Editors' ChoiceImmunology

Recruiting bystanders to fight infection

Sci. Signal.  23 Jun 2015:
Vol. 8, Issue 382, pp. ec167
DOI: 10.1126/scisignal.aac8273

The Gram-negative bacteria Legionella pneumophila encodes a specialized Dot/Icm type IV secretion system (T4SS) that delivers bacterial proteins into host phagocytic cells that they infect, enabling the bacteria to survive and replicate. Several of these bacterial proteins inhibit protein synthesis in the host cells, yet infection with bacteria that encodes T4SS leads to increased protective proinflammatory cytokine production. Copenhaver et al. used a fluorescence-based assay system to investigate this paradox by tracking immune responses in single bone marrow-derived macrophages exposed to L. pneumophila in culture. This system enabled the identification of T4SS-injected and uninjected macrophages. Compared with T4SS-injected macrophages in culture, uninjected macrophages produced more cytokines— in particular, tumor necrosis factor (TNF), interleukin (IL)-6, and IL-12 — and had greater amounts of the costimulatory protein CD86. Injected and uninjected cells produced similar amounts of IL-1α and IL-1β. As expected, the infected macrophages not only had increased abundance of Il1a and Il1b transcripts, but also increased abundance of Tnf and Il6 transcripts, which suggested that selective translation was blocked in the T4SS-injected cells. Investigation of cells harvested from lung tissue of mice that were infected with L. pneumophila intranasally confirmed that T4SS-injected alveolar macrophages and neutrophils did not produce TNF, whereas uninjected cells did. Although monocytes and dendritic cells are not easily infected by L. pneumophila, they are recruited to the site of infection, and these cells were the primary secretors of TNF and were also the cells positive for CD86. IL-1α and IL-1β recruit neutrophils in response to infection. Intranasal infection of wild-type mice and those lacking the IL-1 receptor (Il1r−/−) resulted in an equivalent number of infected alveolar macrophages; however, Il1r−/− mice had reduced recruitment of neutrophils, dendritic cells, and monocytes, which suggested that infected cells release IL-1α and IL-1β to instruct uninfected “bystander” cells to produce inflammatory cytokines. Thus, infected immune cells activate bystander immune cells to mount a response to infection.

A. M. Copenhaver, C. N. Casson, H. T. Nguyen, M. M. Duda, S. Shin, IL-1R signaling enables bystander cells to overcome bacterial blockade of host protein synthesis. Proc. Natl. Acad. Sci. U.S.A. 112, 7557–7562 (2015). [PubMed]