Recombinant BCG-LTAK63 Vaccine Candidate for Tuberculosis Induces an Inflammatory Profile in Human Macrophages

Author(s)

dos Santos, Carina C. ; Walburg, Kimberley, V ; van Veen, Suzanne ; Wilson, Louis G. ; Trufen, Carlos E. M. ; Nascimento, Ivan P. ; Ottenhoff, Tom H. M. ; Leite, Luciana C. C. ; Haks, Marielle C.

• Document type: Journal article
• Source: VACCINES; v. 10, n. 6, p. 14-pg., 2022-06-01.

Abstract

Tuberculosis (TB) is one of the top 10 leading causes of death worldwide. The recombinant BCG strain expressing the genetically detoxified A subunit of the thermolabile toxin from Escherichia coli (LTAK63) adjuvant (rBCG-LTAK63) has previously been shown to confer superior protection and immunogenicity compared to BCG in a murine TB infection model. To further investigate the immunological mechanisms induced by rBCG-LTAK63, we evaluated the immune responses induced by rBCG-LTAK63, BCG, and Mycobacterium tuberculosis (Mtb) H37Rv strains in experimental infections of primary human M1 and M2 macrophages at the transcriptomic and cytokine secretion levels. The rBCG-LTAK63-infected M1 macrophages more profoundly upregulated interferon-inducible genes such as IFIT3, OAS3, and antimicrobial gene CXCL9 compared to BCG, and induced higher levels of inflammatory cytokines such as IL-12(p70), TNF-beta, and IL-15. The rBCG-LTAK63-infected M2 macrophages more extensively upregulated transcripts of inflammation-related genes, TAP1, GBP1, SLAMF7, TNIP1, and IL6, and induced higher levels of cytokines related to inflammation and tissue repair, MCP-3 and EGF, as compared to BCG. Thus, our data revealed an important signature of immune responses induced in human macrophages by rBCG-LTAK63 associated with increased inflammation, activation, and tissue repair, which may be correlated with a protective immune response against TB. (AU)

• FAPESP's process: 17/24832-6 - Development of vaccines based on recombinant BCG: Tuberculosis, Pertussis, Pneumococcus and Schistosoma
• Grantee: Luciana Cezar de Cerqueira Leite
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 14/01271-0 - Identification of biomarkers of protection and immunological characterization of a novel vaccine candidate against tuberculosis based on Recombinant BCG
• Grantee: Carina Carvalho dos Santos
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 17/03332-5 - Advances in TB treatment: identification of biomarkers that predict treatment outcome and the molecular characterization of innate immune responses induced by rBCG-LTAK63
• Grantee: Carina Carvalho dos Santos
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)