Macrophages and parasites: Mortal enemies or partners in crime?

The mammalian immune system has evolved to protect our body from a wide variety of dangers. Fending off pathogens is a major function and under most circumstances it does so efficiently and effectively. However, parasitic pathogens have developed effective means to dampen and abuse the immune system in order to establish themselves within a host.

The mammalian immune system has evolved to protect our body from a wide variety of dangers. Fending off pathogens is a major function, and under most circumstances, it does so efficiently and effectively. However, parasitic pathogens have developed effective means to dampen and abuse the immune system in order to establish themselves within a host. Macrophages, the all-rounder cell of the immune system, are involved in virtually any biological process: immune defence, embryonic development, wound healing and maintenance of tissue integrity as well as whole body metabolism and thermo-regulation. However, macrophages are also drivers of severe pathology (eg cancer, atherosclerosis, fibrosis) and provide "safe havens" for several pathogens (eg Mycobacterium tuberculosis; Salmonella enterica) rendering the host susceptible to infection and disease. Thus, appropriate responses of macrophages are a key determinant of successful immune resistance, and the interaction of macrophages with parasitic pathogens is no exception. However, the question is: what is an "appropriate response?" Scientists have uncovered a myriad of ways in which macrophages contribute to resistance/susceptibility to parasitic infections. Nonetheless, we remain remarkably ignorant as to why some patients are resistant to infection, others get infected but stay asymptomatic and some develop active disease. In this special issue of Parasite Immunology, a series of reviews have collected our current knowledge on the role of macrophages in several parasitic infections. They highlight the intricate balance between protecting the host from invading pathogens while maintaining tissue integrity and ensuring host survival. Jeongho Park and Christopher A. Hunter 1 focus on the evolutionary arms race between Toxoplasma gondii and macrophages.
Toxoplasma can not only survive inside these immune cells but even thrive. Interestingly, Toxoplasma alters macrophage behaviour leading to enhanced migration and, thus, dissemination to distal sites, which may explain the odd choice of preferred host cell. On the other hand, macrophages are essential in avoiding excessive inflammation or aberrant responses to pathobionts. Infection with Toxoplasma gondii therefore prototypically highlights the balance struck by macrophages trying to compromise between pathogen elimination and host health, while the parasite abuses this balance to ensure its own survival .
Coakley and Harris 2 concentrate on the interaction of macrophages with helminth parasites. Helminths were previously considered too large to be phagocytosed, and therefore, macrophages were thought not to be relevant for the immune response. However, it is becoming increasingly evident that macrophages are crucial for immunity and survival of the host. Coakley and Harris therefore sub-divide the functional role of macrophages into three sub-categories: "react," "repair" and "resolve." In the "react" phase, macrophages produce a variety of effector molecules which either have direct anti-helminth activity or recruit other immune cells such as eosinophils. Overall, it seems that one of the major functions of macrophages may be to trap helminth larvae in tissues to make them accessible to immune cells, prevent further tissue damage and/or allow killing within a controlled environment.
In the "repair" phase, macrophages are known mediators in wound healing. During helminth infection, due to the damage caused by migration of the worms, rapid repair of tissue damage is often essential, to prevent excessive haemorrhaging or translocation of microbiota. Thus, several of the mechanisms that trap helminth parasites also help to close the breach they may have caused. At this stage, it is unclear which of the two is the primary objective for macrophages.
Finally, in the "resolve" phase, somewhat counterintuitively, Although typically associated with M2 activation, Arg1 expression during Leishmania infection can occur in a strong Th1 environment and interferon-γ can even synergize with IL-4 to induce Arg1. In addition, macrophages of different origin, tissue resident vs. monocyte-derived, but also macrophages from different tissues (eg liver vs spleen), show different propensity to express Arg1 leading to tissue-specific resistance/susceptibility patterns within the same host.
Thus, dissecting the tissue-and subset-specific regulatory mechanisms governing macrophage activation will be essential for future therapeutic approaches.
Taken together these reviews emphasize the multi-layered, intricate and sometimes confusing interaction of parasitic pathogens with macrophages. Eliminating the threat seems often not to be the prime objective of the immune response, but rather containment and limitation of pathological sequelae. This may allow parasites to infest, proliferate and propagate, but ensures the best possible chances for host survival. Moreover, a beneficial response in one setting may be detrimental in another and so macrophage responses have to be balanced across a variety of scenarios. Thus, macrophages are both, partners in crime as well as mortal enemies of these disease-causing agents and future research will need to dissect these two sides of the coin.