virulence and pathogenesis of mycobacteria.pptx

virulence and pathogenesis of mycobaterium tuberculosis in detail.

1. VIRULENCE AND PATHOGENECITY OF MYCOBACTERIA Presenter- Dr Dinesh Gagan Deepak(PG-JR1) Moderator- Dr R.G Nautiyal (HOD, Professor) -Dr Ravi K. Sharma(Asst. Professor)

2. CONTENTS VIRULENCE PATHOGENECITY

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 ( Fc γ RIIB) 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. 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

16. PATHOGENESIS

17. HOST RISK FACTORS Elderly Children Immunocompromised patients Institutionalized patients IV drug use HIV or other immunodeficiencies Travel to high-risk regions

18. 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

19. 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.

20. 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

21. 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. [

22. 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

23. Microscopy of tuberculous epididymitis. H&E stain

24. 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%.

25. 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 )

26. 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

27. 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.

28. CHEST X RAY DEPICTING GHONS FOCUS

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