Dengue and chikungunya: the key role of minority immune cells in controlling infection

Science

An increasing number of people are now at risk from the dengue and chikungunya virus due to the growing spread of the tiger mosquito. However, no specific treatment for these infections is currently available. The solution could stem from greater insight into the body's defense mechanisms, particularly those involving a specific type of white blood cell which, although present in only small quantities, appears to play a key role in fighting these viruses.

Plasmacytoid dendritic cells, or pDC, make up less than 0.5% of the body's white blood cells. It is hard to imagine how these can play an essential role in the body's defense mechanisms. However, this observation seems to be supported by a growing number of studies. The most recent study has just been published by an Inserm* team from the International Infectiology Research Center (Ciri) in Lyon, in partnership with colleagues from Institut Pasteur in Paris and Genentech in San Francisco. This study shows that, although in the minority, pDC are able to make their presence known when it comes to declaring war on the dengue or chikungunya virus, which allows them to orchestrate an effective immune response.

A localized antiviral response

Plasmacytoid dendritic cells are "on the front line" in fighting these infections. Furthermore, despite being very small in number, they have several assets to boost their defense strategies. In particular, they are able to rapidly release large quantities of type I interferons, crucial molecules in controlling infections caused by RNA viruses since they block replication and are able to recruit reinforcements. This new study has deciphered the mechanism at play in triggering this process.

The researchers had already discovered that pDC were not directly activated by the viruses, but rather by contact with other infected cells. Hence, this represents another of their assets: pDC cannot be "attacked" and neutralized by these pathogenic agents. Through their continued research, the scientists were able to demonstrate, in vivo, that contact with infected cells leads to a localized antiviral response at the site of infection.

In practical terms, when a pDC cell detects an infected cell, this sets off an alarm system which then activates the gene enabling the production of type I interferons. This production promptly leads to a cascade of reactions, and the recruitment of other white blood cells, notably "natural killer" (NK) cells. pDC do not therefore need to be large in number to be heard; neither do they need to release numerous substances. This study also shows that pDC only produce type I interferons. They do not secrete other molecules, such as pro-inflammatory cytokines, more harmful to the host.

The researchers have achieved these results using a transgenic mouse model in which only pDC are able to secrete type I interferons. These animals manage to control the virus, whereas those not producing type I interferon are unable to do so.

Boost pDC for faster control of infection

Located at the site of infection and limited to the production of type I interferon, the pDC response to dengue and chikungunya virus infection appears to represent an evolutionary advantage for the host, compared to the generalized pro-inflammatory response affecting all tissues which would cause major harm to the body. "We have yet to determine how to boost pDC for faster control of infection spread in the body," points out Marlène Dreux, the Inserm immunologist-virologist leading this research team. "It could be worth mobilizing this response with a view to designing future treatments. Hence, our recent in vitro tests have shown that low doses of interferon added to the pDC environment could accelerate their response to the dengue virus."

Note

*Inserm unit 1111/CNRS/ENS/Claude Bernard University, Vesicular transport, innate response and viruses team, International Infectiology Research Center, Lyon

Source

B. Webster et al. Plasmacytoid Dendritic Cells Control Dengue and Chikungunya Virus Infections via IRF7-regulated interferon responses. eLife, online edition dated June 8, 2018