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From Transient Infection to Chronic Disease

An infection is considered to be resolved when the causative microbe has been cleared and host structure and function return to normal—except, perhaps, for a scar in the affected tissue. In a recent study, da Fonseca et al.(1) argue that some resolved infections leave scars of another sort—longlasting immune dysfunction. The authors propose that "immunologic scarring" by resolved infections may account for a wide range of chronic diseases.

 

Paving the way to this concept are chronic diseases whose origin had been mysterious for decades, until an ongoing bacterial infection was identified as causal, such as gastric and duodenal ulcers caused by Helicobacter pylori. However, inflammatory bowel disease, rheumatoid arthritis, sarcoidosis, and other inflammatory or autoimmune diseases remain unexplained despite searches for a specific infectious cause(2). Da Fonseca et al. propose that a long-gone infection may set the stage for chronic disease by impairing the immune system's checks and balances. They base this proposal on the observation that most of the mice that had cleared a gastrointestinal tract infection by Yersinia pseudotuberculosis within 3 weeks had persistently leaky lymphatic vessels draining the intestine and persistently enlarged, inflamed lymph glands in the mesentery (a broad membrane in the abdomen). These changes lasted up to 42 weeks (the last period examined), which is roughly equivalent to 28 years of a human life span. Specific populations of immune response–guiding cells called dendritic cells were missing from the mesenteric lymph glands and appeared instead in the mesenteric adipose tissue. The adipose tissue accumulated other immune cells as well, and produced inflammatory cytokines such as tumor necrosis factor and interleukin-1, much like visceral adipose tissue in obese individuals. In obesity, inflammation in visceral adipose tissue has deleterious effects on distant tissues(3), and a similar effect may have contributed to the immune dysfunction observed by da Fonseca et al.: The mice that recovered from Yersinia infection developed an immune response to a new protein in their food instead of becoming tolerant to it, and they responded feebly to vaccination. Thus, the complex regulatory balance between the immune system and the gastrointestinal microbiota that sustains health was apparently converted by a brief, resolved infection into a state of chronic disease marked by altered structure and function of mesenteric lymph vessels, lymph glands, and adipose tissue.

These observations add to earlier evidence of long-standing immunologic dysfunction and chronic disease following a resolved infection. Infected mice cleared a viral infection, but went on to develop an asthma-like disease(4) mediated by sustained activity of natural killer T cells driving macrophages to produce interleukin-13(5).


An infection is considered to be resolved when the causative microbe has been cleared and host structure and function return to normal—except, perhaps, for a scar in the affected tissue. In a recent study, da Fonseca et al. argue that some resolved infections leave scars of another sort—longlasting immune dysfunction. The authors propose that "immunologic scarring" by resolved infections may account for a wide range of chronic diseases.

Bacterial pathogenicity.
In the classic view, bacteria were classified as pathogenic or nonpathogenic, according to their inherent properties. In a contemporary view, bacteria that are usually nonpathogenic can become pathogenic depending on their biological context.
ILLUSTRATION: P. HUEY/SCIENCE


Although the concept proposed by da Fonseca et al. is established, the post-Yersinia disorder they describe may actually illustrate a different phenomenon: context-dependent pathogenicity. Medical microbiologists used to consider pathogenicity as an inherent property of some but not other bacterial species (see the figure). However, it is now recognized that some bacterial species that are usually nonpathogenic may cause disease when the host becomes immune-deficient or when the bacteria occupy a new location in the host, acquire virulence factors through infection by a plasmid, and/or face a sudden lack of competition from their usual microbial neighbors.

What raises the issue of context-dependent pathogenicity in the study of da Fonseca et al. is their observation of persistent, suppurative infection of the mesenteric lymph glands by bacteria other than Yersinia, chiefly lactobacilli. Lactobacilli are usually thought of as beneficial—people swallow them as probiotics. Yet the long-lasting immune dysfunction observed by da Fonseca et al. came to a halt when mice were treated with antibiotics, and was prevented by using germ-free mice for the Yersinia infection. The authors did not attribute the immune dysfunction to the chronic lactobacillus infection because they could reproduce some of the immune dysfunction in antibiotic-treated mice by feeding them nonviable microbial products. However, in mice not treated with antibiotics, the invasive lactobacilli could well have been the functionally relevant source of microbial products that sustained the immune dysfunction. The failure to eliminate the lactobacilli from the lymph glands despite extensive infiltration by neutrophils—the body's most powerful bacteria-killing cells—suggests that the lactobacilli may have acquired some of the immune-evading, -suppressing or -resisting hallmarks of pathogens. Thus, the persistent immune dysfunction observed by da Fonseca et al. may indicate that acute infection by a known pathogen can create a context for an otherwise innocuous microbe to become a chronic pathogen.

Whatever the explanation, the observations of da Fonseca et al. are likely to breathe new life into the search for infectious provocateurs of chronic immune and inflammatory disorders, whether the trigger is a transient infection by a known pathogen or a cryptic, chronic infection by a microbe that is usually nonpathogenic.

References

  1. D. M. da Fonseca et al., Cell 10.1016/j.cell.2015.08.030 (2015). doi:10.1016/j.cell.2015.08.030
  2. C. Nathan, A. Ding, Cell 140, 871 (2010).
  3. C. Nathan, Mol. Med. 14, 485 (2008).
  4. M. J. Walter et al., J. Clin. Invest. 110, 165 (2002).
  5. E. Y. Kim et al., Nat. Med. 14, 633 (2008).

 

Source: Carl Nathan, Science

 

 

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