T6SS and ExoA of flesh-eating Aeromonas hydrophila in peritonitis and necrotizing fasciitis during mono- and polymicrobial infections

Abstract

An earlier report described a human case of necrotizing fasciitis (NF) caused by mixed infection with 4 Aeromonas hydrophila strains (NF1–NF4). While the NF2, NF3, and NF4 strains were clonal and possessed exotoxin A (ExoA), the NF1 strain was determined to be phylogenetically distinct, harboring a unique type 6 secretion system (T6SS) effector (TseC). During NF1 and NF2 mixed infection, only NF1 disseminated, while NF2 was rapidly killed by a contact-dependent mechanism and macrophage phagocytosis, as was demonstrated by using in vitro models. To confirm these findings, we developed 2 NF1 mutants (NF1ΔtseC and NF1ΔvasK); vasK encodes an essential T6SS structural component. NF1 VasK and TseC were proven to be involved in contact-dependent killing of NF2 in vitro, as well as in its elimination at the intramuscular injection site in vivo during mixed infection, with overall reduced mouse mortality. ExoA was shown to have an important role in NF by both NF1-exoA (with cis exoA) and NF2 during monomicrobial infection. However, the contribution of ExoA was more important for NF2 than NF1 in the murine peritonitis model. The NF2∆exoA mutant did not significantly alter animal mortality or NF1 dissemination during mixed infection in the NF model, suggesting that the ExoA activity was significant at the injection site. Immunization of mice to ExoA protected animals from NF2 monomicrobial challenge, but not from polymicrobial infection because of NF2 clearance. This study clarified the roles of T6SS and ExoA in pathogenesis caused by A. hydrophila NF strains in both mouse peritonitis and NF models in monomicrobial and polymicrobial infections.

An Update on the Genus Aeromonas: Taxonomy, Epidemiology, and Pathogenicity

“…They suggested that the type six secretion system (T6SS) and exotoxin A (ExoA) were involved in this complex infection. Recently, using a mouse peritonitis and necrotizing fasciitis models, Fernández-Bravo et al [188] used the mutants of T6SS and ExoA of these strains to elucidate the possible role in mixed infections and demonstrated that both virulence factors play a role after monomicrobial and polymicrobial infection.…”

“…Wound infections due to Aeromonas can progress severely to necrotizing fasciitis (NF), usually in immunocompromised patients [5,211]. NF is commonly known as a flesh-eating disease that can cause hypotension, fever, necrosis, and gangrene and can be a life-threating infection [156,[186][187][188]211]. A. hydrophila is the Aeromonas species most frequently associated in reported NF cases and in some cases, water was considered the source of infection [156,186,[211][212][213][214].…”

“…A. hydrophila is the Aeromonas species most frequently associated in reported NF cases and in some cases, water was considered the source of infection [156,186,[211][212][213][214]. Three studies report the complex interactions, among multiple strains of A. hydrophila that were isolated from an immunocompetent young girl who developed NF resulting in amputation of almost all the extremities [186][187][188]. The NF case involved the exposure of an open wound to river water into which the girl had fallen, and was originally considered to be a monomicrobial infection [186].…”

“…However, it was later recognized that of the four strains recovered from the wound, only two were different strains of A. hydrophila (same species) and the strains were named NF1 and NF2 [186]. Additionally, after mixed and single infections, these studies showed that exoA gene and T6SS play a role in NF developed after monomicrobial and polymicrobial infection [186][187][188].…”

“…Recently, the T6SS was associated with a role in the mixed infections by two A. hydrophila strains (NF1-NF2) recovered from a case of necrotizing fasciitis [187,188]. The data suggested that the expression of the effectors related to T6SS might be differentially regulated in both strains, causing a different progression of the disease following mixed infections from progression following a single infection [187,188].…”