Corynebacterium pseudodiphtheriticum

## *Corynebacterium pseudodiphtheriticum*: Putative probiotic, opportunistic infector, emerging pathogen

Andreas Burkovski\*

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The genus *Corynebacterium* comprises a collection of irregular-formed, rod-shaped or coccoid bacteria. From the 90 species described in 2014, 16 were isolated from different environments such as synthetic surfaces, foodstuff, water and soil, about 50 were initially isolated from humans or human clinical material and 32 appeared to be associated with animals. A few species have been found in humans and animals, implicating a putative zoonotic transmission pathway to humans.1 Within the group of medically relevant corynebacteria only a very limited number of *Corynebacterium* species are potent human pathogens, such as *Corynebacterium diphtheriae*, the etiological agent of diphtheria2,3, while many species are rare causes of infections.

*Corynebacterium pseudodiphtheriticum*, previously designated as *Corynebacterium hofmannii*, is a nonlipophilic, nonfermentive, urease- and nitrate-positive *Corynebacterium* species, which is part of the oropharyngeal bacterial flora.4 As part of the natural microbiota of nares and throat, *C. pseudodiphtheriticum* seems to be able to prevent colonization of epithelia by pathogenic bacteria. Spontaneous elimination of *C. diphtheriae*5 as well as competition with *Staphylococcus aureus* was reported6-9 and based on these observations *C. pseudodiphtheriticum* was discussed as candidate for application as nasal and throat probiotic. In fact, corresponding experiments were carried out with volunteers and showed elimination of *S. aureus* from the nasal cavity.5,6,10

Despite the fact that application of *C. pseudodiphtheriticum* as probiotic has already been tested, the bacterium is associated with opportunistic infections. Based on its natural localization in the oropharyngeal tract, infections of the respiratory tract such as acute and chronic bronchitis, acute exacerbation of bronchiectasis, pneumonia and necrotizing tracheitis were reported.11-17 Together with *Corynebacterium striatum* and *Corynebacterium propinquum*, 2 closely related species, *C. diphtheriticum* forms a group of emerging respiratory pathogens, especially in patients with pre-existing chronic respiratory infections. Corresponding reports include patients with chronic obstructive pulmonary disease (COPD) and cystic fibrosis patients.18,19 As might be expected from the immunosuppressive effects, also HIV-infected patients have a higher risk of *C. pseudodiphtheriticum* infections.20,21

*C. pseudodiphtheriticum* infections are not exclusively restricted to the respiratory tract. Cases of endocarditis, the second most common infection site, urinary tract and wound infections as well as skin ulcer were reported.22-26 Furthermore, keratitis is increasingly observed, with *C. pseudodiphtheriticum* being the major etiological agent of corneal infections by *Corynebacterium* species.27-29

In contrast to closely related species such as *Corynebacterium jeikeium* and *Corynebacterium resistens*, which are often multi-resistant to a wide variety of antibiotics and are consequently difficult to combat, penicillin treatment - alone or in combination with aminoglycosides - is successful in most cases.15,21,22 Nevertheless, antibiotic susceptibility profiling of *C. pseudodiphtheriticum* isolates showed that resistance to oxacillin, erythromycin and clindamycin as well as macrolides seems to be common and previous antibiotics treatment of patients even seems to favor colonization by *C. pseudodiphtheriticum*.18,21,26,30

As reviewed above, *C. pseudodiphtheriticum* has obviously a significant harmful potential as nosocomial, emerging pathogen. Unfortunately, little is known about virulence factors and pathogenesis of this bacterium to date. As a first step toward a better understanding of the host-pathogen interaction process, the colonization of epithelial cells was investigated.31 *C. pseudodiphtheriticum* showed an aggregative adherence pattern and was able to invade HEp-2 epithelial cells. Intracellular survial was observed for 24 h post-infection for some strains, which might be a mechanism to avoid the innate immune system. In invasive *C. pseudodiphtheriticum* strains biofilm formation as well as fibrinogen and fibronectin binding was observed.32 As indicated by a recent genome sequencing project, binding of *C. pseudodiphtheriticum* might be facilitated by fimbrial subunits. In frame of this project, also genes encoding antibiotic resistance determinants, arsenate and heavy metal detoxification systems and a putative hemolysin were annotated.5

Data of the host response to *C. pseudodiphtheriticum* infection were completely lacking until now and are reported for the first time in this issue of *Virulence* by Roy et al.29 In human corneal epithelial cells increased expression of Toll-like receptors, IL-6 and IL-β as well as activation of NFκB and MAPK signaling pathways was observed. Obviously, the innate immune system is activated to combat the pathogen and as response, a mixture of different antimicrobial peptides is synthesized in corneal ulcers caused by *C. pseudodiphtheriticum*.29 In healthy persons, part of this response discovered in corneal epithelia might be responsible also in other tissues to balance the detrimental effects of *C. pseudodiphtheriticum* and restrict the bacterium to a commensal life style.

In summary, the interesting switch between commensalism and pathogenicity, the progressively increasing multi-antibiotics resistance and the high mortality in compromised hosts make *C. pseudodiphtheriticum* - as other understated *Corynebacterium* species - an interesting target for future basic medical research.

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### Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

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