Immunomodulators as an antimicrobial tool

Abstract

The spectrum of infectious diseases has shifted in the past 50 years to include those caused by microbes that cause disease predominantly in immunocompromised individuals. This phenomenon has underscored the dependence of microbial virulence on the immune status of the host. The limited efficacy of the available antimicrobial armamentarium in immunocompromised individuals, combined with increasing resistance to these agents, has led to an urgent need for new therapies for infectious diseases. Immunomodulation represents a novel approach to antimicrobial therapy that depends on bolstering host immunity, rather than direct antimicrobial activity. Immunomodulators can be divided into those that are specific to pathogens (pathogen-specific) and those that are not specific to pathogens (non-specific). However, to date only a few immunomodulators have been evaluated for their efficacy as antimicrobial tools.

Figure 1

The possible effects of IFN–γ therapy in two patients with cryptococcosis in the context of the Damage-response framework. Patient 1 is an individual with AIDS-related cryptococcosis, where susceptibility to infection is associated with a profound defect in Th1-type immunity as a result of CD4 T-cell deficiency. In this patient, the administration of IFN–γ is pro-inflammatory and the increased inflammatory response might facilitate control of the infection, thus reducing damage and symptoms of disease. By contrast, Patient 2 is an individual with cryptococcal disease following immune reconstitution with HAART. In this patient, administration of IFN–γ might be detrimental, as cryptococcal disease is caused by an exuberant inflammatory response. Hence, the outcome of IFN–γ therapy depends on the immune status of the host.

Figure 2

Illustration of the dichotomous requirements for immunomodulation in patients with different immune status. Patient 1 has an infectious disease that reflects the outcome of a weak immune response, such as HIV-associated histoplasmosis or aspergillosis following stem cell transplantation. In this individual enhancement of the inflammatory response with a pro-inflammatory immunomodulator could facilitate microbial clearance, thus reducing damage and symptoms of disease. By contrast, Patient 2 has an infectious disease that reflects the outcome of an overly exuberant immune response, such as mediastinal fibrosis from histoplasmosis or allergic aspergillosis. In this individual, an anti-inflammatory immunomodulator could dampen the host the inflammatory response, thus reducing damage and symptoms of disease. Notably, the immune response of this individual could have already resulted in microbial clearance. These patients illustrate that the kind of immunomodulator that would be beneficial is probably to be influenced by the immune status of the affected individual.