Flagella Overexpression Attenuates Salmonella Pathogenesis

Abstract

Flagella are cell surface appendages involved in a number of bacterial behaviors, such as motility, biofilm formation, and chemotaxis. Despite these important functions, flagella can pose a liability to a bacterium when serving as potent immunogens resulting in the stimulation of the innate and adaptive immune systems. Previous work showing appendage overexpression, referred to as attenuating gene expression (AGE), was found to enfeeble wild-type Salmonella. Thus, this approach was adapted to discern whether flagella overexpression could induce similar attenuation. To test its feasibility, flagellar filament subunit FliC and flagellar regulon master regulator FlhDC were overexpressed in Salmonella enterica serovar Typhimurium wild-type strain H71. The results show that the expression of either FliC or FlhDC alone, and co-expression of the two, significantly attenuates Salmonella. The flagellated bacilli were unable to replicate within macrophages and thus were not lethal to mice. In-depth investigation suggests that flagellum-mediated AGE was due to the disruptive effects of flagella on the bacterial membrane, resulting in heightened susceptibilities to hydrogen peroxide and bile. Furthermore, flagellum-attenuated Salmonella elicited elevated immune responses to Salmonella presumably via FliC’s adjuvant effect and conferred robust protection against wild-type Salmonella challenge.

Antibodies against In Vivo -Expressed Antigens Are Sufficient To Protect against Lethal Aerosol Infection with Burkholderia mallei and Burkholderia pseudomallei

“…For instance, constitutive production of the Cryptococcus neoformans adhesin Cfl1 appears to reduce virulence through untimely and excessive adhesion to host cells (128). In contrast, overproduction of the Salmonella enterica flagellar apparatus has been shown to disrupt the structural integrity of bacterial membranes, which promotes clearance of the organism by innate immune mechanisms (129). Interestingly, constitutive production of the B. mallei oligomeric AT BpaB was also found to attenuate the virulence of the organism (77).…”

The Virulence of Salmonella enterica Serovar Typhimurium in the Insect Model Galleria mellonella Is Impaired by Mutations in RNase E and RNase III

“…Expression of flagella is induced in response to a number of stimuli and is normally downregulated inside the host (72). There are reports showing that both the overexpression and downregulation of flagella can significantly attenuate Salmonella virulence (73)(74)(75). In S. Typhimurium, expression of flagella is controlled by phase variation, a mechanism by which the organism alternately expresses two different types of flagellin subunit proteins, FljB and FliC (76).…”

Adhesion Protein ApfA of Actinobacillus pleuropneumoniae Is Required for Pathogenesis and Is a Potential Target for Vaccine Development

“…Otherwise, formidable consequences would result. This has been illustrated by the overexpression of ETEC colonization factor antigen I (CFA/I) fimbriae (32) and flagella (33), which resulted in a dramatic attenuation of wt Salmonella. The expression of flagella, for example, has the potential to turn on to provide a great advantage in the early stage of infection (34) and then turn off to minimize host recognition once infection is established (35).…”