Lecture 5 Mycobacterium 2023.pdf

BMS2037 The Mycobacteria Objectives Appreciate the general attributes of mycobacteria Understand the importance of pathogenic mycobacteria For both M.tuberculosis and M.leprae Appreciate the process of pathogenesis as an interaction betwe...

BMS2037 The Mycobacteria Objectives Appreciate the general attributes of mycobacteria Understand the importance of pathogenic mycobacteria For both M.tuberculosis and M.leprae Appreciate the process of pathogenesis as an interaction between host and pathogen -establishment of infection -progression to disease -transmission Understand control strategies and their limitations Vaccination Diagnosis Drug Therapy  The Mycobacteria Background Unicellular and branched rods Gram positive Complex cell wall –containing sugars, proteins and a lot of lipid -Acid fast staining-Ziehl Neelson stain stain-carbol fuchsin destain acid alcohol counterstain methylene blue (mycobacteria are red and everything else is blue!)  Grouping Mycobacteria ▪ Split into two groups ▪ FAST growers (1-2 days on plates) eg M.phlei, Msmegmatis ▪ SLOW growers (several weeks) ▪ Most are saprophytes but all the major pathogens are slow growers ▪ Eg. M.tuberculosis ▪ M.bovis-closely related to tb ▪ M.avium-intracellulare-scofulaceum complex-animal pathogens and opportunist of man. Very common with HIV ▪ M.paratuberculosis –ruminant pathogen ▪ M.ulcerans-human pathogen ▪ M.leprae-human pathogen ▪ M.marinum-disease of fish and frogs and humans! M. Ulcerans Buruli ulcer  Grouping Mycobacteria ▪ Split into two groups ▪ FAST growers (1-2 days on plates) eg M.phlei, Msmegmatis ▪ SLOW growers (several weeks) ▪ Most are saprophytes but all the major pathogens are slow growers ▪ Eg. M.tuberculosis ▪ M.bovis-closely related to tb ▪ M.avium-intracellulare-scofulaceum complex-animal pathogens and opportunist of man. Very common with HIV ▪ M.paratuberculosis –ruminant pathogen ▪ M.ulcerans-human pathogen ▪ M.leprae-human pathogen ▪ M.marinum-disease of fish and frogs and humans!  Tuberculosis Global emergency 35000 die every week 2 billion people are infected High incidence in HIV infected individuals Drug resistant strains Tuberculosis - a disease of poverty  Clinical Manifestations of TB General – fever, weight loss, weakness, “consumption”, persistent cough – result from inflammatory response ▪ In most a pulmonary infection. Disease is pneumonia but rather than inflammatory infiltrate in the airways it is an impairment of the lung tissue itself , but may spread to anywhere in body (15% cases) Central nervous system Lymphatic system Genitourinary systems Bones and joints Disseminated (miliary TB) The outcome of TB infection Transmission, protection and Pathogenesis -1 Aerosol travels to alveoli of lungs M. tuberculosis engulfed by alveolar macrophages if activated due to an aquired immune response(e.g. healthy adult), host may clear bacteria, or at least contain infection if unactivated (e.g. infant or naïve adult), bacteria survive and replicate in macrophages – attract more cells (PMN’s, T-cells), damage tissue, and form granulomatous tubercle The immune response is protective  Transmission, protection and Pathogenesis - 2 ▪ Tubercle can remain silent (X-ray) ▪ Granulomatous response may fail to contain bacteria ▪ Immediate lymphatic / hematogenous spread (primary TB) ▪ Granuloma may remain walled off for years to decades, then allow release of viable bacteria: reactivation (post primary)  Transmission, protection and Pathogenesis - 3 Clinical syndrome requires intact immune response airway airway Inflammatory response correlates with degree of cavitation Decreased infectivity of PTB in late HIV Steroids increase rate of sputum clearance The immune response is required for transmission PET CT scan 18F fluoro- deoxyglucose TB Control and Treatment King George V Sanatorium Diagnosis ▪ Radiology ▪ Microscopy of sputum looking for acid fast rods ▪ Culture of sputum samples - grown on medium containing egg (Lowenstein Jenson) or oleic acid and albumin. Antibiotics or malachite green used to inhibit the growth of other bacteria. Takes about 6 weeks!! PCR Immunological – T cell response to TB antigens  TB control - strategies ▪ Preventive vaccination ▪ Immunize prior to exposure with goal to ▪ Prevent establishment of infection ▪ Prevent infection from developing to disease ▪ Antibiotic treatment ▪ Can target active TB or latent infection ▪ WHO has targeted active infection (transmission) ▪ Problem: Can’t treat 2 billion people with asymptomatic infection  Vaccination Bacille Calmette-Guérin (BCG) Derived from M. bovis by serial passage Avirulent Effective in experimental models Safe Inexpensive 100 million doses given per year Is BCG effective in humans? Debated for 70 years Protects against disseminated disease in children Protects against leprosy Efficacy varies by geographic location and population Why? Differences between vaccine sub-strains? ‘Interference’ by environmental mycobacteria? Too attenuated? Genetic differences between populations?  TB treatment regimen Multi-drug treatment required because of resistance ▪ First line oral anti-TB drugs (given to new previously untreated cases, 6 months) ▪ Isoniazid ▪ Rifampicin ▪ Ethambutol ▪ Pyrazinamide Zumla et al Lancet 2015 WITH TB?  % MDR/RR-TB in new TB cases Figures are based on the most recent year for which data have been reported, which varies among countries. Data cover the period 2002–2018  AMR and tuberculosis ▪ MDR-TB – Resistant to at least rifampicin and isoniazid ▪ XDR-TB – Resistant to rifampicin, isoniazid , any fluoroquinolone and at least one of the three injectable second line drugs kanamycin, amikacin, capreomycin  Treatment regimen for MDR TB ▪ At least 4 potentially active drugs New drugs ▪ Bedaquiline ▪ Delaminid ▪ Linezolid Repurposed▪ Late generation fluoroquinolone eg. Moxifloxacin drugs ▪ Injectable aminoglycoside eg. Kanamycin ▪ First line drug to which strain has known susceptibility eg. Pyrazinamide ▪ One other such as cycloserine, paraaminosalicylic acid, ethionamide The recommendations for DR TB treatment are changing fast and are updated by the WHO yearly. ▪ Globally, only 55% success rate in treating MDR TB Leprosy Causative agent Mycobacterium leprae 15 million affected in 1985, now less than 0.5 million Non-cultivatable but can be grown in 9 banded armadillos and in mouse footpads Intracellular parasite which can grow in macrophages and other cells such as schwann cells. Transmission is still a mystery. Most people who come in contact with leprosy patients do not get infected. Patients have high bacterial counts in nasal discharges, but disease does not spread in epidemic fashion Not always limited to the tropics Leprosy in UK Red Squirrels Disease 95% of infected individuals do not develop clinical disease. 2 clinical manifestations of disease Tuberculoid- very few bacilli in the tissue, usually a mild disease with few skin lesions Host response - strong cellular immune response, low antibody. Competent tuberculoid granulomas form to contain infection. Lepromatous- severe disease with massive numbers of bacilli in the tissue. Multiple lesions –skin nodules packed full of bacteria Nerve damage is common leading to paralysis and anaesthesia. Can lead to loss of fingers, toes, nasal deformation, eventually death Host response - poor cellular immune response, high antibody Foam cell granulomas indicate poor host resistance The immune response determines the infection. Leprosy disease Control of Leprosy Vaccination with BCG has been shown to be effective Drug Treatment Dapsone is the most used antibiotic For lepromatous leprosy treatment may be for life. Resistance to Dapsone is becoming increasingly common -like in tuberculosis the answer is multidrug therapy Dapsone, clofazamine, rifampicin