Oral Delivery of Novel Recombinant Lactobacillus Elicit High Protection against Staphylococcus aureus Pulmonary and Skin Infections

Abstract

Staphylococcus aureus is a leading cause of nosocomial and community-associated infection worldwide; however, there is no licensed vaccine available. S. aureus initiates infection via the mucosa; therefore, a mucosal vaccine is likely to be a promising approach against S. aureus infection. Lactobacilli, a non-pathogenic bacterium, has gained increasing interest as a mucosal delivery vehicle. Hence, we attempted to develop an oral S. aureus vaccine based on lactobacilli to cushion the stress of drug resistance and vaccine needs. In this study, we designed, constructed, and evaluated recombinant Lactobacillus strains synthesizing S. aureus nontoxic mutated α-hemolysins (HlaH35L). The results from animal clinical trials showed that recombinant Lactobacillus can persist for at least 72 h and can stably express heterologous protein in vivo. Recombinant L. plantarum WXD234 (pNZ8148-Hla) could induce robust mucosal immunity in the GALT, as evidenced by a significant increase in IgA and IL-17 production and the strong proliferation of T-lymphocytes derived from Peyer’s patches. WXD234 (pNZ8148-Hla) conferred up to 83% protection against S. aureus pulmonary infection and significantly reduced the abscess size in a S. aureus skin infection model. Of particular interest is the sharp reduction of the protective effect offered by WXD234 (pNZ8148-Hla) vaccination in γδ T cell-deficient or IL-17-deficient mice. In conclusion, for the first time, genetically engineered Lactobacillus WXD234 (pNZ8148-Hla) as an oral vaccine induced superior mucosal immunity, which was associated with high protection against pulmonary and skin infections caused by S. aureus. Taken together, our findings suggest the great potential for a delivery system based on lactobacilli and provide experimental data for the development of mucosal vaccines for S. aureus.

Use of genetically modified lactic acid bacteria and bifidobacteria as live delivery vectors for human and animal health

“…For this purpose, a strain of lactobacilli synthesizing S. aureus nontoxic mutated-hemolysins (HlaH35L) was constructed, and the GM strain was able to induce the mucosal immune response in mice and protected against pulmonary and skin infection. 77 This study demonstrated the potential of lactobacilli to be used as a delivery vector in the development of oral vaccines against bacterial pathogens.…”

Oral Vaccination with Engineered Probiotic Limosilactobacillus reuteri Has Protective Effects against Localized and Systemic Staphylococcus aureus Infection

“…The feasibility of implementing a Lactobacillus delivery system for development of an S. aureus oral vaccine was discussed in our 2021 study ( 21 ). Five antigens utilized in this study are well-known staphylococcal virulence factors or structural proteins shown in previous studies to elicit protective immunity in animal models of staphylococcal infections.…”

“…Recombinant forms of various Lactobacillus species have been used as bases for vaccines against Streptococcus pneumoniae ( 16 ), transmissible gastroenteritis coronavirus ( 17 ), Bacillus anthracis ( 18 ), rotavirus ( 19 ), and tetanus toxin ( 20 ). Lactobacillus -based antigen delivery systems against localized S. aureus infections were demonstrated in our 2021 study ( 21 ); however, their possible application against systemic infections has not been investigated. The species generally known as Lactobacillus reuteri (renamed Limosilactobacillus reuteri in a 2020 taxonomic revision [ 22 ]) has been proposed as a novel probiotic in view of many host health-promoting properties, including modulation of immune responses, enhancement of mucosal integrity, inhibition of bacterial translocation, and secretion of antimicrobial metabolites ( 23 ).…”

“…The feasibility of implementing a Lactobacillus delivery system for development of an S. aureus oral vaccine was first discussed in our 2021 study ( 21 ). In the present follow-up study, the probiotic L. reuteri WXD171 was selected as a delivery vehicle strain, following systematic screening of six potentially useful strains, based on its tolerance of the gastrointestinal environment, adhesion ability, and antimicrobial activities in vitro and in vivo .…”

Native and Engineered Probiotics: Promising Agents against Related Systemic and Intestinal Diseases

“…Lacticaseibacillus casei was chosen to express F4 fimbrial adhesin main subunit and conjunction with adjuvants to combat F4 + enterotoxigenic Escherichia coli infections [ 258 ]. The anti-bacteria effect of the engineered Lacticaseibacillus casei carrying antigens of the corresponding pathogenic bacteria was also demonstrated in mouse models of Staphylococcus aureus [ 260 ] and Clostridium perfringens [ 257 ] infection. In general, Lactic acid bacteria have the potential to become oral vaccines against infection.…”