Mechanism of mixed vaginitis
Polymicrobial infections generally involve the formation of mixed biofilms, dominated by bacteria and/or fungi, embedded in an extracellular matrix(14). It is even common to find mixed biofilms in the lower female reproductive tract in the clinical setting. The specific characteristics of mixed biofilms, especially their enhanced drug resistance and their ability to evade components of the host immune response, make them of high clinical importance. However, despite the importance of such mixed infections, mixed infection research, particularly research involving vastly diverse microorganism, is in its infancy(15). Bacteria and/or fungi can coexist within a host, and the nature of interspecies interactions can determine the fate of the microbial populations. They influence each other in diverse ways via synergistic or antagonistic interactions(16).
1. Medically antagonistic interactions between microorganism are common in the lower female reproductive tract. For example, studies on the vaginal microbiota have revealed that Lactobacillus species lower the local pH (by releasing lactic acid), which results in the inhibition of initial adherence of Candida albicans and Gardnerella vaginalis to the vaginal mucosal surface(17). Many environmental cues impact biofilm formation, such as hypoxia, elevated extracellular pH, body temperature, and elevated CO2(18). A previous study reported thatPseudomonas aeruginosa killed C. albicans cells after attachment to C. albicans hyphae(19). The contemporaneous process may be dependent on the species present. Little is known about pathophysiological vaginal conditions during infection, but antagonistic interactions between probiotics and pathogens are more likely to occur than antagonistic interactions between pathogens.
2. Some synergistic relationships result in complex pathogenic processes, providing protection to one or both species in mixed-species biofilms. This occurs in the following ways: ⑴ Cells of certain species can directly bind to cells of other species. For example, recent evidence has indicated thatStaphylococcus aureus can “piggyback” on C. albicans hyphae to penetrate host cells, infiltrate deep tissues and participate in the pathogenic process of host cells(20). ⑵ Similar synergies providing a protective microenvironment have also been observed; for example, the presence of a C. albicans biofilm enables the proliferation of anaerobic pathogens in an otherwise hostile, oxygen-rich environment. Moreover, the bacteria seem to induce the formation of these protective structures(21). ⑶ A recent study has linked this protective interaction to enhanced drug resistance; when C. albicans and methicillin-resistant Staphylococcus aureus (MRSA) strains were grown together, the presence of C. albicans seemed to protect MRSA from eradication by vancomycin(22). ⑷ Synergistic interactions can also enhance virulence during infection(19). For example, higher host mortality was observed when S. aureus and C. albicans were introduced together at sublethal doses in a mouse peritonitis infection model than when either species was introduced alone(23). A limitation of these studies was that this interaction was evaluated not in the lower female reproductive tract. However, these observations illustrate the dynamic nature of polymicrobial infections in part. In other words, the contemporaneous process may be interdependent. The mechanisms behind these synergistic interactions have not been described.
3. We have focused on antagonistic versus synergistic interactions, but additional distinct interactions exist. Polymicrobial infections challenge the immune system in different ways compared with infection with a single organism. An host response to one pathogen may promote the proliferation of another pathogen. For example, coinfection withStreptococcus agalactiaesignificantly attenuated the hyphal development of C. albicans in vitro, but it may attenuate host vaginal mucosal TH17 immunity and contribute to mucosal colonization by C. albicans in vivo(24). A multicountry cross-sectional study reported that the factor independently associated with S. agalactiae was C. albicans presence(25). Similarly, another study suggested that C. albicans may suppress the local host immune response, allowing subclinical P. aeruginosa to proliferate, resulting in disease(26) (Figure 1). Thus, these interactions are highly complex, and the type of interaction that occurs often depends on a range of environmental, pathogenic and host factors. The mechanisms of mixed infections in vaginitis are unknown thus far, and further exploration is needed.