Conclusion

Infectious agents are extremely diverse and highly robust. These mostly free-living organisms have several advantages over their human hosts: much more evolutionary time, a shorter time between generations, and remarkable plasticity. As their hosts, we have our own assets, like a highly evolved immune system, including both innate and adaptive elements that have been tailored by their interactions with these infectious agents, both friend and foe. Humans also have, arguably, an intellectual and technical advantage, which we have used to great effect to fight back: first in primitive but effective ways and more recently in the form of antibiotics and vaccines, which now save many lives, especially the lives of young children. However, emerging and, to some degree, re-emerging infectious diseases will probably always be an issue. Some re-emergence of infectious disease is controllable; less encroachment on animal habitats, efforts to reduce or reverse global warming, and improvement of sanitation should all make a dent in this. Finally, the recent spread of Ebola to other continents should serve as a warning; attention to the needs of those who suffer the greatest from poverty and increasing global inequities is a problem for all, and one that no wall will contain.

REFERENCES

Useful Websites

https://www.niaid.nih.gov The National Institute of Allergy and Infectious Diseases is the institute within the National Institutes of Health that sponsors research in infectious diseases, and its website provides a number of links to other relevant sites.

www.who.int This is the home page of the World Health Organization, the international organization that monitors infectious diseases worldwide.

https://www.cdc.gov The Centers for Disease Control and Prevention (CDC) is a U.S. government agency that tracks infectious disease outbreaks and vaccine research in the United States.

www.upmchealthsecurity.org The Johns Hopkins Bloomberg School of Public Health Center for Health Security website providing information about select agents and emerging diseases that may pose a biosafety or health security threat.

www.gavi.org The Global Alliance for Vaccines and Immunization (GAVI) is a source of information about vaccines in developing countries and worldwide efforts at disease eradication. This site contains links to major international vaccine information sites.

www.ecbt.org Every Child by Two offers useful information on childhood vaccination, including recommended immunization schedules.

STUDY QUESTIONS

  1. Describe the nonspecific defenses that operate when a disease-producing microorganism first enters the body.
  2. Describe specific immune defense mechanisms, both innate and adaptive, that the immune response focuses on when combating each of the major types of pathogens (viruses, bacteria, fungi, and parasites).
  3. Explain the phenomenon of herd immunity. How does it relate to the appearance of certain epidemics?
  4. What is the role of the humoral response in protection from influenza?
  5. Describe the unique mechanisms each of the following pathogens has for escaping the immune response: (a) African trypanosomes and (b) influenza virus.
  6. Michael F. Good and co-workers analyzed the effect of MHC haplotype on the antibody response to a key malarial surface protein, the circumsporozoite (CS) peptide antigen, in several recombinant congenic mouse strains. Their results are shown in the following table:
    Strain H2 alleles Antibody response to CS peptide
    K A E S D
    B10.BR k k k k k <1
    B10.A (4R) k k b b b <1
    B10.HTT s s k k d <1
    B10.A (5R) b b k d d 67
    B10 b b b b b 73
    B10.MBR b k k k q <1
    1. Based on the results of this study, which MHC molecule(s) are best at presenting this peptide antigen (i.e., which demonstrate MHC restriction)?
    2. Since antigen recognition by B cells is not MHC restricted, why is the humoral antibody response influenced by the MHC haplotype?
  7. Fill in the blanks in the following statements.
    1. The current vaccine for tuberculosis consists of an attenuated strain of M. bovis called .
    2. Variation in influenza surface proteins is generated by and .
    3. Variation in pilin, which is expressed by many gram-negative bacteria, is generated by the process of .
    4. The mycobacteria causing tuberculosis are walled off in granulomatous lesions called , which contain a small number of and many .
    5. The diphtheria vaccine is a formaldehyde-treated preparation of the exotoxin, called a .
    6. A major contribution to nonspecific host defense against viruses is provided by and .
    7. The primary host defense against viral and bacterial attachment to epithelial surfaces is .
    8. Two cytokines of particular importance in the response to infection with M. tuberculosis are , which stimulates development of TH1 cells, and , which promotes activation of macrophages.
  8. Despite the fact that there are no licensed vaccines for them, life-threatening fungal infections are not a problem for the general population. Why? Who may be at greatest risk for these types of infection?
  9. Discuss the factors that contribute to the emergence of new pathogens or the re-emergence of pathogens previously thought to be controlled in human populations.
  10. Which of the following are strategies used by pathogens to evade the immune system? Give a specific example when possible.
    1. Changing the antigens expressed on their surfaces
    2. Going dormant in host cells
    3. Secreting proteases to inactivate antibodies
    4. Having low virulence
    5. Developing resistance to complement-mediated lysis
    6. Allowing point mutations in surface epitopes, resulting in antigenic drift
    7. Increasing phagocytic activity of macrophages
  11. Which of the following is a characteristic of the inflammatory response against extracellular bacterial infections?
    1. Increased levels of IgE
    2. Activation of self-reactive CD8+ T cells
    3. Activation of complement
    4. Swelling caused by release of vasodilators
    5. Degranulation of tissue mast cells
    6. Phagocytosis by macrophages
  12. Your mother may have scolded you for running around outside without shoes. This is sound advice because of the mode of transmission of the helminth Schistosoma mansoni, the causative agent of schistosomiasis.
    1. If you disobeyed your mother and contracted this parasite, what cells of your immune system would fight the infection?
    2. If your doctor administered a cytokine to drive the immune response, which would be a good choice, and how would this supplement alter maturation of plasma cells to produce a more helpful class of antibody?
  13. Usually, the influenza virus changes its structure very slightly from one year to the next. However, although we are being exposed to these “modified” influenza strains every year, we do not always come down with the flu, even when the virus successfully breaches physical barriers. However, some years we do get a really bad case of the flu, despite the fact that we presumably have memory cells left from an earlier primary response to influenza (via vaccine or natural acquisition). Aside from higher doses of virus and the possibility of a particularly pathogenic strain, why is it that some years we get very sick and other years we do not? For example, I might get a bad case of the flu while you experience no disease, and yet we are both being exposed to the exact same virus strain that year. What is happening here? You can assume that you are not receiving the yearly influenza vaccine.
  14. Indicate whether each of the following statements is true or false. If you think a statement is false, explain why.
    1. Transplacental transfer of maternal IgG antibodies against measles confers short-term immunity on the fetus.
    2. Attenuated vaccines are more likely to induce cell-mediated immunity than killed vaccines are.
    3. One disadvantage of DNA vaccines is that they don’t generate significant immunologic memory.
    4. Macromolecules generally contain a large number of potential epitopes.
    5. A DNA vaccine only induces a response to a single epitope.
  15. What are the advantages and disadvantages of using live attenuated organisms as vaccines?
  16. A young girl who had never been immunized to tetanus stepped on a rusty nail and got a deep puncture wound. The doctor cleaned out the wound and gave the child an injection of tetanus antitoxin.
    1. Why was antitoxin given instead the tetanus vaccine?
    2. If the girl receives no further treatment and steps on a rusty nail again 3 years later, will she be immune to tetanus?
  17. What are the advantages of the Sabin polio vaccine compared with the Salk vaccine? Why is the Sabin vaccine no longer recommended for use in the United States?
  18. Why doesn’t the live attenuated influenza vaccine (FluMist) cause respiratory infection and disease?
  19. In an attempt to develop a synthetic peptide vaccine, you have analyzed the amino acid sequence of a protein antigen for (a) hydrophobic peptides and (b) strongly hydrophilic peptides. How might peptides of each type be used as a vaccine to induce different immune responses?
  20. You have identified a bacterial protein antigen that confers protective immunity to a pathogenic bacterium and have cloned the gene that encodes it. The choices are either to express the protein in yeast and use this recombinant protein as a vaccine or to use the gene for the protein to prepare a DNA vaccine. Which approach would you take and why?
  21. Explain the relationship between the incubation period of a pathogen and the vaccine approach and correlates to immune protection that are required.
  22. List the three types of purified macromolecules that are currently used as vaccines.
  23. Some parents choose not to vaccinate their infants. Reasons include religion, allergic reactions, fear that the infant will develop the disease the vaccine is raised against, and, recently, a fear, unsupported by research, that vaccines can cause autism. What would be the consequence if a significant proportion of the population was not vaccinated against childhood diseases such as measles or pertussis?
  24. For each of the following diseases or conditions, indicate what type of vaccination is used:
    1. Polio
    2. Chickenpox
    3. Tetanus
    4. Hepatitis B
    5. Cholera
    6. Measles
    7. Mumps
    1. Inactivated
    2. Attenuated
    3. Inactivated exotoxin
    4. Purified macromolecule
  25. While on a backpacking trip you are bitten by a poisonous snake. The medevac comes to airlift you to the nearest hospital, where you receive human immunoglobulin treatment (gammaglobulin or antiserum) against the poisonous snake venom. You recover from your snakebite and return home for some TLC. One year later, during an environmental studies field trip, you are bitten once again by the same type of snake. Please answer the following questions:
    1. Since you fully recovered from the first snakebite, are you protected from the effects of the poison this second time (i.e., did you develop adaptive immunity)?
    2. Immunologically, what occurred the first time you were bitten and treated for the bite?
    3. Compared with the first snakebite, are you more sensitive, less sensitive, or equally sensitive to the venom from the second bite?

CLINICAL FOCUS QUESTION

  1. The effect of the MHC on the immune response to peptides of the influenza virus nucleoprotein was studied in H2b mice that had been previously immunized with live influenza virions. The CTL activity of primed lymphocytes was determined by in vitro CML assays using H2k fibroblasts as target cells. The target cells had been transfected with different H2b MHC class I genes and were either infected with live influenza or incubated with nucleoprotein synthetic peptides. The results of these assays are shown in the following table.
    Target cell (H2k fibroblast) Test antigen CTL activity of influenza-primed H2b lymphocytes (% lysis)
    (A) Untransfected Live influenza 0
    (B) Transfected with class I Db Live influenza 60
    (C) Transfected with class I Db Nucleoprotein peptide 365–380 50
    (D) Transfected with class I Db Nucleoprotein peptide 50–63 2
    (E) Transfected with class I Kb Nucleoprotein peptide 365–380 0.5
    (F) Transfected with class I Kb Nucleoprotein peptide 50–63 1
    1. Why was there no killing of the target cells in system A even though the target cells were infected with live influenza?
    2. Why was a CTL response generated to the nucleoprotein in system C, even though it is an internal viral protein?
    3. Why was there a good CTL response in system C to peptide 365–380, whereas there was no response in system D to peptide 50–63?
    4. If you were going to develop a synthetic peptide vaccine for influenza in humans, how would these results obtained in mice influence your design of a vaccine?
  2. A connection between the new pneumococcus vaccine and a relatively rare form of arthritis has been reported. What data would you need to validate this report? How would you proceed to evaluate this possible connection?

ANALYZE THE DATA

Kim and co-workers (Kim, T. W., et al. 2003. Enhancing DNA vaccine potency by combining a strategy to prolong dendritic cell life with intracellular targeting strategies. Journal of Immunology 171:2970) investigated methods to enhance the immune response against human papillomavirus (HPV)-16 E7 antigen. Groups of mice were vaccinated with the following antigens incorporated in DNA vaccine constructs:

A figure shows 9 graphs that depict E7-specific C D 8 plus T-cell response in mice.

(a) Intracellular cytokine staining followed by flow cytometric analysis to determine the E7-specific CD8+ T-cell response in mice vaccinated with DNA vaccines using intracellular targeting strategies. A DNA construct including the anti-apoptosis gene Bcl-xL was coadministered to the group on the right. The number at top right in each graph is the number of cells represented in the top right quadrant.

  • + HPV E7 antigen
  • + E7 + heat-shock protein 70 (HSP70)
  • + E7 + calreticulin
  • + E7 + sorting signal of lysosome-associated membrane protein 1 (Sig/LAMP-1)

A second array of mice received the same DNA vaccines and was coadministered an additional DNA construct incorporating the anti-apoptosis gene Bcl-xL. To test the efficacy of these DNA vaccine constructs in inducing a host response, spleen cells from vaccinated mice were harvested 7 days after injection and the cells were incubated overnight in vitro with MHC class I–restricted E7 peptide (amino acids 49–57), and then the cells were stained for both CD8 and IFN-γ [part (a) of the figure, left]. In another experiment Kim and colleagues determined how effective their vaccines were if mice lacked CD4+ T cells [part (b) of the figure, below.].

  1. Which DNA vaccine(s) is (are) the most effective in inducing an immune response against papillomavirus E7 antigen? Explain your answer.
  2. Propose a hypothesis to explain why expressing calreticulin in the vaccine construct was effective in inducing CD8+ T cells.
  3. Propose a mechanism to explain the data in part (a) of the figure.
  4. If you were told that the +E7 +Sig/LAMP-l construct is the only one that targets antigen to the MHC class II processing pathway, propose a hypothesis to explain why antigen that would target MHC class II molecules enhances a CD8+ T-cell response. Why do you think a special signal was necessary to target antigen to MHC class II?
  5. What four variables contribute to the E7-specific CD8+ T lymphocyte response in vitro as measured in part (b) of the figure?
Two graphs show E7-specific CD8+ T lymphocyte response in wild type mice and C D 4 knockout mice.

(b) E7-specific CD8+ T lymphocyte response in CD4 knockout mice vaccinated with the +E7 +Sig/LAMP-1 DNA construct, with or without the Bcl-xL DNA construct.