Emerging Infectious Determinants of Chronic Diseases

Siobhán M. O'Connor; Christopher E. Taylor; James M. Hughes

Disclosures

Emerging Infectious Diseases. 2006;12(7):1051-1057. 

In This Article

Range of Pathways

Directly or indirectly, infectious agents produce long-term outcomes through pathways that include acute infection, persistent active infection, persistent nonreplicating (latent) infection, immune response to an infectious agent that may not commonly be pathogenic, and malignant transformation. Direct tissue damage or genomic integration explain certain chronic sequelae, but an inflammatory immune response—one of the body's primary means to protect against infection—defines multiple established infectious causes of chronic diseases, including some cancers[1,5,7,14,15,17,21,23,28,29] (http://www.cdc.gov/ncidod/diseases/hepatitis). Inflammation also drives many chronic conditions that are still classified as (noninfectious) autoimmune or immune-mediated (e.g., systemic lupus erythematosus, rheumatoid arthritis, Crohn disease).[33,34,35,38,40,41] Both innate and adaptive immunity play critical roles in the pathogenesis of these inflammatory syndromes.[34,35] Therefore, inflammation is a clear potential link between infectious agents and chronic diseases. Aberrant cellular and humoral responses to infections could launch the continuum from infection to long-term sequelae, consistent with the proposed damage-response framework[6]

Biofilms, or microbial communities that behave like biofilms, also represent potential, unrecognized stages in the pathways from infectious agent exposure to chronic disease. In both situations, cultures and even PCR results can be negative. For example, tympanic fluid cultures from animal models of chronic Hamophilus influenzae otitis media, associated with biofilms, are frequently negative;[45] uropathogenic Escherichia coli can invade bladder epithelial cells to establish intracellular communities that behave like biofilms, evade immune surveillance, and produce sterile urine cultures.[46] Similarly, imbalances within communities of normal gut flora or between commensals and pathogens residing in the gut are proposed to produce or exacerbate chronic syndromes such as Crohn disease.[35,36,37] These observations suggest that novel and already characterized infectious agents are likely to determine a substantially greater—and potentially preventable—portion of chronic disease than yet realized. If so, upstream (earlier) primary and secondary prevention of infection will become opportunities to avoid irreversible or severe chronic disease across large populations.

Frequently, the opportunity to identify new infectious determinants of chronic diseases may lie in the study of complex systems. Chronic diseases are often multifactorial, with established noninfectious risk factors. Yet infection actually defines more than a few of these conditions (e.g., cervical cancer, reactive arthritis). In such settings, complex systems, interactions between human, microbe, and the environment, tempered by time, determine microbial exposure, human infection, and the development of chronic sequelae (Figure 3). Simulating the balance, flux, and networks of multicomponent systems biology, many factors can converge to produce chronic disease, among them genetic susceptibility to infection or to adverse chronic outcome, duration of infection, co-infections, microbial factors, host microbial communities, age, micronutrient status, sex hormones, behavior-dependent exposures such as smoking and diet, chemical exposures, zoonoses, and the strength of an exposed person's immune response to an infectious agent(s)[1,14,15,17,21,24,25,47,48,49] (http://www.cdc.gov/ncidod/diseases/hepatitis). Human migration or travel, human-human interactions, evolving economies, political change, education, new medical interventions, changes in climate and ecology, and other factors further influence these complex systems.

Figure 3.

Complex systems framework, showing interaction of multiple factors leading to chronic sequelae of infections.

Also diverging from the usual perceptions of causality, some hypotheses propose that infections may actually protect against certain chronic conditions; some microbial exposures may be critical to normal human immune development. Perhaps reduced or delayed exposure(s) to an infectious agent(s), or alterations in the balance of normal flora, increase a person's susceptibility to inflammatory conditions like asthma and Crohn disease.[37,50]

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