Soluble lytic transglycosylase SLT of Francisella novicida is involved in intracellular growth and immune suppression


Autoři: Takemasa Nakamura aff001;  Takashi Shimizu aff001;  Akihiko Uda aff002;  Kenta Watanabe aff001;  Masahisa Watarai aff001
Působiště autorů: Joint Faculty of Veterinary Medicine, Laboratory of Veterinary Public Health, Yamaguchi University, Yamaguchi, Japan aff001;  Department of Veterinary Science, National Institute of Infectious Diseases, Shinjuku, Tokyo, Japan aff002
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: 10.1371/journal.pone.0226778

Souhrn

Francisella tularensis, a category-A bioterrorism agent causes tularemia. F. tularensis suppresses the immune response of host cells and intracellularly proliferates. However, the detailed mechanisms of immune suppression and intracellular growth are largely unknown. Here we developed a transposon mutant library to identify novel pathogenic factors of F. tularensis. Among 750 transposon mutants of F. tularensis subsp. novicida (F. novicida), 11 were isolated as less cytotoxic strains, and the genes responsible for cytotoxicity were identified. Among them, the function of slt, which encodes soluble lytic transglycosylase (SLT) was investigated in detail. An slt deletion mutant (Δslt) was less toxic to the human monocyte cell line THP-1 vs the wild-type strain. Although the wild-type strain proliferated in THP-1 cells, the number of intracellular Δslt mutant decreased in comparison. The Δslt mutant escaped from phagosomes during the early stages of infection, but the mutant was detected within the autophagosome, followed by degradation in lysosomes. Moreover, the Δslt mutant induced host cells to produce high levels of cytokines such as tumor necrosis factor-α, interleukin (IL)-6, and IL-1β, compared with the wild-type strain. These results suggest that the SLT of F. novicida is required for immune suppression and escape from autophagy to allow its survival in host cells.

Klíčová slova:

Autophagic cell death – Cytokines – Cytotoxicity – Francisella – Francisella tularensis – Immune suppression – Intracellular pathogens – Transposable elements


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