Engineering live attenuated vaccines: Old dogs learning new tricks

Abstract

Autoimmune diseases such as rheumatoid arthritis and type 1 diabetes are increasingly common global problems. Concerns about increases in the prevalence of such diseases and the limited efficacy of conventional treatment regimens necessitates new therapies to address these challenges. Autoimmune disease severity and dysbiosis are interconnected. Although probiotics have been established as a therapy to rebalance the microbiome and suppress autoimmune symptoms, these microbes tend to lack a number of advantageous qualities found in non-commensal bacteria. Through attenuation and genetic manipulation, these non-commensal bacteria have been engineered into recombinant forms that offer malleable platforms capable of addressing the immune imbalances found in RA and T1D. Such bacteria have been engineered to express valuable gene products known to suppress autoimmunity such as anti-inflammatory cytokines, autoantigens, and enzymes synthesizing microbial metabolites. This review will highlight current and emerging trends in the field and discuss how they may be used to prevent and control autoimmune diseases.

Keywords: Attenuation; Autoimmunity; Bacteria vaccines; Immunomodulation; Immunotherapy; Non-commensal.

Fig. 1

Type 1 diabetes and rheumatoid arthritis overview. T1D and RA are two of the most prominent autoimmune conditions impacting a significant population. Many drivers and predispositions stimulate the production of autoantibodies targeting the respective cells and organs of each condition. Following the migration of APCs carrying autoantigens to the pancreas, autoreactive immune cells induce destruction of islet β-cells, therefore disrupting insulin synthesis. As a result, T1D symptoms include hyperglycemia, polyuria, polydipsia, and insulitis. Similarly in RA, immune cells infiltrating the synovium of joints produce pro-inflammatory cytokines and proteinase, resulting in bone and cartilage damage and pain that can result in functional disabilities. This figure was made with BioRender.

Fig. 2

Advantages of non-commensal bacteria as novel treatments for conditions such as T1D and RA. Non-commensal bacteria pose several benefits for disease prevention that are not offered with traditionally used probiotics. These benefits are innate characteristics of these microbes that remain functional after a bacteria is attenuated and deemed non-virulent. Such properties include increased intracellular activity, innate immune responses, and tissue tropism. This figure was made with BioRender.

Fig. 3

Bm ΔvjbR:tnaA inhibits and improves RA via the increased proliferation and expression of Treg cells, thereby reducing the impacts of anti-inflammatory cytokines on joints. Both Bm ΔvjbR and indole have been observed to improve Treg cell expansion individually, but the effect increases significantly by combining their activity via the expression of tryptophanaseA in Bm ΔvjbR culture. CIA mice supplemented with Bm ΔvjbR:tnaA exhibit higher IL-10 expression, reduced immune cell infiltration in joints, and increased macrophage polarization towards a more tolerant state. This figure was made with BioRender.