Portuguese scientist publishes article in «Science» proposing new strategies in the treatment of infectious diseases

Virtually all of conventional medicine is based on the use of two strategies employed by the immune system against infectious diseases: detection […]

Virtually all of conventional medicine is based on the use of two strategies employed by the immune system against infectious diseases: detection and elimination of invading agents.

Miguel Soares, from the Gulbenkian Institute of Science, Ruslan Medzhitov, from the Yale School of Medicine, and David Schneider, from Stanford University, propose in an article published on February 24, 2012 in “Science”* that it should be considered a new and third strategy: tolerance to infection, a phenomenon in which the infected host protects itself against the infection by reducing the harmful effects caused either by the pathogen or by the immune response engineered against the invader.

The authors argue that knowledge of the mechanisms underlying this phenomenon of tolerance may pave the way for the development of new therapies to combat various infectious diseases.

After invasion of an organism by pathogens (bacteria, viruses or parasites), the immune system kicks in: detects, destroys and ultimately eliminates the pathogen. This phenomenon, called “infection resistance”, is essential in protecting the host against infections, but often causes collateral damage to some of the host's vital organs (liver, kidney, heart, brain).

If left unchecked, damage to these tissues can have deadly consequences, such as severe malaria, severe sepsis, and possibly other infectious diseases.

Tolerance reduces the detrimental impact of the infection and subsequent immune response on the host.

Although it is a well-known phenomenon in plant immunology, tolerance to infection in mammals, including humans, has received little attention. Despite how much remains to be known about how and under what circumstances tolerance to infection is employed by the host, almost everything that is known about the molecular mechanisms underlying this host defense strategy was discovered at the Gulbenkian Institute of Science, by the group led by Miguel Soares.

Infections cause two types of “damage” to the host. Pathogens can directly damage host tissues (rising pink arrow). The host's immune system reduces the amount of pathogen in the body (downward green arrow) through resistance mechanisms. The immune system can also damage host tissues (green and pink ascending arrow). The host reduces these “damages” through tolerance mechanisms that reduce direct damage caused by pathogens and the negative impact of immune defenses (green balloons). (Source: Science/AAAS)

This team is interested in identifying the specific tolerance mechanisms for each disease, and also in unraveling the general tolerance strategies that could possibly be used to protect the host against future infections.

In animal and human studies, resistance to infection is generally the only mechanism taken into account when there is infection. Thus, whenever a host succumbs to an infection, this result is attributed to deficiencies in the immune system.

The authors argue that this should not be generalized, and stress the importance of distinguishing between failed resistance and failed tolerance, when analyzing the cause of morbidity and mortality resulting from infectious diseases. This distinction will define which therapeutic approach to choose.

When the main problem is tolerance failure, boosting the immune system or administering antibiotics will do nothing. In these cases, it would probably be more effective to improve tolerance, in combating infections, inflammatory diseases and autoimmune diseases.

(*) Ruslan Medzhitov, David Schneider, Miguel Soares (2012) Disease Tolerance as a Defense Strategy. Science.

Science, 24 February 2012: Vol. 335 no. 6071 pp. 936-941;

DOI: 10.1126/science.1214935