lecture 29- immunity to infection

Immunity to Infection

• Infectious diseases annually cause 14 million human deaths, caused by six pathogens
  • Extracellular bacteria
  • Intracellular bacteria
  • Viruses
  • Parasites
  • Fungi
  • Prions
• Infection occurs when an organism successfully avoids innate defenses, colonizing a niche.
• A biological "horse race" or "war" between pathogen and immune system. The pathogen tries to replicate and expand, while the immune system attempts to eliminate it.
• A pathogen damages the host only if its replication is detectable clinically.
• Bacterial toxins can cause disease even without colonization.
• Immunopathic damage results when host tissues are unintentionally harmed by the immune response.
• Innate and adaptive effector mechanisms are best suited to pathogens with particular lifestyles and replication modes.

Host-Pathogen Encounters

• Innate defense mechanisms help combat pathogens.
• First obstacle for invaders is intact skin and mucosa. A breach allows pathogen access to sub-epithelial tissues.
• Compromised immune systems (from disease or treatment) invite opportunistic pathogens.
• Invasive pathogens can enter the body even with intact surface defenses.
• Pathogens gain access to mucosae, possibly through M cells or by binding to host surface molecules initiating internalization.

Host-Pathogen Encounters (continued)

• A pathogen penetrating skin or mucosa initiates influx of acute phase proteins, pro-inflammatory cytokines (IL-1, TNF, IL-6), and complement components.
• Coating pathogens with C3b or mannose-binding lectin facilitates removal via alternate/lectin complement cascades.
• Cellular innate defense is mediated by PRRs of resident DCs, neutrophils, other granulocytes, macrophages, NK cells, γδ T cells, and NKT cells.
• These PRRs include TLRs, NLRs, RLRs, CLRs, scavenger receptors, cell-bound collectins, and antigen recognition receptors of NK, NKT, and γδ T cells.
• Soluble collectins in the extracellular matrix activate complement or stimulate phagocytosis, activated by PRR engagement to eliminate pathogens.
• Leukocytes eliminate pathogens or infected cells by endocytosis/phagocytosis, or by secreting cytotoxic cytokines or perforin/granzyme-mediated cytotoxicity.
• Also produces toxic NO and ROIS.
• Chemokines draw neutrophils and leukocytes to infection sites.
• In blood infections, neutrophils and monocytes provide innate defenses. Organisms reaching the liver or spleen face resident macrophages.
• Innate response proceeds: local DCs (after maturation due to pathogen components) present pMHCs to naïve T cells, triggering the adaptive immune response.
• T and B cell activation occur in inductive sites (MALT/SALT), and effector cells migrate to effector sites.
• Systemic response if mature DCs move to draining lymph nodes or spleen.

Immunity to Extracellular Bacteria

• Extracellular bacteria accumulate in interstitial regions (respiratory, urogenital, gastrointestinal tracts, blood).
• Bacteria often secrete proteins to penetrate/enzymatically cleave mucosal epithelium, gaining access to underlying tissues.
• Many extracellular bacterial disease symptoms are due to toxins.
• Exotoxins are actively secreted proteins from Gram-positive or Gram-negative bacteria.
• Endotoxins are lipid portions of LPS molecules embedded in Gram-negative bacterial walls. They are released when cell walls are damaged, not secreted.
• A given Gram-negative species may produce both exotoxins and endotoxins.
• Different exotoxins and endotoxins cause disease via different means and locations.
  • Vibrio cholerae infection causes local exotoxin release, binding to gut epithelial cells, inducing diarrhea.
  • Clostridium botulinum produces neurotoxins that block nerve impulse transmission to muscles, resulting in paralysis.
  • Endotoxin damage to a host is always immunopathic (septic shock).

Immunity to Extracellular Bacteria (Table)

• Table 13-1 lists examples of extracellular bacteria and diseases.

Immunity to Intracellular Bacteria

• Most intracellular bacteria access the host through breaches in mucosa or skin. Some enter the bloodstream via vectors (ticks, mosquitoes, mites.)
• Intracellular bacteria evade phagocytes, complement, and antibodies by moving inside host cells.
• Epithelial and endothelial cells, hepatocytes, and macrophages are popular targets within the host.
• Dissemination of infection occurs because macrophages are mobile; bacteria that infect them are spread.
• Intracellular bacteria often enter host cells via clathrin-mediated endocytosis and may remain in a vesicle or escape into the cytoplasm.
• Intracellular bacteria are usually not very toxic and do not produce tissue-damaging toxins.
• Intracellular bacteria are hard to eradicate and cause chronic diseases.

Immunity to Intracellular Bacteria (Table)

• Table 13-3 lists examples of intracellular bacteria and the diseases they cause.

Granuloma Formation

• When intracellular pathogens like Mycobacterium tuberculosis resist CTL killing and hyperactive macrophages, the body walls off the pathogens in granuloma structures around infected macrophages
• Granuloma has an inner layer with macrophages and CD4+ T cells, while the exterior contains CD8+ T cells.
• Granulomas may calcify and become fibrotic, with central cell necrosis..
• In some cases, all pathogens within the dying cells are killed, resolving the infection.
• In other cases, some pathogens remain viable and dormant within the granuloma, which persists indicating chronic disease.
• If the granuloma breaks down, trapped pathogens resume replication. Immunosuppression allows pathogens to enter the bloodstream.
• Cytokines IL-17, IL-12, and IFN-γ (Th1 cells) play roles in granuloma formation
• IL-4 and IL-10 (Th2 cells) control granuloma formation, damping down inflammation as the bacterial threat is controlled.
• Bacteria can infect organs causing body widespread damage and death.

Immune System Evasion by Bacteria (Tables)

• Tables 13-2 and 13-4 detail immune system elements thwarted by extracellular and intracellular bacteria, respectively, along with the bacteria's methods.

Next Lecture

• Chapter 13: Immunity to infection

Explore the critical dynamics of immunity as it combats infectious diseases caused by various pathogens. Understand the roles of innate and adaptive immune responses, the effects of bacterial toxins, and the biological 'war' occurring between pathogens and the immune system. This quiz covers the fundamental concepts of how immunity functions and the challenges faced.