Review Article | Published:

The damage-response framework of microbial pathogenesis

Nature Reviews Microbiologyvolume 1pages1724 (2003) | Download Citation



The late twentieth century witnessed the emergence of numerous infectious diseases that are caused by microorganisms that rarely cause disease in normal, healthy immunocompetent hosts. The emergence of these diseases shows that the existing concepts of pathogenicity and virulence do not take into account the fact that both the microorganism and the host contribute to microbial pathogenesis. To address this impediment to studies of host–microorganism interactions, we propose a new theoretical approach to understanding microbial pathogenesis, known as the 'damage-response' framework.

Key Points

  • Existing definitions of microbial pathogenicity and virulence are inadequate to explain many infectious diseases and do not incorporate the contribution of the host to these processes. A new theoretical approach to understanding microbial pathogenesis — the damage-response framework – is proposed.

  • The damage-response framework differs from other views of microbial pathogenesis as it is neither microorganism-centred nor host-centred. Instead, the damage-response framework is based on the fact that microbial pathogenesis is the outcome of an interaction between a host and a microorganism, and uses host damage as a common principle that incorporates the role of both the host and the microorganism.

  • The host-immune response can augment or delimit the nature and amount of host damage resulting from a host–microorganism interaction. Therefore, in the damage-response framework, pathogens are classified by the amount, or degree, of host damage that results from host–microorganism interactions as a function of the host-immune response. Six different classes are proposed, and are depicted in parabolic damage-response curves that represent the amount of host damage as a function of the intensity and degree of the host response.

  • The amount or degree of host damage that results from the host–microorganism interaction as a function of time can be used to define and characterize the outcome of infection as the states of commensalism, colonization, latency or disease.

  • The damage-response framework is based on clinical and experimental observations of the outcome of host–microorganism interactions. Its associated classifications and predictions can be subjected to further experimental studies to validate or refute its ability to account for the contributions of both host and microorganism to microbial pathogenesis.

  • The damage-response framework of microbial pathogenesis could assist in the design of vaccines and immunotherapies and in the characterization of new infectious diseases. Its simplified classification system is a useful educational tool. Additionally, use of the damage-response framework could foster collaboration between investigators in different, and at present separate, areas of microbial pathogenesis research.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1

    Casadevall, A. & Pirofski, L. Host–pathogen interactions: redefining the basic concepts of virulence and pathogenicity. Infect. Immun. 67, 3703–3713 (1999). Introduces the 'damage-response' framework and proposes a new classification for pathogens based on their ability to damage the host as a function of the host response.

  2. 2

    Casadevall, A. & Pirofski, L. Host–pathogen interactions: the basic concepts of microbial commensalism, colonization, infection, and disease. Infect. Immun. 68, 6511–6518 (2000). Expands the 'damage-response' framework to incorporate the variable of time and proposes that the outcome of the host–microorganism interaction can be reduced to four states that differ in the amount of damage incurred by the host as a function of time.

  3. 3

    Casadevall, A. & Pirofski, L. A. What is a pathogen? Ann. Med. 34, 2–4 (2002).

  4. 4

    Casadevall, A. & Pirofski, L. Host–pathogen interactions: the attributes of virulence. J. Infect. Dis. 184, 337–344 (2001). Discusses limitations of the existing concepts of virulence and problems with definitions of virulence factors.

  5. 5

    Pirofski, L. & Casadevall, A. The meaning of microbial exposure, infection, colonisation, and disease in clinical practice. Lancet Infect. Dis. 2, 628 (2002). Highlights how the damage-response framework can be used to classify the host–microorganism interaction in clinical practice.

  6. 6

    Casadevall, A. & Pirofski, L. On the definition of virulence. ASM News 69, 217 (2003).

  7. 7

    Margulis, L. The origin of plant and animal cells. Am. Sci. 59, 230–235 (1971).

  8. 8

    Margulis, L. Symbiosis and evolution. Sci. Am. 225, 48–57 (1971).

  9. 9

    King, C. L. in Principles and Practice of Infectious Diseases (eds Mandel, G.L., Bennett, J.E. & Dolin, R.) 2956–2965 (Churchill Livingston, New York, 2003).

  10. 10

    Swanson, M. S. & Hammer, B. K. Legionella pneumophila pathogenesis: a fateful journey from amoebae to macrophages. Annu. Rev. Microbiol. 54, 567–613 (2000).

  11. 11

    Steenbergen, J. N., Shuman, H. A., & Casadevall, A. Cryptococcus neoformans interactions with amoebae suggest an explanation for its virulence and intracellular pathogenic strategy in macrophages. Proc. Natl Acad. Sci. USA 18, 15245–15250 (2001).

  12. 12

    Finlay, B. B. & Falkow, S. Common themes in microbial pathogenicity revisited. Microbiol. Mol. Biol. Rev. 61, 136–169 (1997). Classic paper in the field that focuses on the contributions of microorganisms to the process of microbial pathogenesis.

  13. 13

    Hacker, J., Blum–Oehler, G., Mühldorfer, I. & Tschäpe, H. Pathogenicity islands of virulent bacteria: structure, function and impact on microbial evolution. Mol. Microbiol. 23, 1089–1097 (1997).

  14. 14

    Falkow, S. Molecular Koch's postulates applied to microbial pathogenicity. Rev. Infect. Dis. 10, S274–S276 (1988). Landmark paper that proposed a rigorous approach to establishing whether a gene was involved in microbial virulence.

  15. 15

    von Graevenitz, A. The role of opportunistic bacteria in human disease. Annu. Rev. Microbiol. 31, 447–471 (1977).

  16. 16

    Armstrong, D. History of opportunistic infection in the immunocompromised host. Clin. Infect. Dis. 17, S318–S321 (1993). An informative story of how the concept of microbial opportunism evolved in clinical practice.

  17. 17

    Isenberg, H. D. Pathogenicity and virulence: another view. Clin. Microbiol. Rev. 1, 40–53 (1988). An excellent discussion of the limitations of Koch's postulates. This paper emphasizes the crucial role of the host in the process of microbial pathogenesis.

  18. 18

    Casadevall, A. & Pirofski, L. Exploiting the redundancy of the immune system: vaccines can mediate protection by eliciting 'unnatural' immunity. J. Exp. Med. 197, 1401–1404 (2003).

  19. 19

    Edman, J. C. et al. Ribosomal RNA shows Pneumocystis carinii to be a member of the fungi. Nature 334, 519–522 (1988).

  20. 20

    Jawetz, E. Antimicrobial therapy. Annu. Rev. Microbiol. 10, 85–114 (1956).

  21. 21

    Hawkey, P. M., Bhagani, S. & Gillespie, S. H. Severe acute respiratory syndrome (SARS): breath-taking progress. J. Med. Microbiol. 52, 609–613 (2003).

  22. 22

    Eschette, M. L. & West, B. C. Saccharomyces cerevisiae bacteremia. Arch. Intern. Med. 140, 11539 (1980).

  23. 23

    Wheeler, R. T., Kupiec, M., Magnelli, P., Abeijon, C. & Fink, G. R. A Saccharomyces cerevisiae mutant with increased virulence. Proc. Natl Acad. Sci. USA 100, 2766–2770 (2003).

  24. 24

    Berdoy, M., Webster, J. P. & MacDonald, D. W. Parasite-altered behaviour: is the effect of Toxoplasma gondii on Rattus norvegicus specific? Parasitology 111, 403–409 (1995).

  25. 25

    Romani, L., Bistoni, F., & Pucetti, P. Fungi, dendritic cells and receptors: a host perspective of fungal virulence. Trends Microbiol. 10, 508–514 (2002).

  26. 26

    Ben–Nathan, D. et al. Prophylactic and therapeutic efficacy of human intravenous immunoglobulin in treating west nile virus infection in mice. J. Infect. Dis. 188, 5–12 (2003).

  27. 27

    Loffeld, R. J. et al. Colonization with cagA-positive Helicobacter pylori strains inversely associated with reflux esophagitis and Barrett's esophagus. Digestion 62, 95–99 (2000).

Download references

Author information


  1. Departments of Medicine (Division of Infectious Diseases) and Microbiology & Immunology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, 10461, New York, USA

    • Arturo Casadevall
    •  & Liise-anne Pirofski


  1. Search for Arturo Casadevall in:

  2. Search for Liise-anne Pirofski in:

Corresponding author

Correspondence to Arturo Casadevall.

Related links



An entity in which microorganisms reside and/or replicate; an entity in which microbial pathogenesis occurs.


Disruptions in the normal homeostatic mechanisms of a host that alter the functioning of cells, tissues or organs; for microorganisms, disruptions in the normal mechanisms that enable host entry, replication and/or the ability to establish residence in a host.


A state of infection whereby both the host and the microorganism benefit.


A state of host–microorganism interaction that does not result in host damage after the state is initiated.


A clinical outcome of host damage that occurs after a threshold amount of damage has occurred.


The acquisition of a microorganism by a host.


The relative capacity of a microorganism to cause damage in a host.


A microorganism that has the capacity to cause damage in a host.


A state of host–microorganism interaction that leads to a variable amount of host damage, from minimal to great, thereby reflecting host immune responses that have the capacity to eliminate the microorganism or to promote the development of another state.


A state of host–microorganism interaction in which a microorganism persists in a host and can be associated with damage that can be evident at the cellular or tissue level, but is not associated with disease.


A microbial component that can damage a host.

About this article

Publication history

Issue Date


Further reading