MBI 161 - Elementary Medical Microbiology

Host Defense against Infectious Disease

Specific Host Defense (Immunity)

Adaptive host defense factors are immune factors that are triggered by antigens, substances produced by microbes during infection, and are specific for those pathogens to which one is exposed

• Antibody-mediated immunity (AMI)
  • antibody responses
    • antibody is produced by B cells (lymphocytes) stimulated by T cells in response to antigens made by infectious agents
      • Phagocytes called antigen presenting cells (APCs) engulf, process and present fragments of antigen molecules on their surfaces
      • Lymphocytes called T helper (Th) cells recognize (using antigen receptors on their surfaces) antigen fragments, then proliferate and differentiate to form a large population of cytokine-producing Th cells
      • Lymphocytes called B cells bind antigen (using antigen receptors on their surfaces) and bind cytokines (using cytokine receptors on their surfaces), then proliferate and differentiate to form a large population of antibody-producing plasma cells
    • antibody binds specifically to the antigen that induced its formation
  • mechanisms of action (ways in which AMI functions)
    • neutralization - inhibition of toxin function, viral infectivity, microbe attachment due to antibody binding to surface antigens of pathogens
    • antibody/complement-mediated lysis - complement is activated by binding to IgG or IgM antibody molecules that have bound to antigens, and causes lysis of microbes via formation of a membrane attack complex (MAC)
    • opsonization - antibody and complement both enhance phagocytosis by promoting binding of particles, including pathogens, to phagocytes via C3b receptors (C3bR)

• Cell-mediated immunity (CMI)
  • cellular responses
    • cytotoxic T lymphocytes (CTLs) are activated by T helper cells in the presence of viral antigens on virus-infected cells
      • Phagocytes called antigen presenting cells (APCs)engulf, process and "present" fragments of antigen molecules on their surfaces
      • Lymphocytes called T helper (Th) cells cells recognize (using antigen receptors on their surfaces) antigen fragments, then proliferate and differentiate to form a large population of cytokine-producing Th cells
      • Lymphocytes called Tc cells (CTL precursor cells) bind antigen (using antigen receptors on their surfaces) and bind Th cell-produced cytokines (using cytokine receptors on their surfaces), then proliferate and differentiate to form a large population of CTLs
    • macrophages are also activated by T helper cells
      • APCs engulf, process and "present" fragments of antigen molecules on their surfaces
      • Th cells recognize (using antigen receptors on their surfaces) antigen fragments, then proliferate and differentiate to form a large population of cytokine-producing Th cells
      • macrophages bind Th cell-produced cytokines (especially interferon-gamma) using cytokine receptors on their surfaces, then differentiate to form activated macrophages
  • mechanisms of action (ways in which CMI functions)
    • CTLs kill "target" cells by inducing them to destroy themselves via programmed cell death (apoptosis) ... apoptosis video
    • activated macrophages engulf, kill and digest intracellular bacteria and fungi much more efficiently than normal macrophages do, partially because they starve these microbes (by destroying nutrients the microbes need to grow)

Immunocompromised people are more susceptible to infectious diseases than normal people, and this increased susceptibility can be due to one or more of these:

• genetics - inheritance of defective genes that block normal development or expression of immune response elements (cells or molecules)
• immaturity - newborns are highly susceptible because their immune systems have not yet had a chance to mature and become fully functional
• infectious diseases - lowered resistance caused by diseases such as AIDS
• disease treatment - weakened resistance caused by drug therapy for cancer, etc.
• stress - decreases resistance and immune response development

Vaccination

Killed or attenuated (weakened) preparations containing microbial antigens that are used to stimulate immune responses without causing disease are called vaccines

Development and applications of immunology concepts

• Jenner developed smallpox vaccine, and by doing so helped us (eventually) understand the concept of attenuation as well as paving the way for eradication of the naturally-occuring form of disease in the world today
• Pasteur, building on Jenner's findings, developed fowl cholera, anthrax, rabies vaccines (1881-1885)
• Mechnikov proposed the phagocytic theory of immunity in 1884
• von Behring and Kitasato discovered in 1890 that immunity against diphtheria and tetanus is due to toxin-neutralizing antibodies, leading to the humoral theory of immunity and development of vaccines against diphtheria, tetanus, pertussis, yellow fever, plague, etc.

• Types of vaccines
  • toxoid vaccines - a chemically inactivated toxin that is used to induce production of neutralizing antibody
  • killed vaccines - chemically inactivated microbe used to induce antibody production
    • whole microbe vaccines - include the entire microbe
    • split microbe vaccines - include only the antigens needed to induce antibody responses
  • live attenuated vaccines - living, but less virulent, microbe causes a transient infection that leads to generation of both AMI and CMI
  • recombinant vaccines
    • vector vaccines are those generated by incorporating antigen genes isolated from pathogens into non-harmful bacteria or viruses
    • food vaccines are those generated by incorporating genes for microbial antigens into foods such as bananas or tomatoes
  • DNA vaccines - injection of DNA containing genes that code for microbial antigens can lead to transient expression of those genes, resulting in immunization of the host
• Childhood immunizations (vaccinations)
  • Hepatitis B - vaccinate within 2 months after birth; boost 1 month later; boost again 2 months after the second dose (and 4 months after the first dose); if not vaccinated earlier, assess immunity, then vaccinate as needed at 11-12 years of age (combined vaccine against both hepatitis A and B)
  • DTaP (diphtheria, pertussis, tetanus) - vaccinate with DTaP vaccine at 2, 4, 6,15-18 months, then boost at age 4-6 years; Td vaccine (no pertussis component) is used as a booster at age 11-16, then every 7-10 years after that (combined vaccine ... DTP + HiB)
  • Hepatitis A - vaccinate at 2-12 years of age in areas where high risk of infection occurs; especially recommended for children living in communities with high rates of hepatitis A . Vaccination helps prevent carrier state as well as outright disease. (combined vaccine against both hepatitis A and B)
  • Hib (Haemophilus influenza b) - vaccinate at 2, 4, 6, and 12-15 months (combined vaccine ... DTP + HiB)
  • Poliomyelitis - injectable polio vaccine (IPV) at 2, 4 and 6-18 months; boost at 4-6 years (the oral polio vaccine (OPV) is no longer recommended in the US because it causes the very small number of cases (~4 cases from 1997-1998) of polio in this country
  • MMR (measles, mumps, rubella) - vaccinate at 12-15 months; boost at 4-6 years of age; if not vaccinated earlier, assess immunity, then vaccinate as needed at11-12 years of age; populations that don't get vaccine have Congenital Rubella Syndrome
  • Varicella (chickenpox) - vaccinate at 12-18 months; if not vaccinated earlier, assess immunity, then vaccinate as needed at 11-12 years of age (or up to 18)
• Other immunizations (vaccinations)
  • Anthrax vaccine is not very effective, which has spurred ongoing attempts to develop a better one
  • Gardasil is a newly-developed human papillomavirus (HPV) vaccine that could prevent up to 70% of cervical cancer and 90% of genital warts in females
  • Influenza vaccines must be developed each year and are administered mainly to people over the age of 65 due to their high risk of dying from this disease or its complications; there has recently been interest in vaccinating children in addition to the "usual" over-65 group
  • Menomune induces immunity against major strains of Neisseria meningitidis, the major cause of meningitis in college-age people; currently recommended for first-year college students, especially those living in dorms
  • Prevnar is a new vaccine that induces immunity against major strains of Streptococcus pneumoniae, the major cause of meningitis in infants; this bacterium currently accounts for ~24 million pediatrician visits every year, because it also accounts for 30-50% of otitis media (middle ear infection) cases; the vaccine will be administered at 2, 4 and 6 months of age
  • Rabies vaccine prevents development of the CNS damage that results from infection with rabies virus that can result from bites of animals (bats, raccoons, and skunks as well as dogs or cats that may have been in contact with these wild animals)
  • RotaTeq is a newly-formulated oral vaccine aimed at preventing diarrheal disease (rotavirus causes at ~55,000 hospital admissions and 20-40 infant deaths each year in the US, and is a major cause of death in developing nations, where it causes >600,000 deaths each year) ... more RotaTeq info
  • Shingles vaccine this newly-developed vaccine prevents onset of shingles, a disease resulting from reactivation of the varicella virus that remains latent after childhood chickenpox
  • Smallpox vaccine, used to eradicate smallpox worldwide in 1977, is no longer used in the US outside of research environments, but is still used in many other countries
  • BioThrax (anthrax vaccine) is used extensively by the US military
  • Typhoid fever vaccine prevents this serious gastrointestinal disease
  • Yellow fever vaccine prevents this serious mosquito-borne hemorrhagic disease that affects the liver and kidneys
• Vaccine controversies
  • Vaccines vs. autism and/or Crohn's disease ... viruses, Thimerosal and/or mercury
  • Do Multiple Vaccines Overwhelm or Weaken the Infant’s Immune System?
    • Yes
    • No