Microevolution in response to transient heme-iron restriction enhances intracellular bacterial community development and persistence

Abstract

Bacterial pathogens must sense, respond and adapt to a myriad of dynamic microenvironmental stressors to survive. Adaptation is key for colonization and long-term ability to endure fluctuations in nutrient availability and inflammatory processes. We hypothesize that strains adapted to survive nutrient deprivation are more adept for colonization and establishment of chronic infection. In this study, we detected microevolution in response to transient nutrient limitation through mutation of icc. The mutation results in decreased 3',5'-cyclic adenosine monophosphate phosphodiesterase activity in nontypeable Haemophilus influenzae (NTHI). In a preclinical model of NTHI-induced otitis media (OM), we observed a significant decrease in the recovery of effusion from ears infected with the icc mutant strain. Clinically, resolution of OM coincides with the clearance of middle ear fluid. In contrast to this clinical paradigm, we observed that the icc mutant strain formed significantly more intracellular bacterial communities (IBCs) than the parental strain early during experimental OM. Although the number of IBCs formed by the parental strain was low at early stages of OM, we observed a significant increase at later stages that coincided with absence of recoverable effusion, suggesting the presence of a mucosal reservoir following resolution of clinical disease. These data provide the first insight into NTHI microevolution during nutritional limitation and provide the first demonstration of IBCs in a preclinical model of chronic OM.

Heme Uptake and Utilization by Gram-Negative Bacterial Pathogens

“…The focus of this review is the use of heme as an alternative iron source for these pathogens. The use of heme as an iron source is beneficial for several reasons, including: (i) it is the most abundant source of iron within the host environment; (ii) not all organisms are able to use every form of iron acquisition mentioned above, e.g., C. jejuni is unable to produce its own siderophores (Naikare et al, 2013); (iii) the use of heme allows the pathogen to acquire iron while the host attempts to restrict it; and (iv) some Gram-negative pathogens, termed heme auxotrophs, lack the ability to synthesize heme and must acquire it for their own cellular processes from the environment, e.g., Haemophilus influenzae (Choby and Skaar, 2016; Zambolin et al, 2016; Hardison et al, 2018). For these reasons, it is important to understand how heme acquisition systems work in Gram-negative pathogens.…”

<p>COPD-Related Modification to the Airway Epithelium Permits Intracellular Residence of Nontypeable <em>Haemophilus influenzae</em> and May Be Potentiated by Macrolide Arrest of Autophagy</p>

“…Clustering depicted in Figure 2G is also suggestive of cell division, and aligns with the observation of an intracellular bacterial community that was recently applied to NTHi in a clinical model of otitis media. 24 Interestingly, their close proximity to the transwell membrane ( Figure 2F and G) suggests a mode of propagation from the apical to the basal progenitor cell population, which differentiate to generate the three-dimensional epithelial architecture that defines the ALI culture model. Given basal AEC remain viable for an extended period, the ability to traverse the epithelial compartment may partly explain the clinical persistence of NTHi within the COPD airways, whereby exacerbating factors lead to epithelial fragility and senescence that allows a reservoir of NTHi to express virulence factors after a period of host-cell adaption.…”

Archaea Symbiont of T. cruzi Infection May Explain Heart Failure in Chagas Disease

“…The microbial community is considered as having decisive in determining health and disease susceptibility, usually in the gut (Hardison et al, 2017 ; Manrique et al, 2017 ).…”