Bacterial colonizer vs. pathogen.
Recent studies have uncovered several molecular reasons for the pathogen vs. colonizer dichotomy:
* Strains within a species can have variants of a gene that make them more disease producing.
* Some usually colonizing strains produce disease after acquiring new genes.
* Some strains have native genes with on-off switches that convert them from colonizing to disease producing under selected circumstances.
* Molecular targets in the respiratory tract increase, allowing more dense colonization that increases chances of AOM.
J.R. Gilsdorf, MD, and his group (1) at the University of Michigan, Ann Arbor, recently showed that, among the various high-molecular-weight molecules (HMW) produced by 170 ntHi from three different geographically diverse countries, one variant in particular (HMW-A) was more likely to be found in strains producing AOM than strains simply colonizing the nasopharynx. The protein product of this gene allows better adherence to respiratory epithelia. So more bacteria sticking in the NP near the eustachian tube opening make development of AOM more likely. Some call this the "more barbarians at the gate" phenomenon.
SPN inherently has a somewhat incomplete arginine synthesis pathway. Because arginine is essential for growth of SPN, S. pneumoniae utilizes some host factors to compensate; but this compensation is inefficient. However, SPN strains can acquire new genes --usually from other gram-positive organisms in their environment--by a process called conjugation.
One recently reported acquired gene set is that which completes functionality of SPN's arginine synthesis pathway. (2) Investigators showed that SPN that acquire these arginine synthesis genes replicate more readily in bodily fluids, such as serum or cerebrospinal fluid, making these strains more aggressive, more virulent, and more likely to produce disease. More efficient replication makes it very difficult for host immune responses to handle these SPN.
On-off gene switches
Another group of investigators reported that a thing called "phasevarion," which is fancy lingo for an on-off switch is at the root of more virulence in ntHi. (3) It seems that some strains of ntHi have a version of the ModA2 gene, which is always turned off, while other strains have a gene that is always on. Then, there is a third version in which the gene is usually off, but turns on when in places like the middle ear. The ModA2 gene appears to affect several other downstream protein groups that include HMW-A, antibiotic susceptibility, and biofilm formation. When inoculated into the middle ear in a chinchilla AOM model, the ntHi strains that can turn on their ModA2 gene were much more likely to produce AOM than either version that could not change. Interestingly, the authors postulate that preventing the switch capability could be a novel way to prevent ntHi disease, such as pediatric AOM, acute bacterial sinusitis, or some bronchitis in adults.
Molecular environment becomes more favorable
Another group (4) reported that adherence receptor for ntHi is intercellular adhesion molecule 1 (ICAM1), a molecule found in modest quantities on respiratory epithelium. What makes this interesting is that adenovirus, respiratory syncytial virus, and exposure to cigarette smoke (5) markedly increase expression of ICAM1 on respiratory epithelium, predisposing to more ntHi adhering and more likely to produce an inflammatory process, such as AOM. This is another version of the barbarians at the gate phenomenon. I hope you found these explanations helpful.
COMMENTARY BY DR. PICHICHERO
> Each of the mechanisms used by bacteria to become pathogenic described by Dr. Harrison in this article have a sound scientific basis to explain, in part, why many children are colonized in their nasopharynx with potential respiratory bacteria, but few actually go on to experience disease. Not mentioned but equally important is the host factor of immunity and the resident microbiome of each child.
(1.) Infect Genet Evol. 2014 Dec;28:223-32
(2.) J Infect Dis. 2014 Jun 1;209:1781-91.
(3.) J Infect Dis. 2016 Jun 10. pii: jiw243.
(4.) Cell Microbiol. 2016 Feb 9. doi: 10.1111/cmi.12575.
(5.) Am J Respir Cell Mol Biol. 2003 Oct;29:472-82.
BY CHRISTOPHER J. HARRISON, MD
Dr. Harrison is professor of pediatrics and pediatric infectious diseases at Children's Mercy Hospitals and Clinics, Kansas City, Mo. He said he had no relevant financial disclosures.
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|Author:||Harrison, Christopher J.|
|Date:||Sep 1, 2017|
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