the pathogen is inhaled-An airborne pathogen
makes its way into the respiratory tract → bronchial
system
Involve particularly in the right middle and lower lobe
first
Generally, we may see an area of consolidation close to
pleura (subpleural)
28. GENERAL MYCOBACTERIAL PATHOPHYSIOLOGY
In humans, mycobacterial infections can affect
multiple anatomical sites.
Bacteria enter through the skin and mucosal barriers.
Pulmonary and cutaneous infections are the most
common.
Infections with NTM occur most commonly
in immunocompromised hosts as
opportunistic infections.
Mycobacteria can colonize their hosts and cause
latent infections without any obvious clinical signs
29. The primary site of infection in the lungs, known as
the Ghon focus, is generally located in either the upper part
of the lower lobe, or the lower part of the upper lobe.
Tuberculosis of the lungs may also occur via infection from
the blood stream. This is known as a Simon focus and is
typically found in the top of the lung.
This hematogenous transmission can also spread infection
to more distant sites, such as peripheral lymph nodes, the
kidneys, the brain, and the bones.
All parts of the body can be affected by the disease, though
for unknown reasons it rarely affects the heart, skeletal
muscles, pancreas, or thyroid.
