Immunology feature: landlords, tenants and immune response

When you're a parasitic lodger with no independent means of survival, it's bad form to kill the landlord. And it pays not to challenge your host or draw attention to yourself, so you can't be evicted.

Perth immunologist Dr Mariapia Degli-Esposti, of the Lions Eye Institute, spends her time trying to understand why the mammalian immune system efficiently deals with some viral infections, yet responds ineffectually to others.

Her model host is the mouse, and its persistent tenant is the herpes virus, Murine Cytomegalovirus (MCMV).

The virus manipulates cellular immune responses so that it is not eliminated, but rather is allowed to establish a life-long relationship with its host.

Degli Esposti will describe her team's latest findings at annual conference of the Australasian Society for Immunology in Sydney this week.

"We're trying to understand how the immune system responds to challenges and why it sometimes doesn't respond in the best way possible," she says.

Sometimes, the immune response is not efficient enough to clear persistent pathogens like MCMV, or overlooks malignancies that can then develop into tumours.

She believes the mouse MCMV model is an ideal system for understanding what happens during the course of a viral infection, how the immune system responds, and how the virus manipulates that system to evade detection and elimination.

"The findings from these studies will not only generate critical information about the development of improved anti-viral therapies, but will also provide essential insights into key cellular processes and check-points," she says.

Indeed, this is what Degli-Esposti finds the most exciting aspect of her research and the discoveries her team has made to date.

Forward sentries

In 2001, Degli Esposti and her colleagues showed that MCMV preferentially infects the immune system's forward sentries, dendritic cells (DCs). Dendritic cells detect pathogens and migrate to lymph nodes, where they are classically known to activate CD4 helper-inducer T cells, and CD8 cytotoxic T cells.

Following MCMV infection, dendritic cells become irreversibly paralysed, explaining why infected hosts become transiently, but severely, immunosuppressed and unable to respond to subsequent challenges, such as infections with other viruses and/or bacteria.

"When we confirmed that the virus did interfere with dendritic cell functions, we wondered what it meant for their ability to generate downstream responses," she says.

Instead of focusing exclusively on CD4 and CD8 T cells, Degli Esposti's team extended their investigation to natural killer (NK) cells. In a paper in Nature Immunology in 2003, they described how dendritic cells interact with NK cells in a reciprocal fashion.

NK cells are an important arm of innate immunity and can quickly detect and destroy infected or transformed cells through mechanisms such as the display of low levels of MHC class I antigens - an early indicator of viral infection. NK cells are critical to mounting an effective immune response before cytotoxic T cells become activated.

Activated NK cells can kill infected cells and can secrete cytokines that have anti-viral functions, as well as the ability to affect other cellular effectors.

They can also produce chemotactic factors that may help to recruit cytotoxic T cells that specialise in detecting and destroying infected cells that, by now, are beginning to display specific viral peptides complexed with MHC Class I molecules on their surface.

---PB---

Sub-specialists

In recent years, immunologists have discovered that dendritic cells have sub-specialisations. Degli Esposti says MCMV infection activates at least two subsets of dendritic cells: conventional DCs as well as the recently identified plasmacytoid DCs.

It had been thought that plasmacytoid DC sounded the type 1 interferon alarm bells, but the Degli Esposti team showed that this function is not restricted to this DC subset.

Type I interferons are critical players in anti-viral immunity, as they not only have important direct anti-viral activities, but are also required for efficient activation of NK cell killing.

In a paper published in Nature Immunology in 2005, Degli-Esposti and colleagues showed that conventional DCs can secrete type I interferons in response to MCMV infection, and that this response is sufficient to activate NK cells.

"In showing that different subsets of dendritic cells can interact with NK cells in the very early phase of the immune response, we've discovered important new aspects of innate immunity."

While controlling pathogens is important, few viral infections are lethal in their own right - it makes no evolutionary sense for a virus to kill its host.

"It seems that it is much more detrimental to the host to be unable to switch off the immune response itself," she says.

"If the immune system cannot control activated effectors, it is a big problem and the pathology that ensues is often fatal. Activated effectors secrete a number of cytokines, including TNF-alpha and interferon gamma, which we have shown can cause very detrimental pathological effects.

"If the immune system can't turn off that response and avoid a massive cytokine storm, it can cause much more damage that being unable to control viral loads per se."

Some particularly virulent viruses, like the current H5N1 strain of avian influenza, trigger a deadly cytokine storm that can kill the host.

"The fact that most viruses do not directly kill their hosts makes perfect evolutionary sense. You must never compromise your ability to generate progeny and spread.

"For the host's part, it has to deal with the pathogen so it doesn't take over completely, but it's just as critical to ensure that immune responses are limited and can be switch off.

"We need to understand the balance between the host and the pathogen - how they 'talk' to each other and how the immune system is geared so that damaging responses, that can cause immunopathology, are controlled and limited."