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Microbes & Immunity Dynamics between phage, bacteria, and mammalian cells

immunity and/or the subdiffusion characteristic of phages immobilized fibronectin on the host cell surface. Similar
within the mucus layer, increasing the contact between adhesion mechanisms may be applied to the BEAS-2B
the phage and bacteria. 17,18 Shan et al. reported that a bronchial epithelial cells noted in Figure 3C.
non-mucus-producing HT-29 colon cancer cell line could Previous reports 17,18,25 demonstrated that phages with
also promote the antibacterial efficiency of a Clostridium capsid proteins, expressing hypervariable Ig-like domains,
difficile phage phiCDHS1 in an anaerobic culturing could adhere to mucus-producing mammalian cells through
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condition. The BEAS-2B bronchial epithelial cell used in interactions with the mucin glycoproteins. However, the
the present study is also a non-mucus-producing cell line. exact mechanisms governing the attachment of phages
As A. baumannii is an aerobic bacteria, all experiments onto non-mucus-producing cells remain largely unknown.
were performed under aerobic conditions in the present In the study by Shan et al., the adsorption of phages onto
study. Despite the difference in research environment non-mucus-producing cells was found to be phage-specific
(aerobic vs. anaerobic), the results obtained here were and mammalian cell-specific. They reported that ~70% of
in agreement with the findings reported by Shan et al.
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Comparing the three treatment periods (Figure 1), pre- phiCDHS1 phages were bound to HT29 cells, higher than
incubating the epithelial cells with AB406 phages had the adhesions of phiCDHM6 (~40%) and phiCDHM3 (0%)
the most profound effect on enhancing the antibacterial phages. All three phages were not adsorbed onto the Hela
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efficiency. Likewise, adding phages simultaneously with cells. Notably, phage adsorption was determined from the
bacteria or 4 h after bacteria pre-incubation displayed difference between the initial titer and the free phages after
comparable enhancement in the antibacterial efficiency. 8-h incubation with mammalian cells in their study. They
These results suggest that the administration time of phage reported that the phage adsorption rate was within the
therapy would likely affect the therapeutic outcomes with uncertainty level of the plaque assay used to determine the
prophylactic phage administration being most promising. phage titer, possibly leading to over- or under-estimations
of the phage adsorption. As a result, a low level of phage
While bacteria were reported to be able to invade host adsorption might be overlooked. Nonetheless, the low
cells to escape any bactericidal effects , the possibility of the phage adhesion level was sufficient to enhance the overall
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noted enhanced antibacterial efficiency in Figures 1 and 2 antibacterial efficiency, possibly due to the close proximity
due to the internalization of bacteria within the epithelial between the phages and host bacteria adhered to the
cells was minor because the bacteria count was below the epithelial cells, facilitating the replication of phages. This
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detection limit (Figure 3B). We hypothesize that increasing finding could explain the higher number of phages (2 log
the adsorption of bacteria and phages onto the BEAS-2B enhancement compared with the bacteria-free system)
cell surface would increase the contacts between them recovered from the cell layer in the present study (Figure 3B).
and subsequently promote the lytic activity of phages.
Phage adsorption onto the bronchial epithelial cells As bacteria regrowth was noted in the absence of
was experimentally confirmed in Figure 3A and B. The BEAS-2B cells (Figure 4A), we hypothesized that the
adhesion of A. baumannii to epithelial cell (NCI-H292, epithelial cells could inhibit or delay the development of
A549, and Caco2 cells) surfaces has also been reported in phage resistance by the bacteria, which is another possible
previous studies. 39-41 Lee et al. reported that all the clinical contributing factor to the enhanced antibacterial efficiency
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isolates of MDR A. baumannii (a total of 23 strains) were noted in the three-component system. Figure 4B and C
capable of adhering efficiently to the human bronchial confirmed the emergence of phage-resistant phenotypes.
epithelial cell line NCI-H292 and such capacity was Interestingly, these phage-resistant phenotypes were
positively correlated with the biofilm formation ability of significantly suppressed in the presence of epithelial cells,
phages. They, further, demonstrated that isolates carrying providing the first experimental evidence of this effect.
the extended-spectrum β-lactamase gene, blaPER-1, Phage resistance is a natural phenomenon that occurs in
had significantly higher cell adhesiveness and biofilm the co-evolution of a bacterial virus and its host. There
formation capability. Their findings were consistent with are several mechanisms for bacteria to develop phage
the findings of Sechi et al., who reported a positive resistance, including (i) spontaneous mutations or phase
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association between PER-1 type β-lactamase production variation of surface receptors to prevent phage recognition;
and Caco2 cell adhesion. Smani et al. investigated the (ii) poising the restriction-modification systems (RMS)
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binding mechanisms of A. baumannii with host cells to specifically cleave phage DNA from within; and (iii)
and identified fibronectin-binding proteins (FBPs) as the obtaining adaptive immunity through the CRISPR-Cas9
key adhesins mediating the binding of A. baumannii to system. The first stage for phage infection is adsorption
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human lung epithelial cells (A549 cells). The adhesion of onto a bacterial surface, with which the phage is allowed
A. baumannii was achieved through interaction with the to inject its genetic materials into the host bacteria to

Volume 1 Issue 1 (2024) 90 doi: 10.36922/mi.3141