Tuberculosis Immunology Overview

Tuberculosis Immunology

• Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb).
• Mtb is a small (2-5 µm), aerobic, non-motile bacillus.
• Mtb has a high lipid content, contributing to its clinical characteristics and pathogenesis.
• Mtb doubles every 16-20 hours.
• Mtb has drug-susceptible and drug-resistant forms.
• The incidence of TB is expressed per 100,000 population.

Tuberculosis Incidence, 2020

• The figure provided is a world map showing the incidence of new active TB infections and reactivated latent TB infections in 2020.
• The map shows the geographical distribution of TB incidence rates.
• The incidence varies greatly across different regions of the world.
• The regions with higher TB incidence coincide with regions with higher rates of HIV.

Mycobacterium tuberculosis

• Mtb is a small, aerobic, non-motile bacillus (2-5 µm).
• High lipid content contributes to clinical characteristics and pathogenesis.
• Slow growing (doubles every 16-20 hrs)
• Acid fast
• Drug susceptible and resistant forms exist.

What is Tuberculosis?

• Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb).
• TB usually affects the lungs (pulmonary) but can affect other body parts, such as organs, brain, and bones (extra-pulmonary).
• Most TB infections are latent, meaning no symptoms are present.
• About 1/4 of the world's population is infected with latent TB.
• Active TB is characterized by symptoms like bloody cough, fever, night sweats, weight loss, chest pain, and shortness of breath.
• TB spreads via airborne droplets (droplet nuclei) that contain 1-5 bacteria.

How is Tuberculosis Diagnosed?

• Radiographic evidence (chest X-ray)
• Culture (liquid or solid)
• Immunological detection (IGRA or Mantoux test)
• Smear microscopy
• Nucleic acid detection (GeneXpert or Hain LPA)
• Urine testing for LAM (lipoarabinomannan)

Treatment of Tuberculosis

• First-line treatments include Isoniazid (INH), Rifampicin, Pyrazinamide, Ethambutol, and Streptomycin.
• Second-line treatments include Kanamycin, Rifabutin, Thiacetazone, Fluoroquinolones, Amikacin, Capreomycin, Ethionamide/Prothionamide, Para-aminosalicylic acid, and Cycloserine.
• Newer drugs are also under development and in various clinical phases.

Is There a Vaccine for TB?

• BCG or Bacillus Calmette-Guérin is a vaccine for TB, though older than 100 years.
• BCG is predominantly used in Sub-Saharan Africa to prevent childhood tuberculous meningitis and miliary disease.
• BCG vaccine effectiveness varies against various forms of TB, and might potentially interfere with tuberculin skin tests.
• Protection from the BCG vaccine can last up to 15 years.

Development of New TB Vaccines

• Several new TB vaccine candidate developments are underway, in different stages of clinical development.

Novel TB Vaccine (South African)

• A study details a modified BCG vaccine targeting Mtb and its interactions with the immune response.

What Happens When a Person is Exposed to Mtb

• Upon inhalation, Mycobacterium tuberculosis (Mtb) encounters the first line of defense (airway epithelial cells, professional phagocytes).
• Effective defense halts or clears the infection.
• If the initial defense is not effective, Mtb reproduces inside phagocytes, and the infection might cause few symptoms if any, at the start of infection progression.
• Whether or not the initial infection advances and causes active TB depends on the intricate relationship between the pathogen and the host.
• Absence of symptoms but uncleared infection means that the infection is latent.

Incipient and Subclinical Tuberculosis

• TB infection involves a spectrum of metabolic bacterial activity and opposing immune responses.
• Five states have been documented: eliminated, latent, insipient, subclinical, and active TB.

Range of TB Disease

• A range of states associated with Tuberculosis infection exists, from complete elimination of the pathogen to active disease.

Bacterial Pathogenesis and the Immune Response

• Genetic variation in Mtb strains impacts infection virulence and immunogenicity.
• Variation in Mtb strains influence different immune responses.
• Modern strains tend to elicit lower cytokine production, replicate faster in the lungs, and are more pathogenic to mice.
• Ancient strains present with fewer symptoms, lower or equivalent virulence compared to modern strains, and exhibit fewer differences in the T-cell response.

Bacterial Pathogenesis and the Immune Response (Individual)

• Different infection sites within the lung differ significantly in their micro-environments.
• Variations in cellular compositions and activation levels of immune cells in granulomas expose Mycobacterium tuberculosis to differences in nutrients, reactive oxygen species, and cytokine profiles.

Tuberculosis Pathogenesis

• Illustrations of different aspects of the mechanism of pathogenicity of Mycobacterium tuberculosis.

Granuloma Physiology

• Transmission of Mycobacterium tuberculosis occurs via inhaled aerosols, prompting a complex immune response.
• Infection results in the primary granuloma formation.
• The pathogen persists despite the host immune response.

Adaptation of Mtb in the Granuloma

• Mtb uses various strategies to survive the hostile environment within the granuloma.
• These strategies are identified through in vitro and in vivo experiments.

Evasion of Host Response by Mtb

• Mtb glycolipids prevent the accumulation of proteins on phagosomal membranes.
• Mtb utilizes lipids to escape from the phagosome and kill host cells.

Innate vs Adaptive Immune Systems

• The innate immune system provides a rapid, non-specific defense against pathogens.
• Components include leukocytes, dendritic cells, natural killer cells, plasma proteins.
• The adaptive immune system provides antigen-specific responses with immune memory.
• Helper T cells activate B and cytotoxic T cells.
• Cytotoxic T cells destroy infected or damaged cells.
• B cells produce antibodies.

Cells of the Innate and Adaptive Immune Systems

• Diagrams depicting the various innate and adaptive immune cells involved in the response to Mycobacterium tuberculosis.

Macrophages

• Macrophages are white blood cells derived from monocytes.
• They engulf and digest pathogens.
• Expression of Toll-like receptors initiates an inflammatory response and cytokine production.
• Macrophages provide surveillance in tissues.

Monocyte

• Differentiate into macrophages and dendritic cells, initiating adaptive immunity.
• Critical in controlling Mycobacterium tuberculosis infection via the production of reactive nitrogen intermediates (RNI).
• Transport of infected monocytes to lymph nodes coordinates downstream immune responses.

Natural Killer Cells (NK)

• Innate lymphocytes producing IFN-γ.
• Recognize Mtb-specific components and mediate direct killing of infected macrophages.
• Restrict intracellular bacterial replication by increasing phagolysosomal fusion.
• Possess memory cell characteristics after BCG vaccination.

Adaptive Immunity

• Dendritic cells are antigen-presenting cells initiating adaptive immunity.
• Upon Mtb infection, dendritic cells mature and migrate to lymph nodes stimulating antigen specific T-cell responses.
• Interventions to improve DC function can lead to enhanced crosstalk between DCs and antigen-specific T-cells.

CD4 T-cells and IFNy Response

• CD4 T cells (helper T cells) are essential for controlling bacterial replication.
• CD4-T cells help other blood cells and produce an immune response.
• Interaction with infected macrophages limits intracellular Mtb replication.
• Appropriate trafficking to Mtb-infected lung cells is key to effectiveness.
• Deficiencies in IFN-γ and IL-12 signaling lead to higher susceptibility to mycobacterial infections .

CD8 T-Cell Response

• CD8 T cells directly kill infected macrophages.
• Secreting cytokines and cytolytic molecules limits bacterial replication and are important for preventing reactivation.
• CD8 T cells are critical for fighting Mycobacterium tuberculosis.

T-Regulatory Cells (T-regs)

• T-regs modulate the immune response, maintaining tolerance to self-antigens.
• T-regs impair anti-mycobacterial T-cell responses and delay the expansion of CD4 and CD8 T cells, potentially contributing to increased susceptibility and disease.

Memory T-cell Response

• Antigen-specific CD4 and CD8 T cells rapidly expand after treatment and can offer short-term protection against Mtb infection.
• Generated memory T cells have limited capacity in protecting against re-infection, so secondary infection can still cause disease.

B-cell (Lymphocyte)

• B cells produce antibodies to neutralize and clear extracellular pathogens.
• They also play a role in intracellular pathogens by influencing the outcome of Mtb infection through cytokine and antibody production.

Why is M. Tuberculosis Still a Successful Pathogen

• Mtb displays genetic multiplicity, utilizes various carbon sources, and occupies complex organs.
• Mtb infection is often chronic and difficult to treat, leading to the spread of disease.

Explore the intricate details of Tuberculosis (TB) immunology, including the characteristics of Mycobacterium tuberculosis and its incidence rates worldwide in 2020. This quiz delves into the disease's pathogenesis, growth rate, and geographical distribution, shedding light on its connection to HIV rates. Test your knowledge on this critical topic in infectious diseases.